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1
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Basappa S, Prakash A, K P A, Mane MV, Bose SK. Base Mediated 1,2-Carboboration: Direct Access to Multisubstituted Alkenyl and Alkylboronates. Org Lett 2025; 27:4811-4816. [PMID: 40298609 DOI: 10.1021/acs.orglett.5c01382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
We have developed a base-mediated 1,2-carboboration of commercially accessible alkynes for the construction of regio- and stereodefined alkenylboronates. This unprecedented reaction is enabled by sodium ethoxide (NaOEt) as a base and alkyl halide as an electrophile, with B2pin2 under mild reaction conditions. The protocol is simple, clean, and more economical compared to reported transition metal-catalyzed systems. The highlights of this methodology include readily available precursors, broad substrate scope and functional group compatibility, gram scale synthesis, and late-stage functionalization of alkenylboronates. The reaction is also applicable for the carboboration of alkenes. Experimental results and density functional theory (DFT) calculations provide insights into the mechanism.
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Affiliation(s)
- Suma Basappa
- Centre for Nano and Material Sciences (CNMS), Jain University, Jain Global Campus, Bangalore 562112, India
| | - Aishwarya Prakash
- Centre for Nano and Material Sciences (CNMS), Jain University, Jain Global Campus, Bangalore 562112, India
| | - Adithya K P
- Centre for Nano and Material Sciences (CNMS), Jain University, Jain Global Campus, Bangalore 562112, India
| | - Manoj V Mane
- Centre for Nano and Material Sciences (CNMS), Jain University, Jain Global Campus, Bangalore 562112, India
| | - Shubhankar Kumar Bose
- Centre for Nano and Material Sciences (CNMS), Jain University, Jain Global Campus, Bangalore 562112, India
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2
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Bernardo VS, Torres FF, Zucão ACA, Chaves NA, Santana ILR, da Silva DGH. Disrupted homeostasis in sickle cells: Expanding the comprehension of metabolism adaptation and related therapeutic strategies. Tissue Cell 2025; 93:102717. [PMID: 39805212 DOI: 10.1016/j.tice.2024.102717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/02/2024] [Accepted: 12/29/2024] [Indexed: 01/16/2025]
Abstract
Sickle cell disease (SCD) is a hereditary hemolytic anemia associated with the alteration of the membrane composition of the sickle erythrocytes, the loss of glycolysis, dysregulation of the pyruvate phosphatase pathway, and changes in nucleotide metabolism of the sickle red blood cell (RBC). This review provides a comprehensive overview of the impact of the presence of Hb S, which leads to the disruption of the normal RBC metabolism. The intricate interplay between the redox and energetic balance in erythrocytic cells, where the glycolysis, pentose phosphate pathway, and methemoglobin reductase pathways are all altered in sickle RBC, is a key focus. Moreover, this review summarizes the current knowledge about the disease-modifying agents and their action mechanisms based on the sickle RBC alterations previously mentioned (i.e., their association with beneficial effects on the sickle cells' membrane, to their RBCs' energy metabolism, and to their oxidative status). Therefore, providing a comprehensive understanding of how sickle cells cope with the disruption of metabolic homeostasis and the most promising therapeutic agents able to ameliorate the various consequences of abnormal sickle RBC alterations.
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Affiliation(s)
| | | | | | - Nayara Alves Chaves
- Department of Biology, Universidade Estadual Paulista (UNESP), São Paulo, Brazil
| | | | - Danilo Grünig Humberto da Silva
- Department of Biology, Universidade Estadual Paulista (UNESP), São Paulo, Brazil; Campus de Três Lagoas, Universidade Federal de Mato Grosso do Sul (CPTL/UFMS), Mato Grosso do Sul, Brazil.
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3
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Shan X, Cai Y, Zhu B, Sun X, Zhou L, Zhao Z, Li Y, Wang D. Computer-Aided Design of Self-Assembled Nanoparticles to Enhance Cancer Chemoimmunotherapy via Dual-Modulation Strategy. Adv Healthc Mater 2025; 14:e2404261. [PMID: 39828527 DOI: 10.1002/adhm.202404261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 01/05/2025] [Indexed: 01/22/2025]
Abstract
The rational design of self-assembled compounds is crucial for the highly efficient development of carrier-free nanomedicines. Herein, based on computer-aided strategies, important physicochemical properties are identified to guide the rational design of self-assembled compounds. Then, the pharmacophore hybridization strategy is used to design self-assemble nanoparticles by preparing new chemical structures by combining pharmacophore groups of different bioactive compounds. Hydroxychloroquine is grafted with the lipophilic vitamin E succinate and then co-assembled with bortezomib to fabricate the nanoparticle. The nanoparticle can reduce M2-type tumor-associated macrophages (TAMs) through lysosomal alkalization and induce immunogenic cell death (ICD) and nuclear factor-κB (NF-κB) inhibition in tumor cells. In mouse models, the nanoparticles induce decreased levels of M2-type TAMs, regulatory T cells, and transforming growth factor-β (TGF-β), and increase the proportion of cytotoxicity T lymphocytes. Additionally, the nanoparticles reduce the secretion of Interleukin-6 (IL-6) by inhibiting NF-κB and enhance the programmed death ligand-1 (PD-L1) checkpoint blockade therapy. The pharmacophore hybridization-derived nanoparticle provides a dual-modulation strategy to reprogram the tumor microenvironment, which will efficiently enhance the chemoimmunotherapy against triple-negative breast cancer.
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Affiliation(s)
- Xiaoting Shan
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China
| | - Ying Cai
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong, 264000, China
| | - Binyu Zhu
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China
| | - Xujie Sun
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China
| | - Lingli Zhou
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Zhiwen Zhao
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China
| | - Yaping Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong, 264000, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264000, China
| | - Dangge Wang
- Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China
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4
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Fu N, Zeng Y, Zhang J, Zhang P, Zhang H, Yang S, Zhang J. A Facile Strategy for PEGylated Nanoprodrug of Bortezomib with Improved Stability, Enhanced Biocompatibility, pH-Controlled Disassembly, and Release. Macromol Biosci 2025; 25:e2400383. [PMID: 39401274 DOI: 10.1002/mabi.202400383] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/26/2024] [Indexed: 04/26/2025]
Abstract
The therapeutic efficacy of bortezomib (BTZ) is often limited due to low solubility, poor stability in vivo and nonspecific toxicity. Herein, a kind of catechol-functionalized polyethylene glycol (mPEG-CA) is first synthesized and then mPEG-CA is readily used to conjugate with BTZ by the formation of dynamic boronate bonds to obtain PEGlyated BTZ prodrug (mPEG-CA-BTZ) with the ability of pH-controlled disassembly and drug release. The structure and morphology, physicochemical characteristics, drug loading, and release as well as in vitro cytotoxicity of mPEG-CA-BTZ nanoparticles are investigated in detail. The results demonstrated that mPEG-CA-BTZ can not only self-assemble into nanostructures with uniform size and stable dispersion in physiological pH condition (pH 7.4) but also respond to the tumor acid microenvironment and achieve pH-controlled BTZ release by acid-triggered cleavage of boronate bonds, decomposition of mPEG-CA-BTZ and thus disassembly of mPEG-CA-BTZ nanoparticles. mPEG-CA-BTZ nanoparticles are expected to have great potential as a promising nanoplatform for pharmaceutical formulations of BTZ to increase therapeutic efficacy and decrease side effects of BTZ. Considering the easily available and biocompatible excipients and simple preparation process, the strategy designed herein provides a facile and promising approach to synergistically integrate the function of PEGylation and pH-sensitiveness into boronic acid-containing small molecule pharmaceutical agents.
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Affiliation(s)
- Naikuan Fu
- Department of Cardiology, Chest Hospital, Tianjin University, Tianjin, 300222, China
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Chest Hospital, Tianjin University, Tianjin, 300222, China
| | - Yinan Zeng
- Department of Polymer Science and Engineering, Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300350, China
| | - Jing Zhang
- Department of Cardiology, Chest Hospital, Tianjin University, Tianjin, 300222, China
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Chest Hospital, Tianjin University, Tianjin, 300222, China
| | - Peng Zhang
- Department of Cardiology, Chest Hospital, Tianjin University, Tianjin, 300222, China
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Chest Hospital, Tianjin University, Tianjin, 300222, China
| | - Hong Zhang
- Department of Cardiology, Chest Hospital, Tianjin University, Tianjin, 300222, China
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Chest Hospital, Tianjin University, Tianjin, 300222, China
| | - Shicheng Yang
- Department of Cardiology, Chest Hospital, Tianjin University, Tianjin, 300222, China
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Chest Hospital, Tianjin University, Tianjin, 300222, China
| | - Jianhua Zhang
- Department of Polymer Science and Engineering, Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300350, China
- Tianjin Key Laboratory of Membrane Science and Desalination Technology, Tianjin University, Tianjin, 300350, China
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5
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Liu J, Li H, Guo W, Cai Z, Li M, Zhang LB. Electrochemical Decarboxylation Coupling Reactions. Chemistry 2024; 30:e202402621. [PMID: 39413120 DOI: 10.1002/chem.202402621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Indexed: 10/18/2024]
Abstract
Carboxylic acids are attractive synthetic feedstocks with stable, non-toxic, and inexpensive properties that can be easily obtained from natural sources or through synthesis. Carboxylic acids have long been considered environmentally friendly coupling agents in various organic transformations. In recent years, electrochemically mediated decarboxylation reactions of decarboxylic acids and their derivatives (NHPI) have emerged as effective new methods for constructing carbon-carbon or carbon-heterocarbon chemical bonds. Compared with transition metal and photochemistry-mediated catalytic reactions, which do not require the addition of oxidants and strong bases, electrochemically-mediated decarboxylative transformations are considered a sustainable strategy. In addition, various functional groups tolerate the electrochemical decarboxylation conversion strategy well. Here, we summarize the recent electrochemical decarboxylation reactions to better elucidate the advantages of electrochemical decarboxylation reactions.
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Affiliation(s)
- Jiaxiu Liu
- State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of Science & Technology, Qingdao, 266042, China
| | - Haoran Li
- School of Chemistry and Chemical Engineering/State Key Laboratory Incubation Base for Green Processing of Chemical Engineering, Shihezi University, Shihezi, 832003, China
| | - Weisi Guo
- State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of Science & Technology, Qingdao, 266042, China
| | - Zhihua Cai
- School of Chemistry and Chemical Engineering/State Key Laboratory Incubation Base for Green Processing of Chemical Engineering, Shihezi University, Shihezi, 832003, China
| | - Ming Li
- State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of Science & Technology, Qingdao, 266042, China
| | - Lin-Bao Zhang
- State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of Science & Technology, Qingdao, 266042, China
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6
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Wu Z, Herok C, Friedrich A, Engels B, Marder TB, Hudson ZM. Impurities in Arylboronic Esters Induce Persistent Afterglow. J Am Chem Soc 2024; 146:31507-31517. [PMID: 39499625 DOI: 10.1021/jacs.4c08329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2024]
Abstract
Several recent reports suggest that arylboronic esters can exhibit room temperature phosphorescence (RTP), an optical property that is desirable for applications in security printing, oxygen sensing, and bioimaging. These findings challenged the fundamental notion that heavy elements or changes in orbital symmetry were required for intersystem crossing to occur in organic compounds. As we had not observed long afterglow in the many arylboronic esters we had synthesized over many years, we suspected that the RTP observed in these systems had a simpler explanation: the materials reported were impure. Herein, we synthesized 12 arylboronic esters that were previously reported to show RTP, and carefully purified them by column chromatography, recrystallization, and sublimation. We re-examined their photophysical properties alongside single-crystal X-ray diffraction analysis and detailed theoretical studies. While 4 of the 12 compounds showed long afterglows as crude products, none of them showed persistent RTP after careful purification. We also successfully isolated the impurity 4-amino-3,5-bis(pinacolatoboryl)benzonitrile (2), identifying it as the impurity responsible for inducing delayed fluorescence in 3,5-bis(pinacolatoboryl)benzonitrile (1). Doping 1 with 1.0 mol % 2 led to a persistent afterglow with a lifetime of 67 ms, which is mediated by a dimer charge transfer state. Our findings call for a re-examination of previous studies reporting RTP from arylboronic esters, highlight the importance of careful purification in photophysical research, and provide a practical strategy for designing organic materials with a long afterglow.
