Synthesis of water-soluble (aminoalkyl)camptothecin analogs: inhibition of topoisomerase I and antitumor activity
| Autor: | Jeffrey C. Boehm, Dalia R. Jakas, Robert P. Hertzberg, Sidney M. Hecht, Gregory Gallagher, Randall K. Johnson, William Dennis Kingsbury, Leo F. Faucette, Francis L. McCabe, Mary Jo Caranfa, K. G. Holden |
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| Rok vydání: | 1991 |
| Předmět: |
Lung Neoplasms
Tertiary amine Stereochemistry Transplantation Heterologous Drug Evaluation Preclinical Melanoma Experimental Antineoplastic Agents Thymus Gland Cell Line Mice Structure-Activity Relationship Drug Discovery medicine Animals Humans Structure–activity relationship Leukemia L1210 Mannich reaction Molecular Structure biology DNA Superhelical Chemistry Topoisomerase Total synthesis Biological activity Transplantation Colonic Neoplasms biology.protein Molecular Medicine Camptothecin Cattle Indicators and Reagents Drug Screening Assays Antitumor Topoisomerase I Inhibitors Plasmids medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 34:98-107 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Water-soluble analogues of the antitumor alkaloid camptothecin (1) were prepared in which aminoalkyl groups were introduced into ring A or B. Most of the analogues were prepared by oxidation of camptothecin to 10-hydroxycamptothecin (2) followed by a Mannich reaction to give N-substituted 9-(aminomethyl)-10-hydroxycamptothecins (4-12) or by subsequent modification of Mannich product 4 (13, 15, 17, 19, 21). Others were obtained by modification of the hydroxyl group of 2 (25,26) or by total synthesis (35,42,43). These analogues, as well as some of their synthetic precursors, were evaluated for inhibition of topoisomerase I, cytotoxicity, and antitumor activity. Although there was not a quantitative correlation between these assays, compounds that inhibited topoisomerase I were also cytotoxic and demonstrated antitumor activity in vivo. Further evaluation of the most active water-soluble analogue led to the selection of 9-[(dimethylamino)methyl]-10-hydroxycamptothecin (4, SK&F 104864) for development as an antitumor agent. In addition to its water solubility, ease of synthesis from natural camptothecin, and high potency, 4 demonstrated broad-spectrum activity in preclinical tumor models and is currently undergoing Phase I clinical trials in cancer patients. |
| Databáze: | OpenAIRE |
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