title: Design, synthesis, anticancer activity and docking studies of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives as mTOR inhibitors.
abstract: 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 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 PI3Ka 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 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.
authors.forename: Wufu
authors.initials: W
authors.lastname: Zhu
authors.forename: Chengyu
authors.initials: C
authors.lastname: Sun
authors.forename: Shan
authors.initials: S
authors.lastname: Xu
authors.forename: Chunjiang
authors.initials: C
authors.lastname: Wu
authors.forename: Jielian
authors.initials: J
authors.lastname: Wu
authors.forename: Mengze
authors.initials: M
authors.lastname: Xu
authors.forename: He
authors.initials: H
authors.lastname: Zhao
authors.forename: Le
authors.initials: L
authors.lastname: Chen
authors.forename: Weipeng
authors.initials: W
authors.lastname: Zeng
authors.forename: Pengwu
authors.initials: P
authors.lastname: Zheng
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C030986:pyrimidine