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拓扑异构酶是负责DNA代谢生物学过程的核酶，例如有丝分裂时复制，转录，重组和染色体分离。 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假定将被诸如Ortho-Quinone之类的小结构单元阻塞。在该研究项目中，我们针对的是对核苷类似物的合成和生物学评估，作为具有AZA-噬蛋白毒素类似物的杂种的新型TOPO II抑制剂。我们的合成包含1，3-二硫烷对手性丁醇的迈克尔添加反应，相当于核苷的脱氧核糖核酸部分，以及silyl-hilbert-Johnson反应作为关键反应。正如预测的那样，正质酮和儿茶醇显示出topo II的抑制作用，而二甲氧基衍生物则无活性。除活性核苷外，还发现缺乏胸腺胺碱基的几种lactone衍生物也抑制了TOPO II，这表明胸腺胺碱不需要topo II抑制作用。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，TBS组或Dithiane部分在分子中的存在对于TOPO II抑制至关重要。