Department of Pharmaceutical Chemistry, University of Vienna, Althanstraße 14, A-1090 Vienna, Austria.
Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
Bioorg Med Chem. 2020 May 1;28(9):115443. doi: 10.1016/j.bmc.2020.115443. Epub 2020 Mar 16.
A series of new Luotonin A derivatives with substituents at rings A and E was synthesized, together with some E-ring-unsubstituted derivatives. Subsequently, the compound library was examined in silico for their binding into a previously proposed site in the DNA/topoisomerase I binary complex. Whereas no convincing correlation between docking scores and biological data from in vitro assays could be found, one novel 4,9-diamino Luotonin A derivative had strong antiproliferative activity based on massive G2/M phase arrest. As this biological activity clearly differs from the reference compound Camptothecin, this strongly indicates that at least some Luotonin A derivatives may be potent antiproliferative agents, however with a different mode of action.
合成了一系列在环 A 和环 E 上带有取代基的新型洛托汀 A 衍生物，以及一些 E 环未取代的衍生物。随后，在计算机上将化合物库进行了虚拟筛选，以研究它们与 DNA/拓扑异构酶 I 二元复合物中先前提出的一个位点的结合情况。尽管在 docking 分数和体外测定的生物学数据之间没有找到令人信服的相关性，但基于大量 G2/M 期阻滞，一种新型的 4,9-二氨基洛托汀 A 衍生物具有很强的抗增殖活性。由于这种生物活性与参考化合物喜树碱明显不同，这强烈表明至少一些洛托汀 A 衍生物可能是有效的抗增殖剂，但作用模式不同。
