Frydman B, Marton L J, Sun J S, Neder K, Witiak D T, Liu A A, Wang H M, Mao Y, Wu H Y, Sanders M M, Liu L F
Medical School, Division of Medicinal Chemistry, School of Pharmacy, University of Wisconsin-Madison, 53706, USA.
Cancer Res. 1997 Feb 15;57(4):620-7.
Recent studies have suggested that 3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (beta-lapachone) inhibits DNA topoisomerase I by a mechanism distinct from that of camptothecin. To study the mechanism of action of beta-lapachone, a series of beta-lapachone and related naphthoquinones were synthesized, and their activity against drug-sensitive and -resistant cell lines and purified human DNA topoisomerases as evaluated. Consistent with the previous report, beta-lapachone does not induce topoisomerase I-mediated DNA breaks. However, beta-lapachone and related naphthoquinones, like menadione, induce protein-linked DNA breaks in the presence of purified human DNA topoisomerase IIalpha. Poisoning of topoisomerase IIalpha by beta-lapachone and related naphthoquinones is independent of ATP and involves the formation of reversible cleavable complexes. The structural similarity between menadione, a para-quinone, and beta-lapachone, an ortho-quinone, together with their similar activity in poisoning topoisomerase IIalpha, suggests a common mechanism of action involving chemical reactivity of these quinones. Indeed, both quinones form adducts with mercaptoethanol, and beta-lapachone is 10-fold more reactive. There is an apparent correlation between the rates of the adduct formation with thiols and of the topoisomerase II-poisoning activity of the aforementioned quinones. In preliminary studies, beta-lapachone and related naphthoquinones are found to be cytotoxic against a panel of drug-sensitive and drug-resistant tumor cell lines, including MDR1-overexpressing cell lines, camptothecin-resistant cell lines, and the atypical multidrug-resistant CEM/V-1 cell line.
最近的研究表明，3,4-二氢-2,2-二甲基-2H-萘并[1,2-b]吡喃-5,6-二酮（β-拉帕醌）通过一种不同于喜树碱的机制抑制DNA拓扑异构酶I。为了研究β-拉帕醌的作用机制，合成了一系列β-拉帕醌及相关萘醌，并评估了它们对药物敏感和耐药细胞系以及纯化的人DNA拓扑异构酶的活性。与之前的报道一致，β-拉帕醌不会诱导拓扑异构酶I介导的DNA断裂。然而，β-拉帕醌及相关萘醌，如甲萘醌，在纯化的人DNA拓扑异构酶IIα存在的情况下会诱导蛋白质连接的DNA断裂。β-拉帕醌及相关萘醌对拓扑异构酶IIα的中毒作用不依赖于ATP，且涉及可逆可裂解复合物的形成。对苯二醌甲萘醌和邻苯二醌β-拉帕醌之间的结构相似性，以及它们在使拓扑异构酶IIα中毒方面的相似活性，表明存在一种涉及这些醌化学反应性的共同作用机制。事实上，两种醌都与巯基乙醇形成加合物，且β-拉帕醌的反应活性高10倍。上述醌与硫醇形成加合物的速率与拓扑异构酶II中毒活性之间存在明显的相关性。在初步研究中，发现β-拉帕醌及相关萘醌对一组药物敏感和耐药肿瘤细胞系具有细胞毒性，包括多药耐药1（MDR1）过表达细胞系、喜树碱耐药细胞系以及非典型多药耐药CEM/V-1细胞系。
