Design,synthesis, and anticancer activity of C8-substituted-4′-thionucleosides as potential HSP90 inhibitors |
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| Institution: | 1. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea;2. College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea;3. College of Life Science, Dalian Nationalities University, Dalian 116600, China;4. College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116-029, China;1. State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China;2. Nanjing Kang Bixin Pharmaceutical Technology Co., Ltd, Nanjing 210046, PR China;3. School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China;1. Graduate School of Pharmaceutical Science, Tokushima University, Shomachi 1-78-1, Tokushima 770-8505, Japan;2. Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-shichono-cho 1, Kyoto 607-8412, Japan;3. Department of Virology III, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo 208-0011, Japan;4. Department of Microbiology, Kanagawa Prefectural Institute of Public Health, 1-3-1 Shimomachiya, Chigasaki, Kanagawa 253-0087, Japan;1. Sapala Organics Pvt. Ltd, Plot Nos. 146B & 147 IDA Mallapur, Phase-II, Hyderabad 500076, Telangana, India;2. Department of Chemistry, National Institute of Technology Raipur, G.E. Road, Raipur, Chhattisgarh 492010, India;3. Rasayan Inc., 2802 Crystal Ridge Road, Encinitas, CA 92024-6615, USA;1. Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA;2. Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA;1. Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49-box 1041, Leuven 3000, Belgium;2. Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Herestraat 49-box 1043, Leuven 3000, Belgium;1. KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49 - Box 1041, Leuven, 3000, Belgium;2. KU Leuven, Rega Institute for Medical Research, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Herestraat 49 - Box 1041, Leuven, 3000, Leuven, Belgium |
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| Abstract: | A series of C8-substituted-4′-thioadenosine analogs 3a–3g, 15, and 17 and their truncated derivatives 4a–4j, 23–25, and 27 have been successfully synthesized from d-ribose and d-mannose, respectively, employing Pummerer type or Vorbrüggen condensation reactions and the functionalization at the C8-position of nucleobase via Stille coupling or nucleophilic aromatic substitution reactions as key steps. All the synthesized compounds were assayed for their HSP90 inhibitory activity, but they were found to be inactive up to 100 μM. However, the 8-iodo derivatives 15, 17, and 27 exhibited potent anticancer activity, indicating that different mechanism of action might be involved in their biological activity. |
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| Keywords: | HSP90 4′-Thionucleosides Structure–activity relationship Anticancer |
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