77(P-73) デヒドロアルテヌシンの全合成と構造解析(ポスター発表の部)

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Eukaryotic multiple organisms are known to contain at least 15 types of DNA polymerases. DNA polymerase a is an essential enzyme for DNA replication and subsequently for cell division. Aphidicolin has been very useful for studying the DNA replication system, however, there have been no previous reports of inhibitors capable of distinguishing among DNA polymerases α, δ and ε. Recently, we have isolated a powerful DNA polymerase a inhibitor (IC_<50>=0.68μM) from Acremonium sp. 98H02B04-1 (2) and revealed it to be dehydroaltenusin, which was discovered from mycelium extracts of Alternaria tennuis and A. kikuchiana by Rosett et al. in 1957 and then from a variety of fungi. The structure was initially suggested to be a γ-lactone derivative of β-resorcylic acid monomethylether based on the chemical and spectroscopic data and later revised to dehydroaltenusin possessing a δ-lactone ring by the X-ray crystallographic analyses. In 1995, dehydroaltenusin was also reported to inhibit the calmodulin-dependent activity of myosin light chain kinase (MLCK). Dehydroaltenusin is the strongest DNA polymerase α inhibitor of all polymerase inhibitors found and inhibits only DNA polymerase α activity, but does not influence the activities of DNA polymerase δ and 5ε. We have also reported dehydroaltenusin suppressed the cell proliferation of the human gastric cell line NUGC-3 by inhibiting DNA polymerase α activity. Specific inhibitors of mammalian DNA polymerase α are not only useful as molecular tools to study the biological functions of this enzyme in vivo, but are potentially useful chemotherapeutic agents in cancer treatment. However, its low producibility has precluded such utilization. Furthermore, no total synthesis of dehydroaltenusin has been reported so far. We report herein the first synthesis of dehydroaltenusin and its inhibitory activity against a series of DNA polymerases. In addition, the tautomerism of dehydroaltenusin in polar solvents is also discussed. We have also acetylated dehydroaltenusin and examined the inhibitory activities of the resultant acetates against different DNA polymerases.
天然有機化合物討論会の論文
2004-10-01

77(P-73) デヒドロアルテヌシンの全合成と構造解析(ポスター発表の部)

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