Pancreatic cancer can be considered as one of the most uncured cancers of the 21st century. Metformin, an antidiabetic drug, has shown interesting anti-cancerous properties towards pancreatic cancer in vitro and in mice. Its biological activity resides in the inhibition of the mitochondrial respiratory chain, leading to cellular death. Its core is a biguanide, which is basically the combination of two guanidines sharing one nitrogen atom. However, the high hydrophilicity of guanidines and biguanides moieties prevents their diffusion through phospholipid bilayers. Metformin’s capacity to enter biological membrane is then driven by organic cationic transporters. As a consequence, high amounts of this drug are required to reach the anti-cancerous effects. We present and discuss our efforts to design amphiphilic guanidine derivatives able to cross the cellular and mitochondrial membrane, their biological activities and application in pancreatic cancer treatment.<br/><br/>Our strategy is then to use guanidine analogs such as iminoguanidines and cyanoguanidines, as they have proven to be good pharmacophores for the treatment of other types of cancer and possess anionophore properties. Thus, our approach is to combine hydrophobic scaffolds able to penetrate phospholipid membranes with these groups in order to increase their uptake inside the cell. In this way, we hope to develop more efficient anticancer drugs, able not only to interfere with the mitochondrial respiratory chain, but also able to modify the homeostatic regulation of ionic gradients in mitochondria.

Guanidine derivatives and their application towards pancreatic cancer treatment

ACS Spring 2022

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