title: Design, synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors.
abstract: Four series of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (12a-e, 13a-f, 14a-f and 15a-i) were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, PC-3 and MCF-7) and c-Met kinase. Five selected compounds (13b, 15b, 15d, 15e and 15f) were further evaluated for the activity against HepG2 and Hela cell lines. Eighteen of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 valuables in single-digit μM to nanomole range. Seven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15f showed superior activity to Foretinib, with the IC50 values of 1.04±0.11μM, 0.02±0.01μM and 9.11±0.55μM against A549, PC-3 and MCF-7 cell lines, which were 0.62 to 19.5 times more active than Foretinib (IC50 values: 0.64±0.26μM, 0.39±0.11μM, 9.47±0.22μM), respectively. Structure-activity relationships (SARs) and docking studies indicated that replacement of quinoline nucleus of the previous active compounds with 1H-pyrrolo[2,3-b]pyridine moiety maintained even improved the potent cytotoxic activity. The results suggested that the introduction of fluoro atoms to the aminophenoxy part of target compounds or the phenyl group of pyrimidine substituted on C-4 position was benefit for the activity.
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China. Electronic address: zhuwf@jxstnu.edu.cn.
authors.forename: Wufu
authors.initials: W
authors.lastname: Zhu
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Wang
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: Qidong
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Jiangxi Province Institute of Materia Medica, Nanchang 330000, PR China.
authors.forename: Rong
authors.initials: R
authors.lastname: Luo
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
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
mesh_terms: D020816:Amino Acid Motifs; D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression; D019073:HT29 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010847:Picolines / Q000138:chemical synthesis* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D019859:Proto-Oncogene Proteins c-met; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; C544831:GSK 1363089; C000607836:N-phenylpicolinamide; D010847:Picolines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D011804:Quinolines; D019859:Proto-Oncogene Proteins c-met
keywords: 1H-Pyrrolo[2,3-b]pyridine; Antitumor activity; Docking; Phenylpicolinamide; Synthesis; c-Met inhibitors