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Affiliation(s)
- Zhu Wu
- Institute of Inorganic Chemistry and Institute for Sustainable Chemistry & Catalysis with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
- Department of Chemistry, The University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada
| | - Christoph Herok
- Institute of Physical and Theoretical Chemistry, Julius-Maximilians-Universität Würzburg, Emil-Fischer-Straße 42, 97074 Würzburg, Germany
| | - Alexandra Friedrich
- Institute of Inorganic Chemistry and Institute for Sustainable Chemistry & Catalysis with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
| | - Bernd Engels
- Institute of Physical and Theoretical Chemistry, Julius-Maximilians-Universität Würzburg, Emil-Fischer-Straße 42, 97074 Würzburg, Germany
| | - Todd B Marder
- Institute of Inorganic Chemistry and Institute for Sustainable Chemistry & Catalysis with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
| | - Zachary M Hudson
- Department of Chemistry, The University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada
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7
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Guria S, Hassan MMM, Dey S, Singh KN, Chattopadhyay B. Sterically Controlled Lewis Acid-Base Interaction Toward para-Selective Borylation of Aromatic Aldimines and Benzylamines. Angew Chem Int Ed Engl 2024; 63:e202409010. [PMID: 39012678 DOI: 10.1002/anie.202409010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/15/2024] [Accepted: 07/16/2024] [Indexed: 07/17/2024]
Abstract
Site-selective C-H bond functionalization of arenes at the para position remains extremely challenging primarily due to its relative inaccessibility from the catalytic site. As a consequence, it is significantly restricted to limited molecular scaffolds. Herein, we report a method for the para-C-H borylation of aromatic aldimines and benzylamines using commercially available ligands under iridium catalysis. The established method displays excellent para selectivity for variously substituted aromatic aldimines, benzylamines and bioactive molecules. Based on several control experiments, it is proposed that a Lewis acid-base interaction between the nitrogen and boron functionality guides the para selectivity via a steric shield for the aromatic aldimines, where Bpin acts as a transient directing group. However, the steric shield of the in situ generated N-Bpin moiety controlled the overall selectivity for the para borylation of benzylamines.
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Affiliation(s)
- Saikat Guria
- Department of Biological & Synthetic Chemistry, Center of Biomedical Research, SGPGIMS Campus, Raebareli Road, Lucknow, 226014, Uttar Pradesh, India
| | - Mirja Md Mahamudul Hassan
- Department of Biological & Synthetic Chemistry, Center of Biomedical Research, SGPGIMS Campus, Raebareli Road, Lucknow, 226014, Uttar Pradesh, India
| | - Sayan Dey
- Department of Biological & Synthetic Chemistry, Center of Biomedical Research, SGPGIMS Campus, Raebareli Road, Lucknow, 226014, Uttar Pradesh, India
| | - Krishna Nand Singh
- Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Buddhadeb Chattopadhyay
- Department of Biological & Synthetic Chemistry, Center of Biomedical Research, SGPGIMS Campus, Raebareli Road, Lucknow, 226014, Uttar Pradesh, India
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8
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Liang M, Liu C, Ju W, Han S, Zhang J, Zhao Y. Iridium-Catalyzed Ortho-Selective C-H Borylation of Aryl Ketones with Transient Imine Ligands. Org Lett 2024; 26:4224-4228. [PMID: 38726872 DOI: 10.1021/acs.orglett.4c01067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
Ortho-selective C-H borylation of aromatic ketones has not been extensively explored. Herein, we report the iridium-catalyzed ortho-selective C-H borylation of aromatic ketones using in situ-formed imine as the ligand. Good compatibility is observed for various substituted acetophenones and other aromatic ketones, and corresponding products are obtained with medium to excellent yields.
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Affiliation(s)
- Min Liang
- Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. China
| | - Chuangchuang Liu
- Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. China
| | - Wenjie Ju
- Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. China
| | - Shuxiong Han
- Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. China
| | - Jingyu Zhang
- College of Energy, Soochow Institute for Energy and Materials Innovations, Soochow University, Suzhou 215006, P. R. China
| | - Yingsheng Zhao
- Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. China
- School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453000, P. R. China
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9
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Xiao M, Ha S, Zhu J, Tao W, Fu Z, Wei H, Hou Q, Luo G, Xiang H. Structure-Activity Relationship (SAR) Studies of Novel Monovalent AR/AR-V7 Dual Degraders with Potent Efficacy against Advanced Prostate Cancer. J Med Chem 2024; 67:5567-5590. [PMID: 38512060 DOI: 10.1021/acs.jmedchem.3c02177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2024]
Abstract
Androgen receptor (AR) has been extensively established as a potential therapeutic target for nearly all stages of prostate cancer (PCa). However, acquired resistance to AR-targeted drugs inevitably develops and severely limits their clinical efficacy. Particularly, there currently exists no efficient treatment for patients expressing the constitutively active AR splice variants, such as AR-V7. Herein, we report the structure-activity relationship studies of 55 N-heterocycle-substituted hydantoins, which identified the structural motifs required for AR/AR-V7 degradation. Among them, the most potent compound 27c exhibited selective AR/AR-V7 degradation over other hormone receptors and excellent antiproliferative activities in LNCaP and 22RV1 cells. RNA sequence analysis confirmed that 27c effectively suppressed transcriptional activity of the AR signaling pathway. Importantly, 27c demonstrated potent antitumor efficacy in an enzalutamide-resistant 22RV1 xenograft model. These results highlight the potential of 27c as a promising dual AR/AR-V7 degrader for overcoming drug resistance in advanced PCa expressing AR splice variants.
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Affiliation(s)
- Maoxu Xiao
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Si Ha
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Jiacheng Zhu
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Wenxiang Tao
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Zixuan Fu
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Hanlin Wei
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Qiangqiang Hou
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Guoshun Luo
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Hua Xiang
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
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10
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Xia R, Sun M, Yin J, Zhang X, Li J. Using Mendelian randomization provides genetic insights into potential targets for sepsis treatment. Sci Rep 2024; 14:8467. [PMID: 38605099 PMCID: PMC11009318 DOI: 10.1038/s41598-024-58457-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 03/29/2024] [Indexed: 04/13/2024] Open
Abstract
Sepsis is recognized as a major contributor to the global disease burden, but there is a lack of specific and effective therapeutic agents. Utilizing Mendelian randomization (MR) methods alongside evidence of causal genetics presents a chance to discover novel targets for therapeutic intervention. MR approach was employed to investigate potential drug targets for sepsis. Pooled statistics from IEU-B-4980 comprising 11,643 cases and 474,841 controls were initially utilized, and the findings were subsequently replicated in the IEU-B-69 (10,154 cases and 454,764 controls). Causal associations were then validated through colocalization. Furthermore, a range of sensitivity analyses, including MR-Egger intercept tests and Cochran's Q tests, were conducted to evaluate the outcomes of the MR analyses. Three drug targets (PSMA4, IFNAR2, and LY9) exhibited noteworthy MR outcomes in two separate datasets. Notably, PSMA4 demonstrated not only an elevated susceptibility to sepsis (OR 1.32, 95% CI 1.20-1.45, p = 1.66E-08) but also exhibited a robust colocalization with sepsis (PPH4 = 0.74). According to the present MR analysis, PSMA4 emerges as a highly encouraging pharmaceutical target for addressing sepsis. Suppression of PSMA4 could potentially decrease the likelihood of sepsis.
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Affiliation(s)
- Rui Xia
- Department of Critical Care Medicine, Chongqing University Jiangjin Hospital, Chongqing, 402260, China
| | - Meng Sun
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jing Yin
- Affiliated Hospital of Medical School, Nanjing Jinling Hospital, Nanjing University, Nanjing, 210016, China
| | - Xu Zhang
- Center for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, 400013, China.
- Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Chongqing, 400013, China.
- Chongqing Reproductive Genetics Institute, Chongqing, 400013, China.
| | - Jianhua Li
- Department of Critical Care Medicine, Chongqing University Jiangjin Hospital, Chongqing, 402260, China.
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11
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Ishitsuka K, Nishikii H, Kimura T, Sugiyama-Finnis A, Yamazaki S. Purging myeloma cell contaminants and simultaneous expansion of peripheral blood-mobilized stem cells. Exp Hematol 2024; 131:104138. [PMID: 38151170 DOI: 10.1016/j.exphem.2023.104138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/03/2023] [Accepted: 12/07/2023] [Indexed: 12/29/2023]
Abstract
Human hematopoietic stem cells (HSCs) are widely used as a cellular source for hematopoietic stem cell transplantation (HSCT) in the clinical treatment of hematological malignancies. After transplantation therapy, delays in hematopoietic recovery due to insufficient donor-derived HSCs can lead to increased risks of life-threatening infections and bleeding. Our previous studies developed an efficient ex vivo expansion culture medium (3a medium) for umbilical cord blood-derived HSCs (CBSCs), offering a potential solution to this problem. Nevertheless, the broader applicability of our culture method to alternative cell sources and, of greater significance, its efficacy in eliminating potentially disease-associated contaminated tumor cells, especially in autologous transplantation, raise critical clinical questions. In this study, we modified the 3a medium by incorporating UM729 to replace UM171, adding FMS-like tyrosine kinase 3 (Flt3) ligand, and adjusting the concentrations of butyzamide, 740Y-P, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG, Soluplus) to create the modified-3a medium. This sophistication allowed the efficient expansion of not only CBSCs but also peripheral blood-mobilized HSCs (PBSCs). Additionally, we successfully removed contaminated myeloma cells by adding bortezomib and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) at appropriate concentrations, although we maintained HSCs through the addition of lenalidomide. Our research findings present the potential for widespread clinical application of the modified-3a medium and suggest a safe ex vivo culture technique for expanding human HSCs within peripheral blood-derived donor grafts used for autologous HSCT.
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Affiliation(s)
- Kantaro Ishitsuka
- Laboratory for Stem Cell Therapy, Faculty of Medicine, Tsukuba University, Ibaraki, Japan
| | - Hidekazu Nishikii
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Takaharu Kimura
- Laboratory for Stem Cell Therapy, Faculty of Medicine, Tsukuba University, Ibaraki, Japan
| | - Ayano Sugiyama-Finnis
- Division of Cell Regulation, Center of Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoshi Yamazaki
- Laboratory for Stem Cell Therapy, Faculty of Medicine, Tsukuba University, Ibaraki, Japan; Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; Division of Stem Cell Biology, Center for Stem Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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12
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Mao X, Lu Z, Zhang J, Xie Z. Catalyst-Free Regioselective Diborylation of Aryllithium with Tetra(o-tolyl)diborane(4). Angew Chem Int Ed Engl 2024; 63:e202317614. [PMID: 38123525 DOI: 10.1002/anie.202317614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 12/18/2023] [Accepted: 12/20/2023] [Indexed: 12/23/2023]
Abstract
A catalyst-free 1,2-diborylation of aryllithium with tetra(o-tolyl)diborane(4) has been achieved, giving a series of 1,2-diborylaryl lithium species in excellent yields under mild reaction conditions, which leads to 1,2-di(tolyl)borylarenes in 60-91 % yields upon treatment with the hydride-abstracting reagent. In these transformations, one sp2 C-H of arene is activated and both boryl units are utilized to build two new (sp2 )C-B bonds. This represents a new strategy for selective arene diborylation. Density functional theory (DFT) calculations suggest that an aromatic nucleophilic substitution is a key step in the formation of the products.
