Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives.
Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives.
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新型20(S)-磺酰脒喜树碱衍生物的设计、合成、细胞毒活性及分子对接研究
DOI：
10.1016/j.ejmech.2016.02.070
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发表时间：
2016-06-10
影响因子：
6.7
通讯作者：
Lee KH
中科院分区：
文献类型：
--
作者：
Song ZL;Wang MJ;Li L;Wu D;Wang YH;Yan LT;Morris-Natschke SL;Liu YQ;Zhao YL;Wang CY;Liu H;Goto M;Liu H;Zhu GX;Lee KH
喜树碱（1）的20-磺酰脒衍生物（9，YQL-9a）作为潜在的直接和选择性抑制拓扑异构酶（Topo）I的抗癌剂正在进行的研究中，磺酰脒药效团保持不变，并且合成了具有各种取代模式的喜树碱衍生物。评价了新化合物对三种人肿瘤细胞系A-549、KB和多药耐药（MDR）KB亚系（KBvin）的抗增殖活性。与临床处方药1和伊立替康相比，几种类似物显示出相当或上级的抗增殖活性（3）。值得注意的是，20-磺酰脒衍生物对KBvin表现出相当的细胞毒性，而1和3对该细胞系的活性较低。其中，化合物15 c显示出比对照1、3和9好得多的细胞毒活性。通过构效关系（SAR）分析确定了与抗增殖活性相关的新的关键结构特征。在分子对接模型中，化合物9和15 c通过与1和3不同的结合模式与Topo I-DNA相互作用。9和15 c的磺酰脒侧链可能与Topo I形成直接氢键，而与Topo I的疏水相互作用和与双链DNA的π-π堆积也被证实是结合驱动力。对接模型的结果与SAR的结论一致。在20位引入大体积取代基有助于改变化合物的结合模式，使它们与拓扑异构体I残基形成新的相互作用。本研究所获得的信息将有助于设计具有最有前途的抗癌活性的1的新衍生物。CPT（绿色）、9（洋红）和15 c（蓝色）在DNA-Topo-I的结合位点。
In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogues showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure-activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π-π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity. CPT (green), 9 (magenta), and 15c (blue) in the binding site of DNA-Topo-I.