Synthesis and structure-activity relationships of dehydroaltenusin derivatives as selective DNA polymerase alpha inhibitors.
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.
Kuramochi
Kouji
K
Graduate School of Life and Environmental Science, Kyoto Prefectural University, Sakyo-ku, Kyoto 606-8522, Japan. kuramoch@kpu.ac.jp
Fukudome
Keishi
K
Kuriyama
Isoko
I
Takeuchi
Toshifumi
T
Sato
Yoshihiro
Y
Kamisuki
Shinji
S
Tsubaki
Kazunori
K
Sugawara
Fumio
F
Yoshida
Hiromi
H
Mizushina
Yoshiyuki
Y
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
D001578:Benzopyrans; D004791:Enzyme Inhibitors; D004256:DNA Polymerase I; C095645:dehydroaltenusin