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Affiliation(s)
- Xiaofeng Mao
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The Chinese University of Hong Kong, Shatin, N. T., Hong Kong, China
| | - Zhenpin Lu
- Department of Chemistry, City University of Hong Kong, Hong Kong, China
| | - Jie Zhang
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The Chinese University of Hong Kong, Shatin, N. T., Hong Kong, China
| | - Zuowei Xie
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The Chinese University of Hong Kong, Shatin, N. T., Hong Kong, China
- Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen, 518055, China
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13
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Song Y, Zhang HJ, Song X, Geng J, Li HY, Zhang LZ, Yang B, Lu XC. Gene signatures to therapeutics: Assessing the potential of ivermectin against t(4;14) multiple myeloma. World J Clin Oncol 2024; 15:115-129. [PMID: 38292661 PMCID: PMC10823940 DOI: 10.5306/wjco.v15.i1.115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/13/2023] [Accepted: 01/02/2024] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Multiple myeloma (MM) is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow. The translocation, (t)(4;14), results in high-risk MM with limited treatment alternatives. Thus, there is an urgent need for identification and validation of potential treatments for this MM subtype. Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets. AIM To elucidate the molecular basis and search for potential effective drugs of t(4;14) MM subtype by employing a comprehensive approach. METHODS The transcriptional signature of t(4;14) MM was sourced from the Gene Expression Omnibus. Two datasets, GSE16558 and GSE116294, which included 17 and 15 t(4;14) MM bone marrow samples, and five and four normal bone marrow samples, respectively. After the differentially expressed genes were identified, the Cytohubba tool was used to screen for hub genes. Then, the hub genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Using the STRING database and Cytoscape, protein-protein interaction networks and core targets were identified. Potential small-molecule drugs were identified and validated using the Connectivity Map database and molecular docking analysis, respectively. RESULTS In this study, a total of 258 differentially expressed genes with enriched functions in cancer pathways, namely cytokine receptor interactions, nuclear factor (NF)-κB signaling pathway, lipid metabolism, atherosclerosis, and Hippo signaling pathway, were identified. Ten hub genes (cd45, vcam1, ccl3, cd56, app, cd48, btk, ccr2, cybb, and cxcl12) were identified. Nine drugs, including ivermectin, deforolimus, and isoliquiritigenin, were predicted by the Connectivity Map database to have potential therapeutic effects on t (4;14) MM. In molecular docking, ivermectin showed strong binding affinity to all 10 identified targets, especially cd45 and cybb. Ivermectin inhibited t(4;14) MM cell growth via the NF-κB pathway and induced MM cell apoptosis in vitro. Furthermore, ivermectin increased reactive oxygen species accumulation and altered the mitochondrial membrane potential in t(4;14) MM cells. CONCLUSION Collectively, the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14) MM diagnosis and treatment, with ivermectin emerging as a potential therapeutic alternative.
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Affiliation(s)
- Yang Song
- School of Basic Medicine, Medical School of Chinese PLA, Beijing 100853, China
| | - Hao-Jun Zhang
- School of Basic Medicine, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Xia Song
- School of Basic Medicine, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Jie Geng
- School of Basic Medicine, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Hong-Yi Li
- School of Basic Medicine, Medical School of Chinese PLA, Beijing 100853, China
| | - Li-Zhong Zhang
- School of Basic Medicine, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Bo Yang
- Department of Hematology, The Second Medical Centre, Chinese PLA General Hospital, Beijing 100853, China
| | - Xue-Chun Lu
- Department of Hematology, The Second Medical Centre, Chinese PLA General Hospital, Beijing 100853, China
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14
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Bhardwaj S, Roy KK. ClpP Peptidase as a Plausible Target for the Discovery of Novel Antibiotics. Curr Drug Targets 2024; 25:108-120. [PMID: 38151841 DOI: 10.2174/0113894501274958231220053714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 11/16/2023] [Accepted: 12/06/2023] [Indexed: 12/29/2023]
Abstract
Antimicrobial resistance (AMR) to currently available antibiotics/drugs is a global threat. It is desirable to develop new drugs that work through a novel target(s) to avoid drug resistance. This review discusses the potential of the caseinolytic protease P (ClpP) peptidase complex as a novel target for finding novel antibiotics, emphasising the ClpP's structure and function. ClpP contributes to the survival of bacteria via its ability to destroy misfolded or aggregated proteins. In consequence, its inhibition may lead to microbial death. Drugs inhibiting ClpP activity are currently being tested, but no drug against this target has been approved yet. It was demonstrated that Nblocked dipeptides are essential for activating ClpP's proteolytic activity. Hence, compounds mimicking these dipeptides could act as inhibitors of the formation of an active ClpP complex. Drugs, including Bortezomib, Cisplatin, Cefmetazole, and Ixazomib, inhibit ClpP activation. However, they were not approved as drugs against the target because of their high toxicity, likely due to the presence of strong electrophiles in their warheads. The modifications of these warheads could be a good strategy to reduce the toxicity of these molecules. For instance, a boronate warhead was replaced by a chloromethyl ketone, and this new molecule was shown to exhibit selectivity for prokaryotic ClpP. A better understanding of the structure and function of the ClpP complex would benefit the search for compounds mimicking N-blocked dipeptides that would inhibit ClpP complex activity and cause bacterial death.
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Affiliation(s)
- Smriti Bhardwaj
- School of Health Sciences and Technology, UPES, Dehradun - 248007, Uttarakhand, India
| | - Kuldeep K Roy
- School of Health Sciences and Technology, UPES, Dehradun - 248007, Uttarakhand, India
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15
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Beumers L, Vlachavas EI, Borgoni S, Schwarzmüller L, Penso-Dolfin L, Michels BE, Sofyali E, Burmester S, Heiss D, Wilhelm H, Yarden Y, Helm D, Will R, Goncalves A, Wiemann S. Clonal heterogeneity in ER+ breast cancer reveals the proteasome and PKC as potential therapeutic targets. NPJ Breast Cancer 2023; 9:97. [PMID: 38042915 PMCID: PMC10693625 DOI: 10.1038/s41523-023-00604-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 11/17/2023] [Indexed: 12/04/2023] Open
Abstract
Intratumoral heterogeneity impacts the success or failure of anti-cancer therapies. Here, we investigated the evolution and mechanistic heterogeneity in clonal populations of cell models for estrogen receptor positive breast cancer. To this end, we established barcoded models of luminal breast cancer and rendered them resistant to commonly applied first line endocrine therapies. By isolating single clones from the resistant cell pools and characterizing replicates of individual clones we observed inter- (between cell lines) and intra-tumor (between different clones from the same cell line) heterogeneity. Molecular characterization at RNA and phospho-proteomic levels revealed private clonal activation of the unfolded protein response and respective sensitivity to inhibition of the proteasome, and potentially shared sensitivities for repression of protein kinase C. Our in vitro findings are consistent with tumor-heterogeneity that is observed in breast cancer patients thus highlighting the need to uncover heterogeneity at an individual patient level and to adjust therapies accordingly.
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Affiliation(s)
- Lukas Beumers
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
- Faculty of Biosciences, University of Heidelberg, Im Neuenheimer Feld 234, 69120, Heidelberg, Germany.
| | - Efstathios-Iason Vlachavas
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany
| | - Simone Borgoni
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany
| | - Luisa Schwarzmüller
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany
- Faculty of Biosciences, University of Heidelberg, Im Neuenheimer Feld 234, 69120, Heidelberg, Germany
| | - Luca Penso-Dolfin
- Division of Somatic Evolution and Early Detection, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany
| | - Birgitta E Michels
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany
| | - Emre Sofyali
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany
| | - Sara Burmester
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany
| | - Daniela Heiss
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany
| | - Heike Wilhelm
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany
| | - Yosef Yarden
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, 76100, Israel
| | - Dominic Helm
- Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany
| | - Rainer Will
- Cellular Tools Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany
| | - Angela Goncalves
- Division of Somatic Evolution and Early Detection, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany
| | - Stefan Wiemann
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
- Faculty of Biosciences, University of Heidelberg, Im Neuenheimer Feld 234, 69120, Heidelberg, Germany.
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16
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Zhang C, Kuo JCT, Huang Y, Hu Y, Deng L, Yung BC, Zhao X, Zhang Z, Pan J, Ma Y, Lee RJ. Optimized Liposomal Delivery of Bortezomib for Advancing Treatment of Multiple Myeloma. Pharmaceutics 2023; 15:2674. [PMID: 38140015 PMCID: PMC10747406 DOI: 10.3390/pharmaceutics15122674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/15/2023] [Accepted: 11/23/2023] [Indexed: 12/24/2023] Open
Abstract
Bortezomib (BTZ), a boronic acid-derived proteasome inhibitor, is commonly employed in treating multiple myeloma (MM). However, the applications of BTZ are limited due to its poor stability and low bioavailability. Herein, we develop an optimized liposomal formulation of BTZ (L-BTZ) by employing a remote-loading strategy. This formulation uses Tiron, a divalent anionic catechol derivative, as the internal complexing agent. Compared to earlier BTZ-related formulations, this alternative formulation showed significantly greater stability due to the Tiron-BTZ complex's higher pH stability and negative charges, compared to the meglumine-BTZ complex. Significantly, the plasma AUC of L-BTZ was found to be 30 times greater than that of free BTZ, suggesting an extended blood circulation duration. In subsequent therapeutic evaluations using two murine xenograft tumor models of MM, the NCI-H929 and OPM2 models showed tumor growth inhibition (TGI) values of 37% and 57%, respectively. In contrast, free BTZ demonstrated TGI values of 17% and 11% in these models. Further, L-BTZ presented enhanced antitumor efficacy in the Hepa1-6 HCC syngeneic model, indicating its potential broader applicability as an antineoplastic agent. These findings suggest that the optimized L-BTZ formulation offers a significant advancement in BTZ delivery, holding substantial promise for clinical investigation in not merely MM, but other cancer types.
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Affiliation(s)
- Chi Zhang
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (C.Z.); (J.C.-T.K.); (Y.H.); (Z.Z.)
| | - Jimmy Chun-Tien Kuo
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (C.Z.); (J.C.-T.K.); (Y.H.); (Z.Z.)
| | - Yirui Huang
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (C.Z.); (J.C.-T.K.); (Y.H.); (Z.Z.)
| | - Yingwen Hu
- The Whiteoak Group, Inc., Rockville, MD 20855, USA; (Y.H.); (L.D.); (B.C.Y.); (X.Z.)
| | - Lan Deng
- The Whiteoak Group, Inc., Rockville, MD 20855, USA; (Y.H.); (L.D.); (B.C.Y.); (X.Z.)
| | - Bryant C. Yung
- The Whiteoak Group, Inc., Rockville, MD 20855, USA; (Y.H.); (L.D.); (B.C.Y.); (X.Z.)
| | - Xiaobin Zhao
- The Whiteoak Group, Inc., Rockville, MD 20855, USA; (Y.H.); (L.D.); (B.C.Y.); (X.Z.)
| | - Zhongkun Zhang
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (C.Z.); (J.C.-T.K.); (Y.H.); (Z.Z.)
| | - Junjie Pan
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH 43210, USA;
| | - Yifan Ma
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH 43210, USA;
| | - Robert J. Lee
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (C.Z.); (J.C.-T.K.); (Y.H.); (Z.Z.)
