Design, synthesis, anticancer activity and docking studies of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d] pyrimidine derivatives as mTOR inhibitors

A series of 7,8-dihydro-5H-thiopyrano[4,3-d] pyrimidine derivatives (7a-q, 10a-q) were designed, synthesized and their chemical structures were confirmed by H-1 NMR, C-13 NMR, MS and HRMS spectrum. All the compounds were evaluated for the inhibitory activity against mTOR kinase at 10 mu M level. Five selected compounds (7b, 7e, 7h, 10b and 10e) were further evaluated for the inhibitory activity against PI3K alpha at 10 mu M 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 mu M, 7.43 +/- 1.45 mu M and 11.90 +/- 0.94 mu M, which were 1.28 to 1.71-fold more active than BMCL-200908069-1 (1.37 +/- 0.07 mu M, 9.52 +/- 0.29 mu M, 16.27 +/- 0.54 mu M), respectively. Structure-activity relationships (SARs) and docking studies indicated that the thiopyrano[4,3-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. (C) 2014 Elsevier Ltd. All rights reserved.