Towards the next generation of dual Bcl-2/Bcl-xL inhibitors |
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| Affiliation: | 1. LIEC—Department of Chemistry, Universidade Federal de São Carlos, Via Washington Luiz, Km 235, PO Box 676, 13565-905 São Carlos, São Paulo, Brazil;2. Department of Chemistry, Universidade Estadual Paulista—Unesp, PO Box 473, 17033-360 Bauru, São Paulo, Brazil;3. Instituto de Física de São Carlos, USP, São Carlos 13560-250, São Paulo, Brazil;4. NanO LaB—Department of Physics, Universidade Federal de São Carlos, Via Washington Luiz, Km 235, PO Box 676, 13565-905 São Carlos, São Paulo, Brazil;5. Institute of Chemistry, Universidade Estadual Paulista—Unesp, Araraquara, São Paulo, Brazil;1. Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Kwei-Shan 333, Taiwan;2. Department of Radiation Oncology, Chang Gung Memorial Hospital, Kwei-Shan 333, Taiwan;3. Department of Medical Imaging and Radiological Sciences, Tzu Chi College of Technology, Hualien 970, Taiwan;4. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan;5. Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan 333, Taiwan;1. Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women''s University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, Republic of Korea;2. Department of Biological Sciences, Sookmyung Women''s University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, Republic of Korea |
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| Abstract: | Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-xL in in vitro biochemical assays and had strong activity in an RS4;11 apoptotic cellular assay. For example, sulfoxide diastereomer 13 maintained good binding affinity and comparable cellular potency to 1 while improving aqueous solubility. The corresponding diastereomer (14) was significantly less potent in the cell, and docking studies suggest that this is due to a stereochemical preference for the RS versus SS sulfoxide. Appending a dimethylaminoethoxy side chain (27) adjacent to the benzylic position of the biphenyl moiety of 1 improved cellular activity by approximately three-fold, and this activity was corroborated in cell lines overexpressing Bcl-2 and Bcl-xL. |
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| Keywords: | Bcl-2 Navitoclax B-cell lymphoma Apoptosis |
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