105(P-58) ヌクレオシド系酵素阻害剤の作用機序に基づく設計と合成(ポスター発表の部)

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DNA topoisomerases are nuclear enzymes responsible for 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. Our previous studies demonstrated that the ortho-quinone or catechol moiety in aza-deoxypodophyllotoxin analogues plays a critical role in showing topoisomerase II (topo II) enzyme inhibition, in which proton transport during cutting and resealing of DNA is presumed to be blocked by a small structural unit like ortho-quinone. We report herein the synthesis and biological evaluation of nucleoside analogues as novel topo II inhibitors that are hybrids with aza-podophyllotoxin analogues. Our synthesis contains a Michael addition reaction of 1,3-dithianes to chiral butenolide 2, an equivalent to the deoxyribose moiety of a nucleoside, and a Silyl-Hilbert-Johnson reaction as key reactions. As predicted, ortho-quinone 1 and catechol 6 showed topo II inhibition, while dimethoxy derivative 7 was inactive. Unexpectedly, intermediates 6 and 8 were shown to be potent inhibitors. In addition to the active nucleosides, it was found that several lactone derivatives lacking a thymine base also inhibited topo II, indicating that a thymine base is not requisite to topo II inhibition. Structure-activity relationship of these lactone derivatives showed that the presence of the TBS group or dithiane moiety in the molecule is essential for topo II inhibition in the case of non-nucleoside derivatives. Further study is now in progress to examine their possible mechanism of action as topo II inhibitors.
2002-09-01

105(P-58) ヌクレオシド系酵素阻害剤の作用機序に基づく設計と合成(ポスター発表の部)

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