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Design and synthesis of DNA topoisomerase II inhibitors targeting the proton-transfer process

针对质子转移过程的 DNA 拓扑异构酶 II 抑制剂的设计与合成

基本信息

批准号：
12470476
负责人：
IIDA Akira
金额：
$ 3.01万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

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. In this research project, we have aimed at 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, an equivalent to the deoxyribose moiety of a nucleoside, and a Silyl-Hilbert-Johnson reaction as key reactions. As predicted, ortho-quinone and catechol showed topo II inhibition, while dimethoxy derivative was inactive. 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.

DNA拓扑异构酶是一种核酶，负责DNA代谢的生物学过程，如复制、转录、重组和有丝分裂时的染色体分离。因此，抑制作为主要细胞靶点的这些酶的化合物是特别感兴趣的，因为它们是有希望的抗癌药物的候选者。我们先前的研究表明，氮杂-脱氧鬼臼毒素类似物中的邻醌或邻苯二酚部分在显示拓扑异构酶II（topo II）酶抑制中起关键作用，其中在DNA的切割和重新密封期间的质子运输被认为被小的结构单元如邻醌阻断。在本研究项目中，我们的目的是合成和生物学评价的核苷类似物作为新的拓扑异构酶II抑制剂，是杂氮-鬼臼毒素类似物的混合物。我们的合成包括1，3-二噻烷与手性丁烯二酰的Michael加成反应，以及作为关键反应的Silyl-Hilbert-约翰逊反应。正如预测的那样，邻醌和邻苯二酚表现出拓扑异构酶II抑制，而二甲氧基衍生物是无活性的。除了活性核苷，人们发现，几个内酯衍生物缺乏胸腺嘧啶基地也抑制拓扑异构酶II，表明胸腺嘧啶基地是不必要的拓扑异构酶II抑制。这些内酯衍生物的结构-活性关系表明，在非核苷衍生物的情况下，分子中TBS基团或二噻烷部分的存在对于拓扑异构酶II抑制是必不可少的。