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17
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Liu X, Moscvin M, Oh S, Chen T, Choi W, Evans B, Rowell SM, Nadeem O, Mo CC, Sperling AS, Anderson KC, Yaqoob Z, Bianchi G, Sung Y. Characterizing dry mass and volume changes in human multiple myeloma cells upon treatment with proteotoxic and genotoxic drugs. Clin Exp Med 2023; 23:3821-3832. [PMID: 37421589 PMCID: PMC10777533 DOI: 10.1007/s10238-023-01124-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/20/2023] [Indexed: 07/10/2023]
Abstract
Multiple myeloma (MM) is a cancer of terminally differentiated plasma cells. MM remains incurable, but overall survival of patients has progressively increased over the past two decades largely due to novel agents such as proteasome inhibitors (PI) and the immunomodulatory agents. While these therapies are highly effective, MM patients can be de novo resistant and acquired resistance with prolonged treatment is inevitable. There is growing interest in early, accurate identification of responsive versus non-responsive patients; however, limited sample availability and need for rapid assays are limiting factors. Here, we test dry mass and volume as label-free biomarkers to monitor early response of MM cells to treatment with bortezomib, doxorubicin, and ultraviolet light. For the dry mass measurement, we use two types of phase-sensitive optical microscopy techniques: digital holographic tomography and computationally enhanced quantitative phase microscopy. We show that human MM cell lines (RPMI8226, MM.1S, KMS20, and AMO1) increase dry mass upon bortezomib treatment. This dry mass increase after bortezomib treatment occurs as early as 1 h for sensitive cells and 4 h for all tested cells. We further confirm this observation using primary multiple myeloma cells derived from patients and show that a correlation exists between increase in dry mass and sensitivity to bortezomib, supporting the use of dry mass as a biomarker. The volume measurement using Coulter counter shows a more complex behavior; RPMI8226 cells increase the volume at an early stage of apoptosis, but MM.1S cells show the volume decrease typically observed with apoptotic cells. Altogether, this cell study presents complex kinetics of dry mass and volume at an early stage of apoptosis, which may serve as a basis for the detection and treatment of MM cells.
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Affiliation(s)
- Xili Liu
- Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - Maria Moscvin
- Amyloidosis Program, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Seungeun Oh
- Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - Tianzeng Chen
- Amyloidosis Program, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Wonshik Choi
- Department of Physics, Korea University, Seoul, Korea
| | - Benjamin Evans
- Amyloidosis Program, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Sean M Rowell
- Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Boston, MA, 02115, USA
| | - Omar Nadeem
- Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Boston, MA, 02115, USA
| | - Clifton C Mo
- Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Boston, MA, 02115, USA
| | - Adam S Sperling
- Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Kenneth C Anderson
- Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Boston, MA, 02115, USA
| | - Zahid Yaqoob
- Laser Biomedical Research Center, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Giada Bianchi
- Amyloidosis Program, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
| | - Yongjin Sung
- College of Engineering and Applied Science, University of Wisconsin, Milwaukee, WI, 53211, USA.
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18
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Choy PY, Tse MH, Kwong FY. Recent Expedition in Pd- and Rh-Catalyzed C (Ar) -B Bond Formations and Their Applications in Modern Organic Syntheses. Chem Asian J 2023; 18:e202300649. [PMID: 37655883 DOI: 10.1002/asia.202300649] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 08/31/2023] [Accepted: 09/01/2023] [Indexed: 09/02/2023]
Abstract
Transition metal-catalyzed borylation has emerged as a powerful and versatile strategy for synthesizing organoboron compounds. These compounds have found widespread applications in various aspects, including organic synthesis, materials science, and medicinal chemistry. This review provides a concise summary of the recent advances in palladium- and rhodium-catalyzed borylation from 2013 to 2023. The review covers the representative examples of catalysts, substrates scope and reaction conditions, with particular emphasis on the development of catalyst systems, such as phosphine ligands, NHC-carbene, and more. The diverse array of borylative products obtained for further applications in Suzuki-Miyaura coupling, and other transformations, are also discussed. Future directions in this rapidly evolving field, with the goal of designing more efficient, selective borylation methodologies are highlighted, too.
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Affiliation(s)
- Pui Ying Choy
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, P. R. China
- Shenzhen Center of Novel Functional Molecules, Shenzhen Municipal Key Laboratory of Chemical Synthesis of Medicinal Organic Molecules, CUHK Shenzhen Research Institute, No. 10. Second Yuexing Road, Shenzhen, 518507, P. R. China
| | - Man Ho Tse
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, P. R. China
| | - Fuk Yee Kwong
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, P. R. China
- Shenzhen Center of Novel Functional Molecules, Shenzhen Municipal Key Laboratory of Chemical Synthesis of Medicinal Organic Molecules, CUHK Shenzhen Research Institute, No. 10. Second Yuexing Road, Shenzhen, 518507, P. R. China
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19
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Loy CA, Muli CS, Ali EMH, Xie D, Ahmed MH, Beth Post C, Trader DJ. Discovery of a non-covalent ligand for Rpn-13, a therapeutic target for hematological cancers. Bioorg Med Chem Lett 2023; 95:129485. [PMID: 37714498 PMCID: PMC10639113 DOI: 10.1016/j.bmcl.2023.129485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 09/11/2023] [Accepted: 09/12/2023] [Indexed: 09/17/2023]
Abstract
The ubiquitin-proteasome system serves as the major proteolytic degradation pathway in eukaryotic cells. Many inhibitors that covalently bind to the proteasome's active sites have been developed for hematological cancers, but resistance can arise in patients. To overcome limitations of active-site proteasome inhibitors, we and others have focused on developing ligands that target subunits on the 19S regulatory particle (19S RP). One such 19S RP subunit, Rpn-13, is a ubiquitin receptor required for hematological cancers to rapidly degrade proteins to avoid apoptosis. Reported Rpn-13 inhibitors covalently bind to the Rpn-13's Pru domain and have been effective anti-hematological cancer agents. Here, we describe the discovery of TCL-1, a non-covalent binder to the Pru domain. Optimization of TCL-1's carboxylate group to an ester increases its cytotoxicity in hematological cancer cell lines. Altogether, our data provides a new scaffold for future medicinal chemistry optimization to target Rpn-13 therapeutically.
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Affiliation(s)
- Cody A Loy
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 West Stadium Avenue, West Lafayette, IN 47907, United States
| | - Christine S Muli
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 West Stadium Avenue, West Lafayette, IN 47907, United States
| | - Eslam M H Ali
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 West Stadium Avenue, West Lafayette, IN 47907, United States
| | - Dan Xie
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 West Stadium Avenue, West Lafayette, IN 47907, United States
| | | | - Carol Beth Post
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 West Stadium Avenue, West Lafayette, IN 47907, United States
| | - Darci J Trader
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 West Stadium Avenue, West Lafayette, IN 47907, United States.
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20
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Lucero B, Francisco KR, Liu LJ, Caffrey CR, Ballatore C. Protein-protein interactions: developing small-molecule inhibitors/stabilizers through covalent strategies. Trends Pharmacol Sci 2023; 44:474-488. [PMID: 37263826 PMCID: PMC11003449 DOI: 10.1016/j.tips.2023.04.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/15/2023] [Accepted: 04/26/2023] [Indexed: 06/03/2023]
Abstract
The development of small-molecule inhibitors or stabilizers of selected protein-protein interactions (PPIs) of interest holds considerable promise for the development of research tools as well as candidate therapeutics. In this context, the covalent modification of selected residues within the target protein has emerged as a promising mechanism of action to obtain small-molecule modulators of PPIs with appropriate selectivity and duration of action. Different covalent labeling strategies are now available that can potentially allow for a rational, ground-up discovery and optimization of ligands as PPI inhibitors or stabilizers. This review article provides a synopsis of recent developments and applications of such tactics, with a particular focus on site-directed fragment tethering and proximity-enabled approaches.
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Affiliation(s)
- Bobby Lucero
- Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Karol R Francisco
- Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Lawrence J Liu
- Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Conor R Caffrey
- Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Carlo Ballatore
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
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21
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Ding Y, Hu X, Piao Y, Huang R, Xie L, Yan X, Sun H, Li Y, Shi L, Liu Y. Lipid Prodrug Nanoassemblies via Dynamic Covalent Boronates. ACS NANO 2023; 17:6601-6614. [PMID: 36999933 DOI: 10.1021/acsnano.2c12233] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
Prodrug nanoassemblies combine the advantages of prodrug and nanomedicines, offering great potential in targeting the lesion sites and specific on-demand drug release, maximizing the therapeutic performance while minimizing their side effects. However, there is still lacking a facile pathway to prepare the lipid prodrug nanoassemblies (LPNAs). Herein, we report the LPNAs via the dynamic covalent boronate between catechol and boronic acid. The resulting LPNAs possess properties like drug loading in a dynamic covalent manner, charge reversal in an acidic microenvironment, and specific drug release at an acidic and/or oxidative microenvironment. Our methodology enables the encapsulation and delivery of three model drugs: ciprofloxacin, bortezomib, and miconazole. Moreover, the LPNAs are often more efficient in eradicating pathogens or cancer cells than their free counterparts, both in vitro and in vivo. Together, our LPNAs with intriguing properties may boost the development of drug delivery and facilitate their clinical applications.
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Affiliation(s)
- Yuxun Ding
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, China
| | - Xiaowen Hu
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, China
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yinzi Piao
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, China
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Rong Huang
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Lingping Xie
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xiaojian Yan
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Hui Sun
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuanfeng Li
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, China
| | - Linqi Shi
- Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Yong Liu
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, China
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22
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Duran CL, Karagiannis GS, Chen X, Sharma VP, Entenberg D, Condeelis JS, Oktay MH. Cooperative NF-κB and Notch1 signaling promotes macrophage-mediated MenaINV expression in breast cancer. Breast Cancer Res 2023; 25:37. [PMID: 37024946 PMCID: PMC10080980 DOI: 10.1186/s13058-023-01628-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 02/27/2023] [Indexed: 04/08/2023] Open
Abstract
Metastasis is a multistep process that leads to the formation of clinically detectable tumor foci at distant organs and frequently to patient demise. Only a subpopulation of breast cancer cells within the primary tumor can disseminate systemically and cause metastasis. To disseminate, cancer cells must express MenaINV, an isoform of the actin regulatory protein Mena, encoded by the ENAH gene, that endows tumor cells with transendothelial migration activity, allowing them to enter and exit the blood circulation. We have previously demonstrated that MenaINV mRNA and protein expression is induced in cancer cells by macrophage contact. In this study, we discovered the precise mechanism by which macrophages induce MenaINV expression in tumor cells. We examined the promoter of the human and mouse ENAH gene and discovered a conserved NF-κB transcription factor binding site. Using live imaging of an NF-κB activity reporter and staining of fixed tissues from mouse and human breast cancer, we further determined that for maximal induction of MenaINV in cancer cells, NF-κB needs to cooperate with the Notch1 signaling pathway. Mechanistically, Notch1 signaling does not directly increase MenaINV expression, but it enhances and sustains NF-κB signaling through retention of p65, an NF-κB transcription factor, in the nucleus of tumor cells, leading to increased MenaINV expression. In mice, these signals are augmented following chemotherapy treatment and abrogated upon macrophage depletion. Targeting Notch1 signaling in vivo decreased NF-κB signaling activation and MenaINV expression in the primary tumor and decreased metastasis. Altogether, these data uncover mechanistic targets for blocking MenaINV induction that should be explored clinically to decrease cancer cell dissemination and improve survival of patients with metastatic disease.
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Affiliation(s)
- Camille L Duran
- Department of Pathology, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA
| | - George S Karagiannis
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA
- Integrated Imaging Program, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA
- Department of Microbiology and Immunology, Albert Einstein College of Medicine / Montefiore Medical Center, Bronx, NY, USA
| | - Xiaoming Chen
- Department of Pathology, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Ved P Sharma
- Department of Pathology, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA
- Integrated Imaging Program, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA
- Bio-Imaging Resource Center, The Rockefeller University, Box 209, 1230 York Avenue, New York City, NY, 10065, USA
| | - David Entenberg
- Department of Pathology, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA
- Integrated Imaging Program, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA
| | - John S Condeelis
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
- Integrated Imaging Program, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
- Department of Cell Biology, Albert Einstein College of Medicine / Montefiore Medical Center, Bronx, NY, USA.
