Lamellarin-inspired potent topoisomerase I inhibitors with the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one scaffold
Lamellarin-inspired potent topoisomerase I inhibitors with the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one scaffold
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DOI：
10.1016/j.bmc.2018.11.037
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发表时间：
2019-01-15
影响因子：
3.5
通讯作者：
Iwao, Masatomo
中科院分区：
文献类型：
--
作者：
Fukuda, Tsutomu;Nanjo, Yusuke;Iwao, Masatomo
基于对海洋生物毒性生物碱lamellarin D的构效关系研究，开发了一类新的拓扑异构酶I抑制剂，该抑制剂含有前所未有的苯并[g][1]苯并吡喃[4，3-B]吲哚-6（13 H）-酮（BBPI）环系统。五环BBPI支架由N-叔丁氧基羰基吡咯通过使用定向锂化、常规亲电取代和钯催化的交叉偶联反应对吡咯核进行顺序和区域选择性官能化而构建。支架的进一步N-烷基化，然后O-异丙基的选择性脱保护，产生了一系列N-取代的BBPI衍生物。由此制备的BBPI在DNA松弛试验中表现出有效的拓扑异构酶I抑制活性。BBPIs的活性高于片螺素D和喜树碱;它们在日本癌症研究基金会建立的39种人类癌细胞系的面板中显示出有效的和选择性的抗增殖活性。比较分析表明，BBPI的抑制模式与已知的拓扑异构酶I抑制剂（如SN-38和TAS-103）的抑制模式相关性良好。该水溶性缬氨酸酯衍生物对小鼠结肠癌colon 26具有体内抗肿瘤活性。活性与获批抗癌药伊立替康相当。
A new class of topoisomerase I inhibitors containing the unprecedented benzo[g][1] benzopyrano[4,3-b] indol-6(13H)-one (abbreviated as BBPI) ring system have been developed based on structure-activity relationship studies of the cytotoxic marine alkaloid lamellarin D. The pentacyclic BBPI scaffold was constructed from N-tertbutoxycarbonylpyrrole by sequential and regioselective functionalization of the pyrrole core using directed lithiation, conventional electrophilic substitution, and palladium-catalyzed cross-coupling reactions. Further N-alkylation of the scaffold followed by selective deprotection of the O-isopropyl group produced a range of N-substituted BBPI derivatives. The BBPIs thus prepared exhibited potent topoisomerase I inhibitory activity in DNA relaxation assays. The activities of BBPIs were higher than those of lamellarin D and camptothecin; they showed potent and selective antiproliferative activity in the panel of 39 human cancer cell lines established by Japanese Foundation for Cancer Research. COMPARE analyses indicated that the inhibition patterns of the BBPIs correlated well with those of the known topoisomerase I inhibitors such as SN-38 and TAS-103. The water-soluble valine ester derivative exhibited antitumor activity in vivo against murine colon carcinoma colon 26. The activity was comparable to that of the approved anticancer agent irinotecan.