Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 257, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2023.115499
Keywords
4-(4-aminophenoxy)pyridinamide; Antitumor; c -Met; Activity; SARs
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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 of the target compounds showed moderate to excellent anti-proliferative activity against three different cell lines. Compound 46 exhibited the most promising results, with a 2.4 times higher activity than cabozantinib and good pharmacokinetic characteristics in rats.
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 anti-proliferative activity against three different cell lines (A549, HeLa and MCF-7). A total of 7 compounds had stronger inhibitory activities than cabozantinib, and the IC50 value of the most promising compound 46 was 0.26 mu M 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 dis-cussed. 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 IC50 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.
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