Synthesis, Anticancer Activity and Mechanism of Phenformin Derivatives

Phenformin has been recognized as a drug with anti- proliferative potential. Due to its excellent pharmaceutical parameters, its structure was modified based on the principle of intermediate derivatization, and the influence of different substituents of phenformin and its position on the benzene ring on its antiproliferative activity was discussed. In this study, 15 phenformin derivatives with different substituents were synthesized by inserting electron-withdrawing or electron-donating groups on the different positions of phenyl side of phenformin, and screened for their antiproliferative activities. It was found that the introduction of electron-donating substituents slightly improves the antiproliferative activity of phenformin, however, the introduction of -Cl and -OCF3 substituents significantly increased the antiproliferative activity of phenformin with N-l-(2-chloro) phenethylbiguanide (2B), the best antiproliferative activity compound. Western blot assay and the molecular docking studies demonstrated that 2B activates AMPK.