Synthesis and biological evaluation of DIDS analogues as efficient inhibitors of RAD51 involved in homologous recombination

Abstract

RAD51 is a pivotal protein of the homologous recombination DNA repair pathway, and is overexpressed in some cancer cells, disrupting then the efficiency of cancer-treatments. The development of RAD51 inhibitors appears as a promising solution to restore these cancer cells sensitization to radio- or chemotherapy. From a small molecule identified as a modulator of RAD51, the 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), two series of analogues with small or bulky substituents on the aromatic parts of the stilbene moiety were prepared for a structure-activity relationship study. Three compounds, the cyano analogue (12), and benzamide (23) or phenylcarbamate (29) analogues of DIDS were characterized as novel potent RAD51 inhibitors with HR inhibition in the micromolar range.

Keywords: DNA repair; Homologous recombination; Inhibitor; RAD51; Stilbene 2,2′-disulfonic compounds.