Graduate School of Life and Environmental Science, Kyoto Prefectural University, Sakyo-ku, Kyoto 606-8522, Japan.
Bioorg Med Chem. 2009 Oct 15;17(20):7227-38. doi: 10.1016/j.bmc.2009.08.051. Epub 2009 Aug 31.
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.
在这里，我们描述了去氢青蒿素衍生物作为哺乳动物 DNA 聚合酶 α 的抑制剂的合成和构效关系。我们新合成了九种侧链或苯醌部分修饰的去氢青蒿素衍生物。我们还首次合成了Alternaria sp. 或 Talaromyces flavus 的代谢产物去甲基青蒿素和去甲基去氢青蒿素。在所合成的所有衍生物中，去甲氧基去氢青蒿素是 DNA 聚合酶 α 的最选择性抑制剂。邻-羟基-p-苯醌（2-羟基环己二烯-2,5-二酮）部分对于 DNA 聚合酶的抑制是必需的。去氢青蒿素在 5 位的取代对于抑制效力很重要。因为去氢青蒿素在邻-羟基-p-苯醌部分与 N-乙酰半胱氨酸甲酯结合，所以 DNA 聚合酶 α 的一个或多个半胱氨酸残基可能是该化合物的靶标。
