title: Design, synthesis and docking studies of novel thienopyrimidine derivatives bearing chromone moiety as mTOR/PI3Kα inhibitors.
abstract: Two series of thienopyrimidine derivatives (10a-k, 16a-j) bearing chromone moiety were designed and synthesized. All the compounds were evaluated for inhibitory activity against mTOR kinase at a concentration of 10uM. Four selected compounds were further evaluated for the IC50 values against mTOR kinase, PI3Kα kinase and two cancer cell lines. Some of the target compounds exhibited moderate to excellent mTOR/PI3Kα kinase inhibitory activity and cytotoxicity. The most promising compound 16i showed good inhibitory activity against mTOR/PI3Kα kinase and good antitumor potency for H460 and PC-3 cell lines with IC50 values of 0.16 ± 0.03 μM, 2.35 ± 0.19 μM, 1.20 ± 0.23 μM and 0.85 ± 0.04 μM, which were 8.6, >5, 7.9 and 19.1 times more active than compound I (1.37 ± 0.07 μM, >10 μM, 9.52 ± 0.29 μM, 16.27 ± 0.54 μM), respectively. Structure-activity relationships (SARs) and docking studies indicated that the chromone moiety is necessary for the potent antitumor activity and cytotoxicity of these compounds. Substitution of the chromone moiety at the 6-position has a significant impact to the inhibitory activity, in particular a carboxylic acid group, produced the best potency.
authors: 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, 110016, PR China. Electronic address: zhuwufu-1122@163.com.
authors: Wufu
authors: W
authors: Zhu
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, PR China.
authors: Chen
authors: C
authors: Chen
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, PR China.
authors: Chengyu
authors: C
authors: Sun
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, PR China.
authors: Shan
authors: S
authors: Xu
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, PR China.
authors: Chunjiang
authors: C
authors: Wu
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, PR China.
authors: Fei
authors: F
authors: Lei
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, PR China.
authors: Hui
authors: H
authors: Xia
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, PR China.
authors: Qidong
authors: Q
authors: Tu
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, PR China. Electronic address: zhengpw@126.com.
authors: Pengwu
authors: P
authors: Zheng
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; C476003:thienopyrimidine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Chromone; Cytotoxicity; Docking; PI3Kα; Synthesis; Thienopyrimidine; mTOR