Synthesis and anticancer activity of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety |
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| Institution: | 1. School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China;2. Fushun Center for Drug Control, Fushun 113000, China;3. School of Pharmaceutical Sciences, China Medical University, 92 Beier Road, Shenyang, Liaoning Province 110001, China;4. Chongqing Three Gorges Medical college, Chongqing, 404120, China;1. AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom;2. AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France;1. Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland;2. Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland;3. Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland;1. Department of Medicinal Chemistry, School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, PR China;2. Department of Genetics and Molecular Biology, School of Basic Medical Science, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, PR China;1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China;2. School of Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China;3. School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, 330013, China;4. Centre for Pharmaceutical Preparations Technology & Research, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China |
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| Abstract: | Herein, we designed and synthesized of a novel series of 7,8-dihydro-5H-thiopyrano4,3-d]pyrimidine derivatives bearing chromone moiety (10a–j, 13a–j). All the compounds were evaluated for the IC50 values against five cancer cell lines (A549, PC-3, MCF-7, Hela and HepG2). Seven of the target compounds exhibited moderate to excellent cytotoxicity. For these compounds, we tested their inhibitory activities against mTOR kinase, and four of them were tested their inhibitory activities against PI3Kα kinase in further. The results indicated that the optimized compound 10j showed excellent inhibitory activity and cytotoxicity against mTOR kinase, PI3Kα kinase and five cancer cell lines with IC50 values of 1.1 μM, 0.92 μM and 8.77–14.3 μM. 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 chromone moiety at C-6 position with carboxyl were benefit to the antitumor activities. |
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| Keywords: | Thiopyranopyrimidine Chromone Synthesis Docking mTOR PI3Kα Antitumor activity |
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