Cyclopent[a]anthraquinones as DNA-intercalating agents with covalent bond formation potential: Synthesis and biological activity Journal Article
| Authors: | Kim, J. Y.; Su, T. L.; Chou, T. C.; Koehler, B.; Scarborough, A.; Ouerfelli, O.; Watanabe, K. A. |
| Article Title: | Cyclopent[a]anthraquinones as DNA-intercalating agents with covalent bond formation potential: Synthesis and biological activity |
| Abstract: | A series of mitomycin C (MMC) analogues, namely cyclopentanthraquinone derivatives, were synthesized via Diels-Alder cyclization of naphthoquinone with 1-vinylcyclopent-1-enes. These new compounds are planar structures, like MMC, and bear an aziridine ring and a methyl carbamate side chain. After bioreduction, they are anticipated to be capable of intercalating into double-stranded DNA and bind covalently. Structure-activity relationships were studied. Of these compounds, 2,3-aziridino-4- [[(methylamino)carbonyl]methyl]cyclopent[a]anthracene. 6,11-dione (4) was shown to have inhibitory activity against several leukemic and solid tumor cell lines. Mice (BDF1) bearing Lewis lung adenocarcinoma were treated with 4 and MMC (ip, QD x 5). At a dose of 30.0 mg/kg, compound 4 was as effective as MMC (0.8 mg/kg). Compound 4 appears to be less toxic than MMC. DNA unwinding assay indicated that 4 is able to intercalate into DNA double strands and is also a topoisomerase II inhibitor. |
| Keywords: | antineoplastic agents; animals; cell line; drug screening assays, antitumor; tumor cells, cultured; enzyme inhibitor; structure activity relation; lung adenocarcinoma; dna; double stranded dna; protein synthesis; mitomycin c; molecular structure; cyclization; mitomycin; dna binding; dna determination; dna topoisomerase; cricetinae; covalent bond; anthraquinone; hl-60 cells; anthraquinones; mitomycins; aziridine derivative; intercalating agents; humans; article |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 39 |
| Issue: | 14 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 1996-07-05 |
| Start Page: | 2812 |
| End Page: | 2818 |
| Language: | English |
| DOI: | 10.1021/jm950881y |
| PUBMED: | 8709111 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 22 November 2017 -- Source: Scopus |
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