Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 116, Issue -, Pages 27-35Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.03.033
Keywords
Thiopyrano[4,3-d]pyrimidine; Synthesis; Docking; PI3K alpha/mTOR inhibitors
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Funding
- National Natural Science Funds [81460527]
- Science and Technology Project [GJJ150796]
- Top-notch talent project of Jiangxi Science & Technology Normal University [2015QNBJRC001]
- Program of Key Laboratory of Drug Design and Optimization, Jiangxi Science & Technology Normal University [300098010306]
- College Students' Science and Technology Innovation Project [20140802034]
- Graduate Students' Science and Technology Innovation Project of Jiangxi Province [YC2015-X25]
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Four series of 2-substituted-4-morpholino- 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives (9-28) were designed, synthesized and their structures were confirmed by H-1 NMR, C-13 NMR and MS spectrum. All compounds were evaluated for the IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). And four selected compounds (10, 11, 24, 27) were further evaluated for the IC50 values against PI3K alpha and mTOR kinases. Seven of the target compounds exhibited moderate to excellent antitumor activities against these three cancer cell lines. The most promising compound 11 showed good antitumor potency for A549, PC-3 and MCF-7 cell lines with IC50 values of 0.52 +/- 0.10 mu M,1.41 +/- 0.10 mu M, 4.82 +/- 0.24 mu M and moderate antitumor activities against PI3K alpha/mTOR with IC50 values of 6.72 +/- 0.30 mu M and 0.94 +/- 0.10 mu M. Structure-activity relationships (SARs) and docking studies indicated that aryl urea scaffolds had a significant impact on the antitumor activities, and aryl pyridine urea scaffolds produced the best potency. Variations in substitutions of the aryl group had a significant impact on the activity and 3-Cl-4-F or 3-CF3-4-Cl substitution was more preferred. (C) 2016 Elsevier Masson SAS. All rights reserved.
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