DNA polymerases have important roles for DNA replication, recomgination, and repair in eukaryotes. Because not all functions of eukaryotic DNA polymerases have been fully elucidated, selective inhibitors to each DNA polymerase will be useful tools to distinguish DNA polymerases and to clarify their biological functions. In the screening of selective inhibitors of eukaryotic DNA polymerases, dehydroaltenusin from the fungus Acremonium sp. was found to be a specific inhibitor of DNA polymerase α(IC_<50>=0.68μM). Dehydroaltenusin did not influence the activities of other replicative DNA polymerases, and also showed no effect on the DNA polymerase α derived from vertebrate (fish) or plant species. The inhibitory effect of dehydroaltenusin is more selective and potent than that of aphidicolin (IC_<50>=20μM), whici is widely known as selective inhibitor of DNA polymerase α. We have newly synthesized nine dehydroaltenusin derivatives modified at the side chains or benzoquinone moiety. Among all synthesized derivatives, desmethoxydehydroaltenusin was the most selective inhibitor of DNA polymerase α. The O-hydroxy-p-benzoquinone (2-hydroxycyclohexa-2,5-dienone) moiety is essential for inhibition of DNA polymerase activities. Substitution at the 5-position of dehydroaltenusin is important for selective inhibition of DNA polymerase α activity. To determine the mechanism of dehydroaltenusin's inhibition, dehydroaltenusin is treated with N-acetylcysteine methyl ester, to give thioether. This result showed that one or more cysteine residues of DNA polymerae α may act as a targeto for this compound.
