Vashisht Gopal Y N, Konuru Neelima, Kondapi Anand K
Department of Biochemistry, School of Life Sciences, University of Hyderabad, 500046, India.
Arch Biochem Biophys. 2002 May 1;401(1):53-62. doi: 10.1016/S0003-9861(02)00037-1.
Topoisomerase II poisoning and anticancer activity by the organometallic compound [RuCl(2)(C(6)H(6))(dmso)] was shown by us in an earlier study [Biochemistry 38 (1999) 4382]. Since high concentrations of this complex were required to achieve either effects, we have synthesized four derivatives of this complex in which the dimethyl sulphoxide group on the ruthenium atom was replaced with pyridine, 3-aminopyridine, p-aminobenzoic acid, and aminoguanidine. Three of these molecules showed enhanced potency of topoisomerase II poisoning and consequently also showed higher anticancer activity in breast and colon carcinoma cells in vitro. Detailed analysis of the molecular action of these compounds on topoisomerase II activity was carried out using the classical relaxation and cleavage activity of the enzyme, which revealed that the compounds poison topoisomerase II by freezing the enzyme and enzyme-cleaved DNA in a ternary "cleavage complex". The cleavage complex is implicated in the anti-neoplastic activity of these compounds. DNA interaction studies showed that these compounds interact with DNA in much the same way as [RuCl(2)(C(6)H(6))(dmso)], by external binding of the DNA helix. This is unlike most other topoisomerase II poisons, which predominantly interact with DNA through intercalation with the double helix.
我们在早期的一项研究中 [《生物化学》38 (1999) 4382] 表明，有机金属化合物 [RuCl₂(C₆H₆)(dmso)] 具有拓扑异构酶 II 中毒作用和抗癌活性。由于需要高浓度的这种配合物才能实现这两种效果，我们合成了该配合物的四种衍生物，其中钌原子上的二甲基亚砜基团被吡啶、3 - 氨基吡啶、对氨基苯甲酸和氨基胍取代。这些分子中的三种显示出增强的拓扑异构酶 II 中毒效力，因此在体外对乳腺癌和结肠癌细胞也显示出更高的抗癌活性。利用该酶的经典松弛和切割活性对这些化合物对拓扑异构酶 II 活性的分子作用进行了详细分析，结果表明这些化合物通过将酶和酶切割的 DNA 冻结在三元“切割复合物”中来使拓扑异构酶 II 中毒。切割复合物与这些化合物的抗肿瘤活性有关。DNA 相互作用研究表明，这些化合物与 DNA 的相互作用方式与 [RuCl₂(C₆H₆)(dmso)] 大致相同，即通过 DNA 螺旋的外部结合。这与大多数其他拓扑异构酶 II 毒物不同，后者主要通过插入双螺旋与 DNA 相互作用。
