Phenylethynylbenzyl-Modified Biguanides Inhibit Pancreatic Cancer Tumor Growth

Abstract

We present the design and synthesis of a small library of substituted biguanidium salts and their capacity to inhibit the growth/viability of pancreatic cancer cells. We first present their in vitro and membrane activity, before we address their mechanism of action in living cells and in vivo activity. We show that phenylethynyl biguanidium salts possess higher ability to cross hydrophobic barriers, improved mitochondrial accumulation and anticancer activity. Mechanistically, the most active compound 1b, like metformin, decreases the NAD+/NADH ratio and mitochondrial respiration, but at 800-fold lower concentration. In vivo studies with, the most active, compound 1b show a significant growth inhibition of pancreatic cancer xenografts in mice, while biguanides currently in clinical trials had no activity.