PMID- 31887474 OWN - NLM STAT- MEDLINE DCOM- 20210308 LR - 20211204 IS - 1090-2120 (Electronic) IS - 0045-2068 (Linking) VI - 95 DP - 2020 Jan TI - Design, synthesis and biological evaluation of substituted 2-(thiophen-2-yl)-1,3,5-triazine derivatives as potential dual PI3Kalpha/mTOR inhibitors. PG - 103525 LID - S0045-2068(19)31695-5 [pii] LID - 10.1016/j.bioorg.2019.103525 [doi] AB - The phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) have been regarded as promising targets for the treatment of cancer. Herein, we synthesized a new series of substituted 2-(thiophen-2-yl)-1,3,5-triazine derivatives as novel PI3Kalpha/mTOR dual inhibitors for cancer therapy. All compounds were evaluated for the IC(50) values against three cancer cell lines (A549, MCF-7 and Hela). Most of the target compounds exhibited moderate to excellent anti-tumor activities against these three tested cancer cell lines especially against A549 and Hela cancer cell lines. Among them, the most promising compound 13g showed excellent anti-tumor potency for A549, MCF-7 and Hela cell lines with IC(50) values of 0.20 +/- 0.05 microM, 1.25 +/- 0.11 microM and 1.03 +/- 0.24 microM, respectively. Notably, according to the result of enzymatic activity assay, compound 13g was identified as a novel PI3Kalpha/mTOR dual inhibitor, which had an approximately 10-fold improvement in mTOR inhibition, compared to the class I PI3K inhibitor 1 (pictilisib, GDC-0941), with IC(50) values of 525 nM to 48 nM. And western blot analysis indicated compound 13g could efficiently suppress the phosphorylation of AKT at the dose of 0.1 microM, which further demonstrated compound 13g had significant inhibitory effect on the PI3K/Akt/mTOR pathway. Furthermore, compound 13g could stimulate A549 cells arrest at G0/G1 phase in a dose-dependent manner, and induced apoptosis at a low concentration. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Zhang, Binliang AU - Zhang B AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China. FAU - Zhang, Qian AU - Zhang Q AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China. FAU - Xiao, Zhen AU - Xiao Z AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China. FAU - Sun, Xin AU - Sun X AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China. FAU - Yang, Zunhua AU - Yang Z AD - College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China. FAU - Gu, Qi AU - Gu Q AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China. FAU - Liu, Ziqin AU - Liu Z AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China. FAU - Xie, Ting AU - Xie T AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China. FAU - Jin, Qingqing AU - Jin Q AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China. FAU - Zheng, Pengwu AU - Zheng P AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China. FAU - Xu, Shan AU - Xu S AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China. Electronic address: shanxu9891@126.com. FAU - Zhu, Wufu AU - Zhu W AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China. Electronic address: zhuwufu-1122@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191220 PL - United States TA - Bioorg Chem JT - Bioorganic chemistry JID - 1303703 RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Thiophenes) RN - 0 (Triazines) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases) RN - EC 2.7.1.137 (PIK3CA protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - A549 Cells MH - Class I Phosphatidylinositol 3-Kinases/*antagonists & inhibitors MH - *Drug Design MH - HeLa Cells MH - Humans MH - Phosphoinositide-3 Kinase Inhibitors/*pharmacology MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors MH - Thiophenes/*chemistry MH - Triazines/chemical synthesis/*chemistry/*pharmacology OTO - NOTNLM OT - 2-(Thiophen-2-yl)-1,3,5-triazine OT - Anti-tumor activity OT - PI3Kalpha/mTOR inhibitors OT - Scaffold hopping COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2019/12/31 06:00 MHDA- 2021/03/09 06:00 CRDT- 2019/12/31 06:00 PHST- 2019/10/09 00:00 [received] PHST- 2019/11/23 00:00 [revised] PHST- 2019/12/18 00:00 [accepted] PHST- 2019/12/31 06:00 [pubmed] PHST- 2021/03/09 06:00 [medline] PHST- 2019/12/31 06:00 [entrez] AID - S0045-2068(19)31695-5 [pii] AID - 10.1016/j.bioorg.2019.103525 [doi] PST - ppublish SO - Bioorg Chem. 2020 Jan;95:103525. doi: 10.1016/j.bioorg.2019.103525. Epub 2019 Dec 20.