title: Synthesis and structure-activity relationships of dehydroaltenusin derivatives as selective DNA polymerase alpha inhibitors.
abstract: Herein, we describe the synthesis and structure-activity relationships of dehydroaltenusin derivatives as inhibitors of a mammalian DNA polymerase alpha. 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 alpha. 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 alpha may act as a target for this compound.
authors.affiliation: Graduate School of Life and Environmental Science, Kyoto Prefectural University, Sakyo-ku, Kyoto 606-8522, Japan. kuramoch@kpu.ac.jp
authors.forename: Kouji
authors.initials: K
authors.lastname: Kuramochi
authors.forename: Keishi
authors.initials: K
authors.lastname: Fukudome
authors.forename: Isoko
authors.initials: I
authors.lastname: Kuriyama
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sato
authors.forename: Shinji
authors.initials: S
authors.lastname: Kamisuki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Tsubaki
authors.forename: Fumio
authors.initials: F
authors.lastname: Sugawara
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D001578:Benzopyrans; D004791:Enzyme Inhibitors; D004256:DNA Polymerase I; C095645:dehydroaltenusin