- Department of Surgery, Albert Einstein College of Medicine / Montefiore Medical Center, Bronx, NY, USA.
| | - Maja H Oktay
- Department of Pathology, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
- Integrated Imaging Program, Albert Einstein College of Medicine / Montefiore Medical Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
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23
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Yang H, Ai H, Zhang J, Ma J, Liu K, Li Z. UPS: Opportunities and challenges for gastric cancer treatment. Front Oncol 2023; 13:1140452. [PMID: 37077823 PMCID: PMC10106573 DOI: 10.3389/fonc.2023.1140452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/20/2023] [Indexed: 04/05/2023] Open
Abstract
Gastric cancer remains the fourth most frequently diagnosed malignancy and the fifth leading cause of cancer-related mortality worldwide owning to the lack of efficient drugs and targets for therapy. Accumulating evidence indicates that UPS, which consists of E1, E2, and E3 enzymes and proteasome, plays an important role in the GC tumorigenesis. The imbalance of UPS impairs the protein homeostasis network during development of GC. Therefore, modulating these enzymes and proteasome may be a promising strategy for GC target therapy. Besides, PROTAC, a strategy using UPS to degrade the target protein, is an emerging tool for drug development. Thus far, more and more PROTAC drugs enter clinical trials for cancer therapy. Here, we will analyze the abnormal expression enzymes in UPS and summarize the E3 enzymes which can be developed in PROTAC so that it can contribute to the development of UPS modulator and PROTAC technology for GC therapy.
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Affiliation(s)
- Hang Yang
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Huihan Ai
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Jialin Zhang
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Jie Ma
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Kangdong Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- China-US Hormel (Henan) Cancer Institute, Zhengzhou, Henan, China
- Research Center of Basic Medicine, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Zhi Li, ; Kangdong Liu,
| | - Zhi Li
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
- *Correspondence: Zhi Li, ; Kangdong Liu,
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24
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Thai-Savard L, Sayes M, Perreault-Dufour J, Hong G, Wells LA, Kozlowski MC, Charette AB. Organocatalyzed Visible Light-Mediated gem-Borosilylcyclopropanation. J Org Chem 2023; 88:1515-1521. [PMID: 36655845 PMCID: PMC10106276 DOI: 10.1021/acs.joc.2c02535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The borosilylcyclopropanation of styrene derivatives using a (diiodo(trimethylsilyl)methyl)boronic ester carbene precursor is reported herein. The key reagent was synthesized in a 4-step sequence using inexpensive and commercially available starting materials. This method enabled the preparation of novel 1,1,2-tri- and 1,1,2,2-tetrasubstituted borosilylcyclopropanes up to excellent yields and diastereoselectivity. The reaction is organocatalyzed by eosin Y in the presence of visible light. A mechanism consistent with the experimental observations was postulated based on density functional theory calculations. The versatility of these entities was highlighted through post-functionalization reactions.
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Affiliation(s)
- Léa Thai-Savard
- Centre in Green Chemistry and Catalysis, Centre for Continuous Flow Synthesis, Department of Chemistry, Université de Montréal, 1375, av. Thérèse Lavoie-Roux, Montréal, Québec H2V 0B3, Canada
| | - Morgane Sayes
- Centre in Green Chemistry and Catalysis, Centre for Continuous Flow Synthesis, Department of Chemistry, Université de Montréal, 1375, av. Thérèse Lavoie-Roux, Montréal, Québec H2V 0B3, Canada
| | - Josiane Perreault-Dufour
- Centre in Green Chemistry and Catalysis, Centre for Continuous Flow Synthesis, Department of Chemistry, Université de Montréal, 1375, av. Thérèse Lavoie-Roux, Montréal, Québec H2V 0B3, Canada
| | - Gang Hong
- Centre in Green Chemistry and Catalysis, Centre for Continuous Flow Synthesis, Department of Chemistry, Université de Montréal, 1375, av. Thérèse Lavoie-Roux, Montréal, Québec H2V 0B3, Canada
| | - Lucille A. Wells
- Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA
| | - Marisa C. Kozlowski
- Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA
| | - André B. Charette
- Centre in Green Chemistry and Catalysis, Centre for Continuous Flow Synthesis, Department of Chemistry, Université de Montréal, 1375, av. Thérèse Lavoie-Roux, Montréal, Québec H2V 0B3, Canada
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25
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Yang B, Chen H. Predicting circRNA-drug sensitivity associations by learning multimodal networks using graph auto-encoders and attention mechanism. Brief Bioinform 2023; 24:6972879. [PMID: 36617209 DOI: 10.1093/bib/bbac596] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/11/2022] [Accepted: 12/04/2022] [Indexed: 01/09/2023] Open
Abstract
Recent studies have shown that the expression of circRNAs would affect drug sensitivity of cells and thus significantly influence the efficacy of drugs. Traditional biomedical experiments to validate such relationships are time-consuming and costly. Therefore, developing effective computational methods to predict potential associations between circRNAs and drug sensitivity is an important and urgent task. In this study, we propose a novel method, called MNGACDA, to predict possible circRNA-drug sensitivity associations for further biomedical screening. First, MNGACDA uses multiple sources of information from circRNAs and drugs to construct multimodal networks. It then employs node-level attention graph auto-encoders to obtain low-dimensional embeddings for circRNAs and drugs from the multimodal networks. Finally, an inner product decoder is applied to predict the association scores between circRNAs and drug sensitivity based on the embedding representations of circRNAs and drugs. Extensive experimental results based on cross-validations show that MNGACDA outperforms six other state-of-the-art methods. Furthermore, excellent performance in case studies demonstrates that MNGACDA is an effective tool for predicting circRNA-drug sensitivity associations in real situations. These results confirm the reliable prediction ability of MNGACDA in revealing circRNA-drug sensitivity associations.
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Affiliation(s)
- Bo Yang
- School of Software, East China Jiaotong University
| | - Hailin Chen
- School of Software, East China Jiaotong University
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26
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Fay CJ, Awh KC, LeBoeuf NR, Larocca CA. Harnessing the immune system in the treatment of cutaneous T cell lymphomas. Front Oncol 2023; 12:1071171. [PMID: 36713518 PMCID: PMC9878398 DOI: 10.3389/fonc.2022.1071171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 12/01/2022] [Indexed: 01/15/2023] Open
Abstract
Cutaneous T cell lymphomas are a rare subset of non-Hodgkin's lymphomas with predilection for the skin with immunosuppressive effects that drive morbidity and mortality. We are now appreciating that suppression of the immune system is an important step in the progression of disease. It should come as no surprise that therapies historically and currently being used to treat these cancers have immune modulating functions that impact disease outcomes. By understanding the immune effects of our therapies, we may better develop new agents that target the immune system and improve combinatorial treatment strategies to limit morbidity and mortality of these cancers. The immune modulating effect of therapeutic drugs in use and under development for cutaneous T cell lymphomas will be reviewed.
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27
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Duran CL, Karagiannis GS, Chen X, Sharma VP, Entenberg D, Condeelis JS, Oktay MH. Cooperative NF-κB and Notch1 signaling promotes macrophage-mediated MenaINV expression in breast cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.03.522642. [PMID: 36711751 PMCID: PMC9881873 DOI: 10.1101/2023.01.03.522642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Metastasis is a multistep process that leads to the formation of clinically detectable tumor foci at distant organs and frequently patient demise. Only a subpopulation of breast cancer cells within the primary tumor can disseminate systemically and cause metastasis. To disseminate, cancer cells must express MenaINV, an isoform of the actin-regulatory protein Mena encoded by the ENAH gene that endows tumor cells with transendothelial migration activity allowing them to enter and exit the blood circulation. We have previously demonstrated that MenaINV mRNA and protein expression is induced in cancer cells by macrophage contact. In this study, we discovered the precise mechanism by which macrophages induce MenaINV expression in tumor cells. We examined the promoter of the human and mouse ENAH gene and discovered a conserved NF-κB transcription factor binding site. Using live imaging of an NF-κB activity reporter and staining of fixed tissues from mouse and human breast cancer we further determined that for maximal induction of MenaINV in cancer cell NF-κB needs to cooperate with the Notch1 signaling pathway. Mechanistically, Notch1 signaling does not directly increase MenaINV expression, but it enhances and sustains NF-κB signaling through retention of p65, an NF-κB transcription factor, in the nucleus of tumor cells, leading to increased MenaINV expression. In mice, these signals are augmented following chemotherapy treatment and abrogated upon macrophage depletion. Targeting Notch1 signaling in vivo decreased NF-κB signaling and MenaINV expression in the primary tumor and decreased metastasis. Altogether, these data uncover mechanistic targets for blocking MenaINV induction that should be explored clinically to decrease cancer cell dissemination and improve survival of patients with metastatic disease.
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28
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Haveric A, Haveric S, Hadzic M, Ezic J, Cetković T, Galic B. Moderate Toxicity of Potential Boron-containing Therapeutic, Dipotassium-trioxohydroxytetrafl uorotriborate -K2(B3O3F4OH) in Rats and Mice. BRAZ J PHARM SCI 2023; 59. [DOI: 10.1590/s2175-97902023e21384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
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29
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Wang G, Wang Y, Li Z, Li H, Yu M, Pang M, Zhao X. Gold-Catalyzed Cyclization/Hydroboration of 1,6-Enynes: Synthesis of Bicyclo[3.1.0]hexane Boranes. Org Lett 2022; 24:9425-9430. [PMID: 36524751 DOI: 10.1021/acs.orglett.2c03812] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The gold-catalyzed cyclization/hydroboration of 1,6-enynes offers facile, versatile, and atom-economical one-step access to bicyclo[3.1.0]hexane boranes. This new protocol proceeds in moderate to good yields under mild conditions. Different from bicyclo[3.1.0]hexane borates, these products are stable in air and during chromatography. Moreover, the borane moiety of the products can readily undergo a diverse array of transformations. The kinetic isotope effect experiment indicates that the hydrogen-transfer step is a fast process, which is not involved in the rate-limiting step.
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Affiliation(s)
- Guanghui Wang
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
| | - Yongqiang Wang
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
| | - Zengzeng Li
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
| | - Haotian Li
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
| | - Mingwu Yu
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
| | - Maofu Pang
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
| | - Ximei Zhao
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
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30
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Qu H, Feldman AM, Hakonarson H. Genetics of BAG3: A Paradigm for Developing Precision Therapies for Dilated Cardiomyopathies. J Am Heart Assoc 2022; 11:e027373. [PMID: 36382946 PMCID: PMC9851466 DOI: 10.1161/jaha.122.027373] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 09/20/2022] [Indexed: 11/18/2022]
Abstract
Nonischemic dilated cardiomyopathy is a common form of heart muscle disease in which genetic factors play a critical etiological role. In this regard, both rare disease-causing mutations and common disease-susceptible variants, in the Bcl-2-associated athanogene 3 (BAG3) gene have been reported, highlighting the critical role of BAG3 in cardiomyocytes and in the development of dilated cardiomyopathy. The phenotypic effects of the BAG3 mutations help investigators understand the structure and function of the BAG3 gene. Indeed, we report herein that all of the known pathogenic/likely pathogenic variants affect at least 1 of 3 protein functional domains, ie, the WW domain, the second IPV (Ile-Pro-Val) domain, or the BAG domain, whereas none of the missense nontruncating pathogenic/likely pathogenic variants affect the proline-rich repeat (PXXP) domain. A common variant, p.Cys151Arg, associated with reduced susceptibility to dilated cardiomyopathy demonstrated a significant difference in allele frequencies among diverse human populations, suggesting evolutionary selective pressure. As BAG3-related therapies for heart failure move from the laboratory to the clinic, the ability to provide precision medicine will depend in large part on having a thorough understanding of the potential effects of both common and uncommon genetic variants on these target proteins. The current review article provides a roadmap that investigators can utilize to determine the potential interactions between a patient's genotype, their phenotype, and their response to therapeutic interventions with both gene delivery and small molecules.
