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Synthesis and Antitumor Cytotoxicity Evaluation of Novel Pyrrolo[2,1-c][1,4]benzodiazepine Imidazole Containing Polyamide Conjugates

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The design, synthesis, and biological evaluation of novel C-8 linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD)–imidazole polyamide conjugates (1–5) are described that involve mercuric chloride-mediated cyclization of the corresponding amino diethyl thioacetals. The compounds were prepared with varying numbers of imidazole- and pyrrole-containing polyamides in order to probe the structural requirements for optimal in vitro antitumor activity. These compounds were tested against a panel of human cancer cells by the National Cancer Institute, demonstrating that the compounds exhibited a higher level of cytotoxic activity than the existing natural and synthetic pyrrolo[2,1-c][1,4]benzodiazepines. The data presented show that the length of the polyamides and also the type of heterocycle play important roles in this series of compounds for anticancer activity. Compounds 1, 2, 3, and 5 have significant cytotoxic activity against the various types of cancer cell lines. It appears that cytotoxic activity is related to both the length and the heterocycles of the polyamides. Compound 1 exhibited a wide spectrum of anticancer activities against all cell lines in nine cancer panels and was especially effective against colon cancer, melanoma, and renal cancer and breast cancer; however, compound 4 did not exhibit any significant anticancer activity. This study found that PBD–imidazole polyamide conjugates are highly cytotoxic against many human cancer cell lines in comparison with the PBD–pyrrole polyamide conjugates.

Keywords: Key words: Cytotoxicity; Polyamide; Pyrrolo[2,1-c][1,4]benzodiazepines; DNA minor groove binders; PBD–polyamide conjugate

Document Type: Research Article


Affiliations: Department of Chemistry, University of Alberta, Edmonton, AB, Canada, T6G 2G2

Publication date: January 1, 2002

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  • Formerly: Oncology Research Incorporating Anti-Cancer Drug Design
    Oncology Research Featuring Preclinical and Clincal Cancer Therapeutics publishes research of the highest quality that contributes to an understanding of cancer in areas of molecular biology, cell biology, biochemistry, biophysics, genetics, biology, endocrinology, and immunology, as well as studies on the mechanism of action of carcinogens and therapeutic agents, reports dealing with cancer prevention and epidemiology, and clinical trials delineating effective new therapeutic regimens.

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