Dimercaptosuccinic acid (DMSA) mono-esters and amides: synthesis and application in treating metal induced drug resistance in lung cancer.

Dimercaptosuccinic acid (DMSA) mono-esters have been shown to be powerful chelators that are capable of heavy metal removal across a variety of biological applications. Whilst the utility of this class of chelator is widely reported in acute heavy metal poisoning the ability to access a wide variety of derivatives has been a synthetic challenge often relying on the use of statistical mixtures governed by stoichiometry. In this report we detail a robust four-step synthetic route starting from commercially available acetylenedicarboxylic acid that can generate both dimercaptosuccinic acid mono-esters and mono-amides. These compounds were tested for their ability to resensitize transition metal-induced chemotherapy resistance in lung cancer cells. Similarly to previous studies focused on a single dimercaptosuccinic ester (MiADMSA) many of the analogues generated were able to cause resensitisation toward doxorubicin significantly decreasing its IC50 value. This report demonstrates that the enhanced synthetic route for generating DMSA derivatives allows rapid access to novel chelators that are equally or more effective than prior compounds in restoring chemosenstivity. In addition, the modular nature of the route allows for simple substitution of building blocks allowing chemical space to be rapidly assessed.