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Affiliation(s)
- Hui‐Qi Qu
- The Center for Applied Genomics, Children’s Hospital of PhiladelphiaPhiladelphiaPA
| | - Arthur M. Feldman
- Department of Medicine, Division of CardiologyThe Lewis Katz School of Medicine at Temple UniversityPhiladelphiaPA
- The Center for Neurovirology and Gene EditingThe Lewis Katz School of Medicine at Temple UniversityPhiladelphiaPA
| | - Hakon Hakonarson
- The Center for Applied Genomics, Children’s Hospital of PhiladelphiaPhiladelphiaPA
- Department of Pediatrics, The Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA
- Division of Human GeneticsChildren’s Hospital of PhiladelphiaPhiladelphiaPA
- Division of Pulmonary MedicineChildren’s Hospital of PhiladelphiaPhiladelphiaPA
- Faculty of MedicineUniversity of IcelandReykjavikIceland
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31
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Farhangnia P, Akbarpour M, Yazdanifar M, Aref AR, Delbandi AA, Rezaei N. Advances in therapeutic targeting of immune checkpoints receptors within the CD96-TIGIT axis: clinical implications and future perspectives. Expert Rev Clin Immunol 2022; 18:1217-1237. [PMID: 36154551 DOI: 10.1080/1744666x.2022.2128107] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
INTRODUCTION The development of therapeutic antibodies targeting immune checkpoint molecules (ICMs) that induce long-term remissions in cancer patients has revolutionized cancer immunotherapy. However, a major drawback is that relapse after an initial response may be attributed to innate and acquired resistance. Additionally, these treatments are not beneficial to all patients. Therefore, the discovery and targeting of novel ICMs and their combination with other immunotherapeutics are urgently needed. AREAS COVERED There has been increasing evidence of the CD96-TIGIT axis as ICMs in cancer immunotherapy in the last five years. This review will highlight and discuss the current knowledge about the role of CD96 and TIGIT in hematological and solid tumor immunotherapy in the context of empirical studies and clinical trials, and provide a comprehensive list of ongoing cancer clinical trials on the blockade of these ICMs, as well as the rationale behind combinational therapies with anti-PD-1/PD-L1 agents, chemotherapy drugs, and radiotherapy. Moreover, we share our perspectives on anti-CD96/TIGIT-related combination therapies. EXPERT OPINION CD96-TIGIT axis regulates anti-tumor immune responses. Thus, the receptors within this axis are the potential candidates for cancer immunotherapy. Combining the inhibition of CD96-TIGIT with anti-PD-1/PD-L1 mAbs and chemotherapy drugs has shown relatively effective results in the context of preclinical studies and tumor models.
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Affiliation(s)
- Pooya Farhangnia
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mahzad Akbarpour
- Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Advanced Cellular Therapeutics Facility (ACTF), Hematopoietic Cellular Therapy Program, Section of Hematology & Oncology, Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA
| | - Mahboubeh Yazdanifar
- Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Ali-Akbar Delbandi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Immunology Research Center, Institute of Immunology and Infectious Disease, Iran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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32
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Yang J, Griffin A, Qiang Z, Ren J. Organelle-targeted therapies: a comprehensive review on system design for enabling precision oncology. Signal Transduct Target Ther 2022; 7:379. [PMID: 36402753 PMCID: PMC9675787 DOI: 10.1038/s41392-022-01243-0] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 10/19/2022] [Accepted: 10/25/2022] [Indexed: 11/21/2022] Open
Abstract
Cancer is a major threat to human health. Among various treatment methods, precision therapy has received significant attention since the inception, due to its ability to efficiently inhibit tumor growth, while curtailing common shortcomings from conventional cancer treatment, leading towards enhanced survival rates. Particularly, organelle-targeted strategies enable precise accumulation of therapeutic agents in organelles, locally triggering organelle-mediated cell death signals which can greatly reduce the therapeutic threshold dosage and minimize side-effects. In this review, we comprehensively discuss history and recent advances in targeted therapies on organelles, specifically including nucleus, mitochondria, lysosomes and endoplasmic reticulum, while focusing on organelle structures, organelle-mediated cell death signal pathways, and design guidelines of organelle-targeted nanomedicines based on intervention mechanisms. Furthermore, a perspective on future research and clinical opportunities and potential challenges in precision oncology is presented. Through demonstrating recent developments in organelle-targeted therapies, we believe this article can further stimulate broader interests in multidisciplinary research and technology development for enabling advanced organelle-targeted nanomedicines and their corresponding clinic translations.
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Affiliation(s)
- Jingjing Yang
- grid.24516.340000000123704535Institute of Nano and Biopolymeric Materials, School of Materials Science and Engineering, Tongji University, 201804 Shanghai, China
| | - Anthony Griffin
- grid.267193.80000 0001 2295 628XSchool of Polymer Science and Engineering, University of Southern Mississippi, Hattiesburg, MS 39406 USA
| | - Zhe Qiang
- grid.267193.80000 0001 2295 628XSchool of Polymer Science and Engineering, University of Southern Mississippi, Hattiesburg, MS 39406 USA
| | - Jie Ren
- grid.24516.340000000123704535Institute of Nano and Biopolymeric Materials, School of Materials Science and Engineering, Tongji University, 201804 Shanghai, China
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33
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Li B, Bunescu A, Gaunt MJ. Multicomponent synthesis of α-chloro alkylboronic esters via visible-light-mediated dual catalysis. Chem 2022. [DOI: 10.1016/j.chempr.2022.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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34
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Zhu F, Yin P, Wu XF. Regioselective catalytic carbonylation and borylation of alkynes with aryldiazonium salts toward α-unsubstituted β-boryl ketones. Chem Sci 2022; 13:12122-12126. [PMID: 36349108 PMCID: PMC9600224 DOI: 10.1039/d2sc04867a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/30/2022] [Indexed: 11/30/2022] Open
Abstract
A new Pd/Cu-catalyzed carbonylation and borylation of alkynes with aryldiazonium salts toward α-unsubstituted β-boryl ketones with complete regioselectivity has been developed. This transformation shows broad substrate scope and excellent functional-group tolerance. Moreover, the obtained 1,2-carbonylboration products provide substantial opportunities for further transformations which cannot be obtained by known carbonylation procedures. Preliminary mechanistic studies indicate that the three hydrogen atoms of the products originated from ethyl acetate.
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Affiliation(s)
- Fengxiang Zhu
- Department School of Chemistry and Chemical Engineering, Shanxi University Taiyuan 030006 China
| | - Pengpeng Yin
- Department School of Chemistry and Chemical Engineering, Shanxi University Taiyuan 030006 China
| | - Xiao-Feng Wu
- Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences Dalian 116023 China
- Leibniz-Institut für Katalyse e.V. Rostock 18059 Germany
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35
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Smith N, Quan D, Nagalingam G, Triccas JA, Rendina LM, Rutledge PJ. Carborane clusters increase the potency of bis-substituted cyclam derivatives against Mycobacterium tuberculosis. RSC Med Chem 2022; 13:1234-1238. [PMID: 36325397 PMCID: PMC9579921 DOI: 10.1039/d2md00150k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 07/28/2022] [Indexed: 08/04/2023] Open
Abstract
Bis-substituted cyclam derivatives have recently emerged as a promising new class of antibacterial agents, displaying excellent activity against drug-resistant Mycobacterium tuberculosis (Mtb) and in vivo efficacy in a zebrafish assay. Herein we report the synthesis and biological activity of new carborane derivatives within this class of antitubercular compounds. The resulting carborane-cyclam conjugates incorporating either hydrophobic closo-1,2-carborane or anionic, hydrophilic nido-7,8-carborane clusters display promising activity in an antibacterial assay employing the virulent Mtb strain H37Rv. The most active of these carborane derivatives exhibit MIC50 values of <1 μM, making them the most active compounds in this unique class of antibacterial cyclams reported to date.
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Affiliation(s)
- Nicholas Smith
- School of Chemistry, The University of Sydney Sydney NSW 2006 Australia +61 2 9351 5020 +61 2 9351 4781
| | - Diana Quan
- Sydney Institute of Infectious Diseases and Charles Perkins Centre, The University of Sydney Sydney NSW 2006 Australia
- School of Medical Sciences, The University of Sydney Sydney NSW 2006 Australia
| | - Gayathri Nagalingam
- Sydney Institute of Infectious Diseases and Charles Perkins Centre, The University of Sydney Sydney NSW 2006 Australia
- School of Medical Sciences, The University of Sydney Sydney NSW 2006 Australia
| | - James A Triccas
- Sydney Institute of Infectious Diseases and Charles Perkins Centre, The University of Sydney Sydney NSW 2006 Australia
- School of Medical Sciences, The University of Sydney Sydney NSW 2006 Australia
| | - Louis M Rendina
- School of Chemistry, The University of Sydney Sydney NSW 2006 Australia +61 2 9351 5020 +61 2 9351 4781
- The University of Sydney Nano Institute (Sydney Nano), The University of Sydney Sydney NSW 2006 Australia
| | - Peter J Rutledge
- School of Chemistry, The University of Sydney Sydney NSW 2006 Australia +61 2 9351 5020 +61 2 9351 4781
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36
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Kaithal A, Wagener T, Bellotti P, Daniliuc CG, Schlichter L, Glorius F. Access to Unexplored 3D Chemical Space:
cis
‐Selective Arene Hydrogenation for the Synthesis of Saturated Cyclic Boronic Acids. Angew Chem Int Ed Engl 2022; 61:e202206687. [PMID: 35612895 PMCID: PMC9400866 DOI: 10.1002/anie.202206687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Indexed: 11/08/2022]
Abstract
A new class of saturated boron‐incorporated cyclic molecules has been synthesized employing an arene‐hydrogenation methodology. cis‐Selective hydrogenation of easily accessible, and biologically important molecules comprising benzoxaborole, benzoxaborinin, and benzoxaboripin derivatives is reported. Among the various catalysts tested, rhodium cyclic(alkyl)(amino)carbene [Rh‐CAAC] (1) pre‐catalyst revealed the best hydrogenation activity confirming turnover number up to 1400 with good to high diastereoselectivity. A broad range of functional groups was tolerated including sensitive substituents such as −F, −CF3, and −silyl groups. The utility of the synthesized products was demonstrated by the recognition of diols and sugars under physiological conditions. These motifs can have a substantial importance in medicinal chemistry as they possess a three‐dimensional structure, are highly stable, soluble in water, form hydrogen bonds, and interact with diols and sugars.
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Affiliation(s)
- Akash Kaithal
- Westfälische Wilhelms-Universität Münster Organisch-Chemisches Institut Corrensstraße 40 48149 Münster Germany
| | - Tobias Wagener
- Westfälische Wilhelms-Universität Münster Organisch-Chemisches Institut Corrensstraße 40 48149 Münster Germany
| | - Peter Bellotti
- Westfälische Wilhelms-Universität Münster Organisch-Chemisches Institut Corrensstraße 40 48149 Münster Germany
| | - Constantin G. Daniliuc
- Westfälische Wilhelms-Universität Münster Organisch-Chemisches Institut Corrensstraße 40 48149 Münster Germany
| | - Lisa Schlichter
- Westfälische Wilhelms-Universität Münster Westfälische Center for Soft Nanoscience (SoN) and Organisch-Chemisches Institut Busso-Peus-Str.10 48149 Münster Germany
| | - Frank Glorius
- Westfälische Wilhelms-Universität Münster Organisch-Chemisches Institut Corrensstraße 40 48149 Münster Germany
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37
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Severe cellular stress drives apoptosis through a dual control mechanism independently of p53. Cell Death Dis 2022; 8:282. [PMID: 35680784 PMCID: PMC9184497 DOI: 10.1038/s41420-022-01078-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 05/30/2022] [Accepted: 06/01/2022] [Indexed: 12/23/2022]
Abstract
For past two decades, p53 has been claimed as the primary sensor initiating apoptosis. Under severe cellular stress, p53 transcriptional activity activates BH3-only proteins such as Bim, Puma, or Noxa to nullify the inhibitory effects of anti-apoptotic proteins on pro-apoptotic proteins for mitochondrial outer membrane permeabilization. Cellular stress determines the expression level of p53, and the amount of p53 corresponds to the magnitude of apoptosis. However, our studies indicated that Bim and Puma are not the target genes of p53 in three cancer models, prostate cancer, glioblastoma, and osteosarcoma. Bim counteracted with Bcl-xl to activate apoptosis independently of p53 in response to doxorubicin-induced severe DNA damage in prostate cancer. Moreover, the transcriptional activity of p53 was more related to cell cycle arrest other than apoptosis for responding to DNA damage stress generated by doxorubicin in prostate cancer and glioblastoma. A proteasome inhibitor that causes protein turnover dysfunction, bortezomib, produced apoptosis in a p53-independent manner in glioblastoma and osteosarcoma. p53 in terms of both protein level and nuclear localization in combining doxorubicin with bortezomib treatment was obviously lower than when using DOX alone, inversely correlated with the magnitude of apoptosis in glioblastoma. Using a BH3-mimetic, ABT-263, to treat doxorubicin-sensitive p53-wild type and doxorubicin-resistant p53-null osteosarcoma cells demonstrated only limited apoptotic response. The combination of doxorubicin or bortezomib with ABT-263 generated a synergistic outcome of apoptosis in both p53-wild type and p53-null osteosarcoma cells. Together, this suggested that p53 might have no role in doxorubicin-induced apoptosis in prostate cancer, glioblastoma and osteosarcoma. The effects of ABT-263 in single and combination treatment of osteosarcoma or prostate cancer indicated a dual control to regulate apoptosis in response to severe cellular stress. Whether our findings only apply in these three types of cancers or extend to other cancer types remains to be explored.
