Methylenedioxy- and ethylenedioxy-fused indolocarbazoles: potent human topoisomerase I inhibitors and antitumor agents.
Methylenedioxy- and ethylenedioxy-fused indolocarbazoles: potent human topoisomerase I inhibitors and antitumor agents.
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DOI：
10.2174/187152012803529628
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发表时间：
2012-10
影响因子：
2.8
通讯作者：
D. Zembower;Yongping Xie;A. Koohang;M. Kuffel;M. Ames;Yasheen Zhou;Rama K. Mishra;A. Mar;M. Flavin;Ze-Qi Xu
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文献类型：
--
作者：
D. Zembower;Yongping Xie;A. Koohang;M. Kuffel;M. Ames;Yasheen Zhou;Rama K. Mishra;A. Mar;M. Flavin;Ze-Qi Xu
吲哚并[2,3-a]咔唑生物碱是一类重要的天然产物，具有有趣且多样的生物活性。合成了一系列新型环稠合吲哚并咔唑，并评估了其对拓扑异构酶 I 介导的超螺旋 DNA 松弛的抑制作用以及体外抗肿瘤活性。带有与非糖基化吲哚 (1a, 1b) 融合的亚甲二氧基或亚乙二氧基环的衍生物表现出更有效的抗拓扑异构酶 I 活性。异丙二氧基类似物 1c 的活性大约是 1a 的一半，而 O-二甲氧基类似物 1d 以及区域异构体 2a 和 2b 基本上没有可测量的活性，这意味着由于空间位阻，这些化合物阻碍了与完整 DNA 链的堆积。新合成的吲哚并咔唑针对 NCI 的 60 种肿瘤细胞系进行了筛选。根据平均 GI50 值，活性顺序如下：1a > 2a ~ 1d > 1b > MCR-47 > 2b。虽然一般来说，对拓扑异构酶 I (1a, 1b) 显示有效活性的类似物也显示出对肿瘤细胞生长的有效体外抑制作用，但抗拓扑异构酶 I 无活性 1d 和 2a 的抗肿瘤活性令人感兴趣。 COMPARE 分析证实拓扑异构酶 I 是 1a 和 1b 的主要靶标；然而，也可能涉及其他靶标或途径，建议使用 PLD1 和 MERTK。有必要对这些吲哚并咔唑的这些分子靶点进行进一步研究。
The indolo[2,3-a]carbazole alkaloids constitute an important class of natural products with interesting and diverse biological activities. A series of novel ring-fused indolocarbazoles were synthesized and evaluated for inhibition of topoisomerase I-mediated relaxation of supercoiled DNA and in vitro antitumor activity. The derivatives bearing a methylenedioxy or an ethylenedioxy ring fused onto the nonglycosylated indole (1a, 1b) demonstrated more potent anti-topoisomerase I activity. The isopropylenedioxy analogue 1c was approximately half as active as 1a, while the O-dimethoxy analogue 1d and the regioisomers 2a and 2b were essentially devoid of measurable activity, implying that the stacking with the intact DNA strand has been impeded by these compounds due to steric hindrance. The newly synthesized indolocarbazoles were screened against the NCI's 60 tumor cell lines. The order of activity, based on the mean GI50 values, is as follows: 1a > 2a ~ 1d > 1b > MCR-47 > 2b. Though in general the analogues that showed potent activity against topoisomerase I (1a, 1b) also showed potent in vitro inhibition of tumor cell growth, the antitumor activity of the anti-topoisomerase I inactive 1d and 2a were intriguing. COMPARE analyses confirmed that the topoisomerase I is the primary target for 1a and 1b; however, other target(s) or pathway(s) may also be involved, with PLD1 and MERTK suggested. Further investigation of these molecular targets against these indolocarbazoles is warranted.