title: Design, synthesis, biological evaluation and docking studies of novel 2-substituted-4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives as dual PI3Kα/mTOR inhibitors.
abstract: 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 (1)H NMR, (13)C 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 PI3Kα 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 μM, 1.41 ± 0.10 μM, 4.82 ± 0.24 μM and moderate antitumor activities against PI3Kα/mTOR with IC50 values of 6.72 ± 0.30 μM and 0.94 ± 0.10 μM. 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.
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Lei
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Sun
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors.forename: Shan
authors.initials: S
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors.forename: Qinqin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: OuYang
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xia
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors.forename: Linxiao
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China. Electronic address: zhengpw@126.com.
authors.forename: Pengwu
authors.initials: P
authors.lastname: Zheng
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China; Key Laboratory of Original New Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: zhuwufu-1122@163.com.
authors.forename: Wufu
authors.initials: W
authors.lastname: Zhu
mesh_terms: D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011487:Protein Conformation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases
keywords: Docking; PI3Kα/mTOR inhibitors; Synthesis; Thiopyrano[4,3-d]pyrimidine