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Ho CJ, Tsai CY, Zhu WH, Pao YH, Chen HW, Hu CJ, Lee YL, Huang TS, Chen CH, Loh JK, Hong YR, Wang C. Compound cellular stress maximizes apoptosis independently of p53 in glioblastoma. Cell Cycle 2022; 21:1153-1165. [PMID: 35311459 PMCID: PMC9103265 DOI: 10.1080/15384101.2022.2041954] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
We examined the apoptotic response of two glioblastoma cells, p53 wild type U87 and p53 mutated T98G, to doxorubicin, bortezomib, and vorinostat, which respectively target DNA, 26S proteasome and histone deacetylase, to clarify p53's function in apoptosis. We demonstrated that doxorubicin induced apoptosis in U87 cells but not in T98G cells. The level of p53 was definitively correlated to the extent of DNA damage and apoptosis initiation. Dominant-negative p53 reduced p21 expression, but did not affect doxorubicin-induced apoptosis, so the transcriptional activity of p53 seemed not to participate in doxorubicin-induced apoptosis. However, p53 concentrated into the nucleus during heavy apoptosis. Bortezomib could induce apoptosis in U87 with high sensitivity and T98G cells with low sensitivity. In contrast, vorinostat promoted apoptosis in both U87 and T98G cells and reduced the basal level of p53 in U87 cells, indicating that p53 played no role in the vorinostat-induced apoptosis. To clearly define the role of p53 in bortezomib- and doxorubicin-induced apoptosis, we combined doxorubicin with bortezomib to treat U87 cells to assess this combination's effect on apoptosis and p53 status. Interestingly, the combination of doxorubicin with bortezomib engendered compound stress, resulting in a synergistic outcome for apoptosis in U87 cells. However, the amounts of p53 in the total count and in the nucleus were much lower with the combination than with doxorubicin alone, suggesting that p53 played no role in either the compound stress, doxorubicin-only or bortezomib-induced apoptosis.
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Affiliation(s)
- Cheng-Jung Ho
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University,Kaohsiung, Taiwan
| | - Cheng-Yu Tsai
- Post Baccalaureate Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Wei-Hua Zhu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Hsuan Pao
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsin-Wen Chen
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chieh-Ju Hu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Lin Lee
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tzu-Shuo Huang
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Hwan Chen
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Joon-Khim Loh
- Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Ren Hong
- Department of Biochemistry & Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chihuei Wang
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- CONTACT Chihuei Wang
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39
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Bisht R, Haldar C, Hassan MMM, Hoque ME, Chaturvedi J, Chattopadhyay B. Metal-catalysed C-H bond activation and borylation. Chem Soc Rev 2022; 51:5042-5100. [PMID: 35635434 DOI: 10.1039/d1cs01012c] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Transition metal-catalysed direct borylation of hydrocarbons via C-H bond activation has received a remarkable level of attention as a popular reaction in the synthesis of organoboron compounds owing to their synthetic versatility. While controlling the site-selectivity was one of the most challenging issues in these C-H borylation reactions, enormous efforts of several research groups proved instrumental in dealing with selectivity issues that presently reached an impressive level for both proximal and distal C-H bond borylation reactions. For example, in the case of ortho C-H bond borylation reactions, innovative methodologies have been developed either by the modification of the directing groups attached with the substrates or by creating new catalytic systems via the design of new ligand frameworks. Whereas meta and para selective C-H borylations remained a formidable challenge, numerous innovative concepts have been developed within a very short period of time by the development of new catalytic systems with the employment of various noncovalent interactions. Moreover, significant advancements have occurred for aliphatic C(sp3)-H borylations as well as enantioselective borylations. In this review article, we aim to discuss and summarize the different approaches and findings related to the development of directed proximal ortho, distal meta/para, aliphatic (racemic and enantioselective) borylation reactions since 2014. Additionally, considering the C-H borylation reaction as one of the most important mainstream reactions, various applications of this C-H borylation reaction toward the synthesis of natural products, therapeutics, and applications in materials chemistry will be summarized in the last part of this review article.
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Affiliation(s)
- Ranjana Bisht
- Center of Bio-Medical Research, Division of Molecular Synthesis & Drug Discovery, SGPGIMS Campus, Raebareli Road, Lucknow 226014, Uttar Pradesh, India.
| | - Chabush Haldar
- Center of Bio-Medical Research, Division of Molecular Synthesis & Drug Discovery, SGPGIMS Campus, Raebareli Road, Lucknow 226014, Uttar Pradesh, India.
| | - Mirja Md Mahamudul Hassan
- Center of Bio-Medical Research, Division of Molecular Synthesis & Drug Discovery, SGPGIMS Campus, Raebareli Road, Lucknow 226014, Uttar Pradesh, India.
| | - Md Emdadul Hoque
- Center of Bio-Medical Research, Division of Molecular Synthesis & Drug Discovery, SGPGIMS Campus, Raebareli Road, Lucknow 226014, Uttar Pradesh, India.
| | - Jagriti Chaturvedi
- Center of Bio-Medical Research, Division of Molecular Synthesis & Drug Discovery, SGPGIMS Campus, Raebareli Road, Lucknow 226014, Uttar Pradesh, India.
| | - Buddhadeb Chattopadhyay
- Center of Bio-Medical Research, Division of Molecular Synthesis & Drug Discovery, SGPGIMS Campus, Raebareli Road, Lucknow 226014, Uttar Pradesh, India.
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40
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Kaithal A, Wagener T, Bellotti P, Daniliuc CG, Schlichter L, Glorius F. Access to Unexplored 3D Chemical Space: cis‐Selective Arene Hydrogenation for the Synthesis of Saturated Cyclic Boronic Acids. Angew Chem Int Ed Engl 2022. [DOI: 10.1002/ange.202206687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Akash Kaithal
- Westfälische Wilhelms-Universität Münster: Westfalische Wilhelms-Universitat Munster Chemistry Münster GERMANY
| | - Tobias Wagener
- Westfälische Wilhelms-Universität Münster: Westfalische Wilhelms-Universitat Munster Chemistry GERMANY
| | - Peter Bellotti
- Westfälische Wilhelms-Universität Münster: Westfalische Wilhelms-Universitat Munster Chemistry GERMANY
| | - Constantin G. Daniliuc
- Westfälische Wilhelms-Universität Münster: Westfalische Wilhelms-Universitat Munster Chemistry GERMANY
| | - Lisa Schlichter
- Westfälische Wilhelms-Universität Münster: Westfalische Wilhelms-Universitat Munster Chemistry GERMANY
| | - Frank Glorius
- Westfälische Wilhelms-Universität Münster: Westfalische Wilhelms-Universitat Munster Organisch-Chemisches Institut Corrensstrasse 40 48149 Münster GERMANY
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41
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McDonald EF, Sabusap CMP, Kim M, Plate L. Distinct proteostasis states drive pharmacologic chaperone susceptibility for Cystic Fibrosis Transmembrane Conductance Regulator misfolding mutants. Mol Biol Cell 2022; 33:ar62. [PMID: 35389766 PMCID: PMC9561855 DOI: 10.1091/mbc.e21-11-0578] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Pharmacological chaperones represent a class of therapeutic compounds for treating protein misfolding diseases. One of the most prominent examples is the FDA-approved pharmacological chaperone lumacaftor (VX-809), which has transformed cystic fibrosis (CF) therapy. CF is a fatal disease caused by mutations in the CF transmembrane conductance regulator (CFTR). VX-809 corrects folding of F508del CFTR, the most common patient mutation, yet F508del exhibits only mild VX-809 response. In contrast, rarer mutations P67L and L206W are hyperresponsive to VX-809, while G85E is nonresponsive. Despite the clinical success of VX-809, the mechanistic origin for the distinct susceptibility of mutants remains unclear. Here we use interactomics to characterize the impact of VX-809 on proteostasis interactions of P67L and L206W and compare these with F508del and G85E. We determine that hyperresponsive mutations P67L and L206W exhibit decreased interactions with proteasomal and autophagy degradation machinery compared with F508del and G85E. We then show inhibiting the proteasome attenuates P67L and L206W VX-809 response. Our data suggest a previously unidentified but required role for protein degradation in VX-809 correction. Furthermore, we present an approach for identifying proteostasis characteristics of mutant-specific therapeutic response to pharmacological chaperones.
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Affiliation(s)
| | | | - Minsoo Kim
- Department of Chemistry.,Chemical and Physical Biology Program
| | - Lars Plate
- Department of Chemistry.,Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
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42
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Mutluay D, Tenekeci GY, Monsef YA. Bortezomib-Induced Ovarian Toxicity in Mice. Toxicol Pathol 2022; 50:381-389. [DOI: 10.1177/01926233221083527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cancer survivors may experience long-term adverse effects of cancer treatments such as premature ovarian failure and infertility. We aimed to investigate the potential effects and toxicity of bortezomib (BTZ) as an effective anticancer drug on ovaries, raise awareness to the negative consequences of the treatment, and help increase the quality of life after treatment. Mice were distributed into bortezomib (BTZ1, BTZ2) and saline-injected control groups (C1, C2) at a dose of 1 mg/kg twice per week for 6 weeks. We sacrificed C1, BTZ1 groups at day 1 and C2, BTZ2 groups at 4 weeks after the last injection. Ovary samples were examined using histopathological and immunohistochemical methods. Ovarian follicle impairment was detected on BTZ-treated mice and was associated with a statistically significant decreased population of primordial and antral follicles compared with control groups. In experimental groups, Caspase-3 and Ki67 expressions were increased, whereas estrogen receptor alpha (ERα) and progesterone receptor (PR) expressions were decreased in various developmental stages of follicles. BTZ specifically targets granulosa cells by inducing granulosa cell apoptosis and may have long-term effects on follicles. Bortezomib treatment may adversely affect ovarian function by accelerating ovarian reserve depletion and changing ERα and PR hormone levels that can cause fertility problems in the long term.
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Affiliation(s)
- Duygu Mutluay
- Mehmet Akif Ersoy University, Faculty of Veterinary Medicine, Burdur, Turkey
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43
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Electrochemically promoted decarboxylative borylation of alkyl N-hydroxyphthalimide esters. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2021.09.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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44
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Berger SM, Marder TB. Applications of triarylborane materials in cell imaging and sensing of bio-relevant molecules such as DNA, RNA, and proteins. MATERIALS HORIZONS 2022; 9:112-120. [PMID: 34842251 DOI: 10.1039/d1mh00696g] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Triarylboranes have been known for more than 100 years and have found potential applications in various fields such as anion sensors and optoelectronics, for example in organic light emitting diodes (OLEDs), field effect transistors (OFETs), and organic photovoltaic devices. However, biological applications, such as bioimaging agents and biomolecule sensors have evolved much more recently. This review summarises progress in this relatively young field and highlights the potential of triarylboranes in biological applications.
