Novel antitumor indolizino[6,7-b]indoles with multiple modes of action: DNA cross-linking and topoisomerase I and II inhibition
| Autor: | Tsann-Long Su, Anamik Shah, Li Fang Lin, Chi-Wei Chen, Xiuguo Zang, Tung Hu Tsai, S. D. Tala, Te-Chang Lee, Rajesh Kakadiya, Shin I. Chien, Ravi Chaniyara, Ching-Huang Chen, Ting-Chao Chou |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Indoles Crosslinking of DNA Stereochemistry Transplantation Heterologous Mice Nude Antineoplastic Agents chemistry.chemical_compound Mice Structure-Activity Relationship Cell Line Tumor Drug Discovery Molecule Animals Humans Topoisomerase II Inhibitors Hydroxymethyl biology Chemistry Topoisomerase Indolizines Multiple modes DNA Intercalating Agents Rats Cross-Linking Reagents S Phase Cell Cycle Checkpoints biology.protein Molecular Medicine Drug Screening Assays Antitumor Topoisomerase I Inhibitors Neoplasm Transplantation |
| Zdroj: | Journal of medicinal chemistry. 56(4) |
| ISSN: | 1520-4804 |
| Popis: | A series of bis(hydroxymethyl)indolizino[6,7-b]indoles and their bis(alkylcarbamates) were synthesized for antitumor studies. These agents were designed as hybrid molecules of β-carboline (topoisomerase inhibition moiety) and bis(hydroxymethyl)pyrrole (DNA cross-linking moiety). The preliminary antitumor studies indicated that these agents exhibited significant cytotoxicity against a variety of human tumor cells in vitro. Treatment of human breast carcinoma MX-1 xenograft-bearing nude mice with compounds 18b and 28c achieved more than 99% tumor remission. We also observed that 18a displayed potent therapeutic efficacy against human lung adenocarcinoma A549 and colon cancer HT-29 xenografts. These results revealed that compound 18a was more potent than irinotecan against HT-29 cells and was as potent as irinotecan against A549 cells in xenograft models. Furthermore, we demonstrated that these derivatives possess multiple modes of action, such as induction of DNA cross-linking, inhibition of topoisomerase I and II, and cell-cycle arrest at the S-phase. |
| Databáze: | OpenAIRE |
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