title: Synthesis and biological evaluation of novel 4-(2-fluorophenoxy)-2-(1H-tetrazol-1-yl)pyridines bearing semicarbazone moieties as potent antitumor agents.
abstract: A series of 4-(2-fluorophenoxy)-2-(1H-tetrazol-1-yl)pyridines bearing semicarbazone moieties were synthesized and evaluated for their in vitro antitumor potency. Some of the compounds (10b, 10c, 10e-10h, 10m-10p, 10r, and 11b) exhibited moderate to excellent antitumor activity as compared to sorafenib and PAC-1, as well as low levels of toxicity toward the human fetal lung fibroblast cell line WI-38. The most promising compound 10p (IC50 = 0.08, 0.36, 0.97 µM) was 45.1-, 6.1-, and 2.4-fold more active than sorafenib (IC50 = 3.61, 2.19, 2.32 µM), and 17, 3.2, and 2.9 times better than PAC-1 (IC50 = 1.36, 1.17, 2.83 µM) against three cancer cell lines (HT-29, H460, and MKN-45), respectively. In addition, further studies examining enzymatic activity suggested that the marked pharmacological activity observed might be ascribed to an inhibitory action against CRAf kinase.
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang, P. R. China.
authors.forename: Mingze
authors.initials: M
authors.lastname: Qin
authors.forename: Weike
authors.initials: W
authors.lastname: Liao
authors.forename: Chen
authors.initials: C
authors.lastname: Xu
authors.forename: Baolin
authors.initials: B
authors.lastname: Fu
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ren
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Gu
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D012664:Semicarbazones / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D000077157:Sorafenib; D013329:Structure-Activity Relationship
chemical_list: C514579:(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine; D000970:Antineoplastic Agents; D006835:Hydrazones; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012664:Semicarbazones; D009536:Niacinamide; D000077157:Sorafenib; D019908:Proto-Oncogene Proteins c-raf
keywords: Antitumor activity; SARs; Semicarbazone moiety; Sorafenib analogs