Design and Synthesis of Metformin Derivatives as Anticancer Agents

Abstract

Metformin is the first-line medication for type II diabetes. It initially entered the spotlight as a promising anti-cancer agent due to epidemiologic reports that reduced cancer risk and improved clinical outcomes in diabetic patients taking Metformin. To uncover the anti-cancer mechanisms of Metformin, preclinical studies determined that Metformin impairs cellular metabolism and suppresses oncogenic signaling pathways. Recently, the anti-cancer potential of Metformin has gained increasing interest due to its inhibitory effects on cancer stem cells (CSCs), which are associated with tumor metastasis, drug resistance, and relapse. There is a need to optimize this drug to target a more general audience of non-diabetic cancer patients. Metformin has low bioavailability, a narrow absorption window, and extensive liver metabolism. Its oral administration is accompanied by gastrointestinal adverse effects, including nausea, abdominal pain, abdominal bloating, flatulence, dyspepsia, and anorexia, resulting in up to 50% of patients. We have synthesized metformin hybrid conjugates with aromatics compounds. Spectral studies characterized all the synthesized compounds. The hybrid conjugates showed improved LogP values, determined from computational analyses, over tenfold of Metformin's 0.15, suggesting that these candidates will show better bioavailability in the body.