Methylenedioxy- and Ethylenedioxy-Fused Indolocarbazoles: Potent Human Topoisomerase I Inhibitors and Antitumor Agents

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)

Volume 16, 12 Issues, 2016

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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex

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Methylenedioxy- and Ethylenedioxy-Fused Indolocarbazoles: Potent Human Topoisomerase I Inhibitors and Antitumor Agents

Anti-Cancer Agents in Medicinal Chemistry, 12(9): 1117-1131.

Author(s): David E. Zembower, Yongping Xie, Ali Koohang, Mary J. Kuffel, Matthew M. Ames, Yasheen Zhou, Rama Mishra, Aye Aye Mar, Michael T. Flavin and Ze-Qi Xu.

Affiliation: Advanced Life Sciences, 1440 Davey Road, Woodridge, Illinois 60517, USA.


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.


Antitumor, COMPARE analysis, GI50, LC50, Methylenedioxy- and ethylenedioxy-fused indolocarbazole, NCI 60 tumor cell lines, Synthesis, TGI, Topoisomerase I inhibitor, Ethylenedioxyindole.

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Article Details

Volume: 12
Issue Number: 9
First Page: 1117
Last Page: 1131
Page Count: 15
DOI: 10.2174/187152012803529628
Price: $58

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