Design, synthesis and biological evaluation of 4-(4-aminophenoxy)picolinamide derivatives as potential antitumor...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Cancer remains a leading cause of human mortality.
• Molecular targeted therapy offers a low-toxicity, high-efficiency approach to cancer treatment.
• The MET protein is a key target in cancer therapy, with drugs like cabozantinib and BMS-777607 showing activity.

Purpose of the Study:

• To design and synthesize novel 4-(4-aminophenoxy)pyridinamide derivatives.
• To evaluate the antiproliferative activity of these compounds against human cancer cell lines.
• To identify potent inhibitors of the MET protein for potential antitumor applications.

Main Methods:

• Synthesis of 36 4-(4-aminophenoxy)pyridinamide derivatives.
• Antiproliferative assays using A549, HeLa, and MCF-7 cell lines.
• Apoptosis assays (AO staining, cell cycle analysis), kinase inhibition assays, molecular docking, and molecular dynamics simulations.
• Pharmacokinetic studies in rats.

Main Results:

• Most synthesized compounds showed moderate to excellent antiproliferative activity.
• Seven compounds outperformed cabozantinib in inhibitory activity.
• Compound 46 exhibited the most potent activity, with an IC50 of 0.26 μM against A549 cells (2.4 times more potent than cabozantinib) and an IC50 of 46.5 nM against c-Met kinase.
• Compound 46 induced apoptosis in A549 cells and arrested them in the G0/G1 phase.
• Molecular simulations indicated key hydrogen bonds between compound 46 and c-Met kinase.
• Compound 46 demonstrated favorable pharmacokinetic properties in rats.

Conclusions:

• Compound 46 is a highly promising antitumor agent with potent MET kinase inhibitory activity.
• The structure-activity relationship analysis provides a basis for further optimization of pyridinamide derivatives.
• Compound 46 warrants further investigation as a potential clinical candidate for cancer therapy.