Methylenedioxy- and Ethylenedioxy-Fused Indolocarbazoles: Potent Human Topoisomerase I Inhibitors and Antitumor Agents
| Autor: | Yasheen Zhou, Yongping Xie, Aye Aye Mar, Michael T. Flavin, Ali Koohang, David E. Zembower, Matthew M. Ames, Ze Qi Xu, Mary J. Kuffel, Rama K. Mishra |
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| Přispěvatelé: | Zembower, David E, Xie, Yongping, Koohang, Ali, Kuffel, Mary J, Ames, Matthew M, Zhou, Yasheen, Mishra, Rama Kumar Umar, Mar, Aye Aye, Flavin, Michael T, Xu, Zeqi |
| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Indoles Stereochemistry Carbazoles Antineoplastic Agents Topoisomerase-I Inhibitor Biology Methylenedioxy Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Neoplasms Humans antitumor activity Ethylenedioxy Cell Proliferation Pharmacology Indole test Topoisomerase methylenedioxy In vitro inhibitor DNA Topoisomerases Type I Biochemistry chemistry biology.protein Molecular Medicine DNA supercoil Drug Screening Assays Antitumor Topoisomerase I Inhibitors DNA |
| Zdroj: | Anti-Cancer Agents in Medicinal Chemistry. 12:1117-1131 |
| ISSN: | 1871-5206 |
| Popis: | 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 Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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