In the screening of selective inhibitors of eukaryotic DNA polymerases (pols), dehydroaltenusin from the fungus Acremonium sp. was found to be an inhibitor of pol α. The present study succeeded in chemically synthesizing dehydroaltenusin, and the compound strongly inhibited calf pol α activity and weakly suppressed rat pol β activity, with IC50 values of 0.68 and 64 µM, respectively. We purified or synthesized various slightly modified derivatives of dehydroaltenusin, and using these, investigated the relationship between chemical structure and the inhibitory effects. These results suggest that the ketone group at the 5'-position in dehydroaltenusin is essential for pol inhibitory activity, and the group at the 5-position is important for the specificity of pol α inhibition. Demethoxydehydroaltenusin was found to be the most specific pol α inhibitor among the prepared derivatives, and the IC50 values for pols α and β were 0.24 and 89 µM, respectively. This compound did not influence the activities of other replicative pols such as pols δ and ε, and also demonstrated no effect on pol α activity from another vertebrate, fish and a plant species. Demethoxydehydroaltenusin also had no influence on the other pols and DNA metabolic enzymes tested. Therefore, demethoxydehydroaltenusin is of interest as a mammalian pol α-selective inhibitor as a ‘chemical knockout agent’ in vitro and in vivo.

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