Synthesis and structure–activity relationships of dehydroaltenusin derivatives as selective DNA polymerase α inhibitors

Abstract Herein, we describe the synthesis and structure–activity relationships of dehydroaltenusin derivatives as inhibitors of a mammalian DNA polymerase α. We have newly synthesized nine dehydroaltenusin derivatives modified at the side chains or benzoquinone moiety. We also achieved the first synthesis of desmethylaltenusin and desmethyldehydroaltenusin, metabolites of Alternaria sp. or Talaromyces flavus , respectively. Among all synthesized derivatives, demethoxydehydroaltenusin was the most selective inhibitor of DNA polymerase α. The o -hydroxy- p -benzoquinone (2-hydroxycyclohexa-2,5-dienone) moiety is essential for the inhibition of DNA polymerases. Substitution at the 5-position of dehydroaltenusin is important for the inhibitory potency. Because dehydroaltenusin is conjugated with N -acetylcysteine methyl ester at the o -hydroxy- p -benzoquinone moiety, one or more cysteine residues of DNA polymerase α may act as a target for this compound.