24 ATPaseドメインを標的とするDNAトポイソメラーゼII阻害剤(口頭発表の部)

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DNA topoisomerases, mechanistically devided into two main classes types I and II, are critical enzymes that control the level of DNA supercoiling by catalyzing the passage of individual DNA strands or double strands through one another. DNA topoisomerases are involved in biological processes of DNA metabolism such as replication, transcription, recombination and chromosome segregation at mitosis. Therefore, compounds that inhibit these enzymes as the primary cellular target are of special interest since those are promising candidates for anticancer drugs. In our continuing studies towards antitumor compounds, we have isolated oleic acid (1) from the fungus Syncephalastrum spp. and six known pentacyclic triterpenoids including ursolic acid (2) from Tabebuia caraiba and Campsis radicans as DNA topoismerase II inhibitors. Acids 1 and 2 inhibited the catalytic topoismerase II activity (the conversion of catenated kDNA to minicircle monomers) in a dose-dependent manner. However, DNA cleavage assay did not afford linear DNA that generates via double-strand breaks, indicating that both acids do not stabilize the cleavable complex consisting of DNA and topoismerase II. On the other hand, inhibitory effects of 1 and 2 on topoismerase II-mediated DNA relaxation were reduced by increasing amounts of ATP in the buffer. These behaviors suggest that acids 1 and 2 competes with ATP for binding at the ATPase domain of the enzyme, though allosteric effect cannot be ruled out. Structure-activity relationship study of acids 1 and 2 was carried out since both acids have a novel carbon framework as the topoismerase II inhibitor. In the case of fatty acids, carbon chains that have at least 14 methylens were required for topoismerase II inhibition and C-C double bonds more than one reduced the activity. On the other hand, the 3β-OH of 2 was found to show a negative effect on the topoismerase II inhibition. In fact, the inhibitory activity of the deoxy form of 2 was markedly enhanced compared with that of 2. Furthermore, the inhibitory activity of both 1 and 2 disappeared completely when the carboxyl group was reduced to the cotresponding alcohol. These results indicate that the presence of the carboxyl group is essential and the lipophilicity of molecules is contributable to increase the inhibitory activity.
天然有機化合物討論会の論文
1998-08-31

24 ATPaseドメインを標的とするDNAトポイソメラーゼII阻害剤(口頭発表の部)

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