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

DNA拓扑异构酶是一种核酶，负责DNA代谢的生物学过程，如有丝分裂时的复制、转录、重组和染色体分离。因此，抑制这些酶的化合物作为主要的细胞靶点是特别感兴趣的，因为它们是抗癌药物的有希望的候选者。我们之前的研究表明，叠氮脱氧鬼臼毒素类似物中的邻醌或儿茶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DNA切割和重封过程中的质子运输可能被邻醌等小结构单元阻断。在这个研究项目中，我们的目标是合成和生物学评价核苷类似物作为新型topo II抑制剂，它是与aza-鬼臼毒素类似物的杂种。我们的合成包含一个1,3 -二硫烷与手性丁烯内酯的Michael加成反应，相当于核苷的脱氧核糖部分，以及一个Silyl-Hilbert-Johnson反应作为关键反应。邻醌和儿茶酚对topo II有抑制作用，二甲氧基衍生物对topo II无抑制作用。除了活性核苷外，还发现几种缺乏胸腺嘧啶碱的内酯衍生物也抑制topo II，这表明胸腺嘧啶碱对topo II的抑制不是必需的。这些内酯衍生物的构效关系表明，在非核苷衍生物的情况下，分子中TBS基团或二硫烷部分的存在对于抑制topo II是必不可少的。

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.