Combinatorial synthesis of novel and potent inhibitors of NADH : ubiquinone oxidoreductase

Background: NADH:ubiquinone oxidoreductase (complex I) is the first of thre e large enzyme complexes located in the cell's inner mitochondrial membrane which form the electron transport chain that carries electrons from NADH t o molecular oxygen during oxidative phosphorylation. There is significant i nterest in developing small molecule inhibitors of this enzyme for use as b iological probes, insecticides and potential chemopreventive/chemotherapeut ic agents. Herein we describe the application of novel natural product-like libraries to the discovery of a family of potent benzopyran-based inhibito rs. Results: Initially a combinatorial library of benzopyrans, modeled after na tural products, was synthesized using a solid phase cycloloading strategy. Screening of this diversity oriented library for inhibitory potency against NADH:ubiquinone oxidoreductase activity in vitro using bovine heart electr on transport particles provided several lead compounds which were further r efined through a series of focused libraries. Conclusions: Using this combinatorial library approach, a family of potent 2,2dimethylbenzopyran-based inhibitors was developed with IC50 values in th e range of 18-55 nM. Cell-based assays revealed that these inhibitors were rather noncytotoxic in the MCF-7 cell line; however, they were quite cytost atic in a panel of cancer cell lines suggesting their potential as chemothe rapeutic/chemopreventive candidates.