Design,synthesis, anticancer activity and docking studies of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives as mTOR inhibitors |
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| Institution: | 1. School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China;2. Key Laboratory of Original New Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, 110016, China;1. Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China;2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;3. School of Chemical Science and Technology, Yunnan University, Kunming 650091, China;1. National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States;2. Department of Biology, Loyola University Chicago, Chicago, IL 60660, United States;1. ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China;2. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100083, China;3. Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China;1. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States;2. Argenta Discovery, 8/9 Spire Green Centre, Flex Meadow, Harlow CM19 5TR, United Kingdom;1. Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India;2. Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India;3. Discovery Informatics, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India;4. Academy of Scientific and Innovative Research, India;1. Research Division, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan;2. Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan |
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| Abstract: | A series of 7,8-dihydro-5H-thiopyrano4,3-d]pyrimidine derivatives (7a–q, 10a–q) were designed, synthesized and their chemical structures were confirmed by 1H NMR, 13C NMR, MS and HRMS spectrum. All the compounds were evaluated for the inhibitory activity against mTOR kinase at 10 μM level. Five selected compounds (7b, 7e, 7h, 10b and 10e) were further evaluated for the inhibitory activity against PI3Kα at 10 μM level, and the IC50 values against mTOR kinase and two cancer cell lines. Twelve of the target compounds exhibited moderate antitumor activities. The most promising compound 7e showed strong antitumor activities against mTOR kinase, H460 and PC-3 cell lines with IC50 values of 0.80 ± 0.15 μM, 7.43 ± 1.45 μM and 11.90 ± 0.94 μM, which were 1.28 to 1.71-fold more active than BMCL-200908069-1 (1.37 ± 0.07 μM, 9.52 ± 0.29 μM, 16.27 ± 0.54 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that the thiopyrano4,3-d]pyrimidine scaffolds exerted little effect on antitumor activities of target compounds. Substitutions of aryl group at C-4 position had a significant impact on the antitumor activities, and 4-OH substitution produced the best potency. |
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| Keywords: | Synthesis Docking mTOR Antitumor activity |
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