Novel antitumor indolizino[6,7-b]indoles with multiple modes of action: DNA cross-linking and topoisomerase i and II inhibition Journal Article
| Authors: | Chaniyara, R.; Tala, S.; Chen, C. W.; Zhang, X.; Kakadiya, R.; Lin, L. F.; Chen, C. H.; Chien, S. I.; Chou, T. C.; Tsai, T. H.; Lee, T. C.; Shah, A.; Su, T. L. |
| Article Title: | Novel antitumor indolizino[6,7-b]indoles with multiple modes of action: DNA cross-linking and topoisomerase i and II inhibition |
| Abstract: | 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. © 2013 American Chemical Society. |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 56 |
| Issue: | 4 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 2013-02-01 |
| Start Page: | 1544 |
| End Page: | 1563 |
| Language: | English |
| DOI: | 10.1021/jm301788a |
| PROVIDER: | scopus |
| PUBMED: | 23360284 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 April 2013" - "CODEN: JMCMA" - "Source: Scopus" |
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