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Affiliation(s)
- Sarina M Berger
- Institut für Anorganische Chemie and Institute for Sustainable Chemistry & Catalysis with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany.
| | - Todd B Marder
- Institut für Anorganische Chemie and Institute for Sustainable Chemistry & Catalysis with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany.
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45
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Bose SK, Mao L, Kuehn L, Radius U, Nekvinda J, Santos WL, Westcott SA, Steel PG, Marder TB. First-Row d-Block Element-Catalyzed Carbon-Boron Bond Formation and Related Processes. Chem Rev 2021; 121:13238-13341. [PMID: 34618418 DOI: 10.1021/acs.chemrev.1c00255] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Organoboron reagents represent a unique class of compounds because of their utility in modern synthetic organic chemistry, often affording unprecedented reactivity. The transformation of the carbon-boron bond into a carbon-X (X = C, N, and O) bond in a stereocontrolled fashion has become invaluable in medicinal chemistry, agrochemistry, and natural products chemistry as well as materials science. Over the past decade, first-row d-block transition metals have become increasingly widely used as catalysts for the formation of a carbon-boron bond, a transformation traditionally catalyzed by expensive precious metals. This recent focus on alternative transition metals has enabled growth in fundamental methods in organoboron chemistry. This review surveys the current state-of-the-art in the use of first-row d-block element-based catalysts for the formation of carbon-boron bonds.
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Affiliation(s)
- Shubhankar Kumar Bose
- Centre for Nano and Material Sciences (CNMS), Jain University, Jain Global Campus, Bangalore-562112, India
| | - Lujia Mao
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, 571199 Haikou, Hainan, P. R. China
| | - Laura Kuehn
- Institute of Inorganic Chemistry and Institute for Sustainable Chemistry & Catalysis with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
| | - Udo Radius
- Institute of Inorganic Chemistry and Institute for Sustainable Chemistry & Catalysis with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
| | - Jan Nekvinda
- Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Webster L Santos
- Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Stephen A Westcott
- Department of Chemistry and Biochemistry, Mount Allison University, Sackville, NB E4L 1G8, Canada
| | - Patrick G Steel
- Department of Chemistry, University of Durham, Science Laboratories South Road, Durham DH1 3LE, U.K
| | - Todd B Marder
- Institute of Inorganic Chemistry and Institute for Sustainable Chemistry & Catalysis with Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
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46
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Hu R, Lin S, Wang M, Li R, Shuai Z, Wei Y. Catechol Moiety Integrated Tri-Aryl Type AIEgen for Visual and Quantitative Boronic Acid Detection. Chemistry 2021; 28:e202103351. [PMID: 34747077 DOI: 10.1002/chem.202103351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Indexed: 11/10/2022]
Abstract
Novel functional AIEgen based on three compact bound aryl skeletons is designed and synthesized. This tri-aryl type luminogen (TA-Catechol) embedded with catechol moiety responds rapidly to series of boronic acids. Real-time visual and quantitative dual-mode detection method is established for the first time with modest precision and low detection limit (8.0 μM). Detailed mechanistic discussion identifies tetra-coordinated boronic species as the key intermediate within sensing procedure. Wide range of organic boronic acids compatible with this strategy is displayed which is promising in high throughput screening technology. Furthermore, solid-state sensing capability of TA-Catechol is also demonstrated.
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Affiliation(s)
- Renjian Hu
- The Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China
| | - Shiyun Lin
- MOE Key Laboratory of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China
| | - Mengshi Wang
- The Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China
| | - Ruoxin Li
- The Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China
| | - Zhigang Shuai
- MOE Key Laboratory of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China
| | - Yen Wei
- The Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China.,Department of Chemistry, Center for Nanotechnology and Institute of Biomedical Technology, Chung-Yuan Christian University, Chung-Li, 32023, P. R. China
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47
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Ho CJ, Ko HJ, Liao TS, Zheng XR, Chou PH, Wang LT, Lin RW, Chen CH, Wang C. Severe cellular stress activates apoptosis independently of p53 in osteosarcoma. Cell Death Discov 2021; 7:275. [PMID: 34608124 PMCID: PMC8490387 DOI: 10.1038/s41420-021-00658-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/25/2021] [Accepted: 09/16/2021] [Indexed: 12/30/2022] Open
Abstract
Apoptosis induced by doxorubicin, bortezomib, or paclitaxel, targeting DNA, 26S proteasome, and microtubules respectively, was assessed in two osteosarcoma cells, p53 wild-type U2OS and p53-null MG63 cells. Doxorubicin-induced apoptosis only occurred in U2OS, not in MG63. In contrast, bortezomib and paclitaxel could drive U2OS or MG63 toward apoptosis effectively, suggesting that apoptosis induced by bortezomib or paclitaxel is p53-independent. The expressions of Bcl2 family members such as Bcl2, Bcl-xl, and Puma could be seen in U2OS and MG63 cells with or without doxorubicin, bortezomib, or paclitaxel treatment. In contrast, another member, Bim, only could be observed in U2OS, not in MG63, under the same conditions. Bim knockdown did not affect the doxorubicin-induced apoptosis in U2OS, suggested that a BH3-only protein other than Bim might participate in apoptosis induced by doxorubicin. Using a BH3-mimetic, ABT-263, to inhibit Bcl2 or Bcl-xl produced a limited apoptotic response in U2OS and MG63 cells, suggesting that this BH3-mimetic cannot activate the Bax/Bak pathway efficiently. Significantly, ABT-263 enhanced doxorubicin- and bortezomib-induced apoptosis synergistically in U2OS and MG63 cells. These results implied that the severe cellular stress caused by doxorubicin or bortezomib might be mediated through a dual process to control apoptosis. Respectively, doxorubicin or bortezomib activates a BH3-only protein in one way and corresponding unknown factors in another way to affect mitochondrial outer membrane permeability, resulting in apoptosis. The combination of doxorubicin with ABT-263 could produce synergistic apoptosis in MG63 cells, which lack p53, suggesting that p53 has no role in doxorubicin-induced apoptosis in osteosarcoma. In addition, ABT-263 enhanced paclitaxel to induce moderate levels of apoptosis.
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Affiliation(s)
- Cheng-Jung Ho
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Huey-Jiun Ko
- Department of Biochemistry & Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Tzu-Shao Liao
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Xiang-Ren Zheng
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Po-Hsu Chou
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Li-Ting Wang
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Ru-Wei Lin
- Department of Plant Industry, National Pingtung University of Science and Technology, Pingtung, 91201, Taiwan
| | - Chung-Hwan Chen
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan
| | - Chihuei Wang
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan.
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48
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Haberecht-Müller S, Krüger E, Fielitz J. Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation. Biomolecules 2021; 11:biom11091327. [PMID: 34572540 PMCID: PMC8468834 DOI: 10.3390/biom11091327] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 09/01/2021] [Accepted: 09/03/2021] [Indexed: 02/07/2023] Open
Abstract
The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed.
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Affiliation(s)
- Stefanie Haberecht-Müller
- Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, 17475 Greifswald, Germany;
| | - Elke Krüger
- Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, 17475 Greifswald, Germany;
- Correspondence: (E.K.); (J.F.)
| | - Jens Fielitz
- DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, 17475 Greifswald, Germany
- Department of Internal Medicine B, Cardiology, University Medicine Greifswald, 17475 Greifswald, Germany
- Correspondence: (E.K.); (J.F.)
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49
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Liu C, Armstrong CM, Ning S, Yang JC, Lou W, Lombard AP, Zhao J, Wu CY, Yu A, Evans CP, Tepper CG, Li PK, Gao AC. ARVib suppresses growth of advanced prostate cancer via inhibition of androgen receptor signaling. Oncogene 2021; 40:5379-5392. [PMID: 34272475 PMCID: PMC8413131 DOI: 10.1038/s41388-021-01914-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 06/09/2021] [Accepted: 06/17/2021] [Indexed: 02/07/2023]
Abstract
Targeting androgen signaling with the second-generation anti-androgen drugs, such as enzalutamide (Enza), abiraterone (Abi), apalutamide (Apal), and darolutamide (Daro), is the mainstay for the treatment of castration-resistant prostate cancer (CRPC). While these treatments are effective initially, resistance occurs frequently. Continued expression of androgen receptor (AR) and its variants such as AR-V7 despite AR-targeted therapy contributes to treatment resistance and cancer progression in advanced CRPC patients. This highlights the need for new strategies blocking continued AR signaling. Here, we identify a novel AR/AR-V7 degrader (ARVib) and found that ARVib effectively degrades AR/AR-V7 protein and attenuates AR/AR-V7 downstream target gene expression in prostate cancer cells. Mechanistically, ARVib degrades AR/AR-V7 protein through the ubiquitin-proteasome pathway mediated by HSP70/STUB1 machinery modulation. ARVib suppresses HSP70 expression and promotes STUB1 nuclear translocation, where STUB1 binds to AR/AR-V7 and promotes its ubiquitination and degradation. ARVib significantly inhibits resistant prostate tumor growth and improves enzalutamide treatment in vitro and in vivo. These data suggest that ARVib has potential for development as an AR/AR-V7 degrader to treat resistant CRPC.
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Affiliation(s)
- Chengfei Liu
- Department of Urologic Surgery, University of California Davis, Davis, CA, USA
- UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA
| | - Cameron M Armstrong
- Department of Urologic Surgery, University of California Davis, Davis, CA, USA
| | - Shu Ning
- Department of Urologic Surgery, University of California Davis, Davis, CA, USA
| | - Joy C Yang
- Department of Urologic Surgery, University of California Davis, Davis, CA, USA
| | - Wei Lou
- Department of Urologic Surgery, University of California Davis, Davis, CA, USA
| | - Alan P Lombard
- Department of Urologic Surgery, University of California Davis, Davis, CA, USA
| | - Jinge Zhao
- Department of Urologic Surgery, University of California Davis, Davis, CA, USA
| | - Chun-Yi Wu
- UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA
- Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA
| | - Aiming Yu
- UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA
- Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA
| | - Christopher P Evans
- Department of Urologic Surgery, University of California Davis, Davis, CA, USA
- UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA
| | - Clifford G Tepper
- UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA
- Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA
| | - Pui-Kai Li
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Allen C Gao
- Department of Urologic Surgery, University of California Davis, Davis, CA, USA.
- UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA.
- VA Northern California Health Care System, Sacramento, CA, USA.
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50
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Voss S, Nitsche C. Targeting the protease of West Nile virus. RSC Med Chem 2021; 12:1262-1272. [PMID: 34458734 PMCID: PMC8372202 DOI: 10.1039/d1md00080b] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 05/17/2021] [Indexed: 01/04/2023] Open
Abstract
West Nile virus infections can cause severe neurological symptoms. During the last 25 years, cases have been reported in Asia, North America, Africa, Europe and Australia (Kunjin). No West Nile virus vaccines or specific antiviral therapies are available to date. Various viral proteins and host-cell factors have been evaluated as potential drug targets. The viral protease NS2B-NS3 is among the most promising viral targets. It releases viral proteins from a non-functional polyprotein precursor, making it a critical factor of viral replication. Despite strong efforts, no protease inhibitors have reached clinical trials yet. Substrate-derived peptidomimetics have facilitated structural elucidations of the active protease state, while alternative compounds with increased drug-likeness have recently expanded drug discovery efforts beyond the active site.
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Affiliation(s)
- Saan Voss
- Research School of Chemistry, Australian National University Canberra ACT 2601 Australia
| | - Christoph Nitsche
- Research School of Chemistry, Australian National University Canberra ACT 2601 Australia
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