Critical role of a methyl group on the γ-lactone ring of annonaceous acetogenins in the potent inhibition of mitochondrial complex I

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Abstract

C34-epi and C34-epi-C35-trifluoro analogues of solamin, a mono-THF annonaceous acetogenin, were synthesized. Their inhibitory activity, along with previously synthesized analogues (C35-fluoro, C35-difluoro, and C35-trifluorosolamins), against bovine mitochondrial NADH–ubiquinone oxidoreductase (complex I) was determined. The present study revealed that the methyl group on the γ-lactone moiety is critical to the potent inhibition of complex I by natural acetogenins.

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Acknowledgments

This study was supported in part by a Grant-in-Aid for Young Scientists (B) [Grant 23790130 to N.K.], a Grant-in-Aid for Scientific Research (B) [Grant 22390021 to T.T., Grant 23380064 to H.M.] from the Japan Society for the Promotion of Sciences (JSPS), and the MEXT (the Ministry of Education, Culture, Sports, Science and Technology, Japan)-Supported Program for the Strategic Research Foundation at Private Universities, 2008–2012. We are indebted to Ms. Natsuki Sawada of our laboratory for her

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