Kragujevac Center for Computational Biochemistry, Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, PO Box 60, 34000 Kragujevac, Serbia.
Department of Biology and Ecology, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, PO Box 60, 34000 Kragujevac, Serbia.
Biochem Pharmacol. 2015 Nov 1;98(1):243-66. doi: 10.1016/j.bcp.2015.08.106. Epub 2015 Aug 28.
Eight chroman-2,4-diones, namely 2a-h, previously investigated as anticoagulants, of which 2a and 2f as the most active, were evaluated as in vivo genotoxic agents in Wistar rat livers and kidneys using the comet assay. Compounds 2a, 2b, and 2f without genotoxic activity were applied prior to ethyl methanesulfonate (EMS) and diminished EMS-induced DNA damage according to the total score and percentage of reduction. EMS produce harmful O(6)-ethylguanine lesion which is incorporated in aberrant genotoxic GT and TG pairing after ATP-dependent DNA strand breaks have been catalyzed by rat Topoisomerase IIα (rTopIIα, EC 5.99.1.3). Therefore, the mechanism of 2a, 2b, and 2f antigenotoxic activity was investigated on the enzyme level using molecular docking and molecular dynamics simulations insamuch as it had been determined that compounds do not intercalate DNA but instead inhibit the ATPase activity. Calculations predicted that compounds inhibit ATP hydrolysis before the DNA-EMS cleavage is being catalyzed by rTopIIα, prevent EMS mutagenic and carcinogenic effects, and beside anticoagulant activity can even be applied in the cancer treatment to control the rate of anticancer alkylation drugs.
八种色满-2,4-二酮，即 2a-h，先前被研究为抗凝剂，其中 2a 和 2f 是最活跃的，被评估为使用彗星试验在 Wistar 大鼠肝脏和肾脏中的体内遗传毒性剂。没有遗传毒性活性的化合物 2a、2b 和 2f 在乙基甲磺酸（EMS）之前应用，并根据总评分和减少百分比减少 EMS 诱导的 DNA 损伤。EMS 产生有害的 O(6)-乙基鸟嘌呤损伤，该损伤在 ATP 依赖性 DNA 链断裂被大鼠拓扑异构酶 IIα（rTopIIα，EC 5.99.1.3）催化后掺入异常遗传毒性 GT 和 TG 配对中。因此，使用分子对接和分子动力学模拟在酶水平上研究了 2a、2b 和 2f 的抗原毒性活性，因为已经确定化合物不嵌入 DNA，而是抑制 ATP 酶活性。计算预测，化合物在 rTopIIα 催化 DNA-EMS 断裂之前抑制 ATP 水解，防止 EMS 的诱变和致癌作用，并且除了抗凝活性之外，甚至可以应用于癌症治疗以控制抗癌烷化剂药物的速度。
