PMID- 37229832 OWN - NLM STAT- MEDLINE DCOM- 20230619 LR - 20230619 IS - 1768-3254 (Electronic) IS - 0223-5234 (Linking) VI - 257 DP - 2023 Sep 5 TI - Design, synthesis and biological evaluation of 4-(4-aminophenoxy)picolinamide derivatives as potential antitumor agents. PG - 115499 LID - S0223-5234(23)00465-8 [pii] LID - 10.1016/j.ejmech.2023.115499 [doi] AB - Cancer is a leading cause of death in humans. Molecular targeted therapy for cancer has become a research hotspot as it is associated with low toxicity and high efficiency. In this study, a total of 36 derivatives of 4-(4-aminophenoxy)pyridinamide were designed and synthesized, based on the analysis of the binding patterns of cabozantinib and BMS-777607 to MET protein. Most target compounds exhibited moderate to excellent antiproliferative activity against three different cell lines (A549, HeLa and MCF-7). A total of 7 compounds had stronger inhibitory activities than cabozantinib, and the IC(50) value of the most promising compound 46 was 0.26 muM against the A549 cells, which was 2.4 times more active than that of cabozantinib. The structure-activity relationship of the target compounds was analyzed and summarized, and the action mechanism was discussed. The acridine orange (AO) staining assay and cell cycle apoptosis revealed that compound 46 dose-dependently induced apoptosis of A549 cells, and blocked the cells mainly in G0/G1 phase. The IC(50) value of compound 46 on c-Met kinase was 46.5 nM. Further docking studies and molecular dynamics simulations signaled that compound 46 formed four key hydrogen bonds to c-Met kinase, and these key amino acids played a major role in binding free energy. In addition, compound 46 also showed good pharmacokinetic characteristics in rats. In conclusion, compound 46 is a promising antitumor agent. CI - Copyright (c) 2023 Elsevier Masson SAS. All rights reserved. FAU - Dai, Jintian AU - Dai J AD - Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China; Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. FAU - Zhang, Jianqing AU - Zhang J AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China; Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430000, China. FAU - Fu, Dongxue AU - Fu D AD - Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. FAU - Liu, Meng AU - Liu M AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China. FAU - Zhang, Han AU - Zhang H AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China. FAU - Tang, Sheng AU - Tang S AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China. FAU - Wang, Linxiao AU - Wang L AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 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, Nanchang, 330013, China. FAU - Zhu, Wufu AU - Zhu W AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China. FAU - Tang, Qidong AU - Tang Q AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. Electronic address: tangqidongcn@126.com. FAU - Zheng, Pengwu AU - Zheng P AD - Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China. Electronic address: zhengpw@126.com. FAU - Chen, Ting AU - Chen T AD - Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. Electronic address: tingchenwfy@163.com. LA - eng PT - Journal Article DEP - 20230518 PL - France TA - Eur J Med Chem JT - European journal of medicinal chemistry JID - 0420510 RN - 1C39JW444G (cabozantinib) RN - I3550CCL59 (picolinamide) RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) SB - IM MH - Humans MH - Animals MH - Rats MH - Cell Line, Tumor MH - Molecular Docking Simulation MH - Structure-Activity Relationship MH - *Antineoplastic Agents/chemistry MH - Drug Screening Assays, Antitumor MH - Cell Proliferation MH - Molecular Structure MH - Drug Design MH - Protein Kinase Inhibitors/chemistry OTO - NOTNLM OT - 4-(4-aminophenoxy)pyridinamide OT - Activity OT - Antitumor OT - SARs OT - c-Met 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- 2023/05/26 01:05 MHDA- 2023/06/19 13:08 CRDT- 2023/05/25 18:01 PHST- 2023/03/14 00:00 [received] PHST- 2023/05/15 00:00 [revised] PHST- 2023/05/15 00:00 [accepted] PHST- 2023/06/19 13:08 [medline] PHST- 2023/05/26 01:05 [pubmed] PHST- 2023/05/25 18:01 [entrez] AID - S0223-5234(23)00465-8 [pii] AID - 10.1016/j.ejmech.2023.115499 [doi] PST - ppublish SO - Eur J Med Chem. 2023 Sep 5;257:115499. doi: 10.1016/j.ejmech.2023.115499. Epub 2023 May 18.