Novel mechanisms of DNA topoisomerase II inhibition by pyranonaphthoquinone derivatives -: Eleutherin, α lapachone, and β lapachone
Novel mechanisms of DNA topoisomerase II inhibition by pyranonaphthoquinone derivatives -: Eleutherin, α lapachone, and β lapachone
复制标题
DOI：
10.1016/s0006-2952(00)00437-8
复制
发表时间：
2000-11-01
影响因子：
5.8
通讯作者：
Bastow, KF
中科院分区：
文献类型：
--
作者：
Krishnan, P;Bastow, KF
吡喃并萘醌类化合物对革兰氏阳性菌、真菌和支原体具有多种生物活性，近年来，人们对它们的抗癌活性也越来越感兴趣。本研究包括三个衍生物：刺五加苷(化合物1)、β-雷帕酮(化合物2)及其结构异构体--α-雷帕酮(化合物3)。从酶催化循环的各个步骤出发，系统地研究了这三种衍生物对拓扑异构酶II的抑制作用机理。以典型的酶毒物依托泊苷作为对照，并与化合物1-3结合，定位其作用机制。研究表明，刺五加蛋白(1)和β-雷帕酮(2)通过在三磷酸腺苷(ATP)存在下诱导拓扑异构酶II从DNA上解离和激活而抑制该酶。化合物2是拓扑异构酶II的“不可逆”抑制剂，而化合物1只是减缓了酶的催化循环。另一方面，Alpha Lapachone(3)抑制了拓扑异构酶II与DNA的初始非共价结合，并在酶从DNA解离之前诱导了DNA断裂的宗教(甚至在预先建立的三元复合体中)。化合物3是一种不可逆的拓扑异构酶II抑制剂。吡喃并萘醌类化合物抑制拓扑异构酶II的不同和独特的机制揭示了以该酶为靶点的潜在抗癌药物设计的新途径。(C)2000年爱思唯尔科学公司。
Pyranonaphthoquinones have diverse biological activities against Gram positive bacteria, fungi and mycoplasms, and, recently, there has also been an increasing interest in their anti-cancer activity. This study includes three derivatives: eleutherin (compound 1), beta lapachone (compound 2), and its structural isomer, alpha lapachone (compound 3). The mechanism of topoisomerase II inhibition by the three derivatives was examined systematically with respect to the steps of the catalytic cycle of the enzyme. Etoposide, the prototypical enzyme poison, was used as a control and in combination with compounds 1-3 to localize their mechanism of action. The study revealed that eleutherin (1) and beta lapachone (2) inhibited topoisomerase II by inducing religation and dissociation of the enzyme from DNA in the presence of ATP. Whereas compound 2 was an "irreversible" inhibitor of topoisomerase II, compound 1 merely slowed the catalytic cycle of the enzyme. alpha Lapachone (3), on the other hand, inhibited initial non-covalent binding of topoisomerase II to DNA and, in addition, induced religation of DNA breaks (even in pre-established ternary complexes) before dissociating the enzyme from DNA. Compound 3 was an "irreversible" inhibitor of topoisomerase II. The diverse and unique mechanisms of topoisomerase II inhibition by pyranonaphthoquinone derivatives reveal novel ways to target the enzyme with potential for anti cancer drug design. (C) 2000 Elsevier Science Inc.