[reaction: see text] The trimeric quinone framework of conocurvone is crucial for its potent anti-HIV activity. A new synthesis of trimeric quinones based on stepwise substitution of the halogens in 2,3-dihaloquinones by hydroxyquinone anions is described. Chlorinated biquinones are key intermediates that undergo regiospecific substitution reactions to yield trimeric quinone monomethyl ethers.

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Cancer cells reprogram their metabolism due to genetic alteration to compensate for increased energy demand and enhanced anabolism, cell proliferation, and protection from oxidative damage. Here, we assessed the cytotoxicity of three dimeric naphthoquinones against the glycolytic MCF-7 versus the oxidative MDA-453 breast carcinoma cell lines. Dimeric naphthoquinones 1 and 2 impaired MDA-453, but not MCF-7, cell growth at IC50 = 15 μM. Significant increase in reactive oxygen species, decrease in oxygen consumption and ATP production were observed in MDA-453 cells but not in MCF-7 cell. These findings suggest that oxidative stress and mitochondrial dysfunction are mechanisms by which these agents exert their cytotoxic effects. Cyclic voltammetry and semi-empirical molecular orbital calculations further characterized the electrochemical behavior of these compounds. These results also suggest that dimeric naphthoquinones may be used to selectively target cancer cells that depend on oxidative phosphorylation for energy production and macromolecular synthesis.