Structure-activity relationships in a series of substituted indolocarbazoles: topoisomerase I and protein kinase C inhibition and antitumoral and antimicrobial properties
| Autor: | Thomas Meyer, Doriano Fabbro, Jean-François Riou, Michelle Prudhomme, Martine Sancelme, Elisabète Rodrigues Pereira, Laure Belin, Monique Ollier, Danièle Sevère, Rapp Maryse |
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| Rok vydání: | 1996 |
| Předmět: |
Indoles
Stereochemistry Rebeccamycin Carbazoles Antineoplastic Agents Microbial Sensitivity Tests Topoisomerase-I Inhibitor Mice Bacillus cereus Drug Discovery medicine Escherichia coli Tumor Cells Cultured Staurosporine Animals Protein kinase A Protein kinase C Protein Kinase C Antibacterial agent biology Chemistry Leukemia P388 Topoisomerase Streptococcus biology.organism_classification Anti-Bacterial Agents Biochemistry biology.protein Molecular Medicine Topoisomerase I Inhibitors Streptomyces griseus medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 39(22) |
| ISSN: | 0022-2623 |
| Popis: | A series of compounds structurally related to staurosporine, rebeccamycin, and corresponding aglycones was synthesized, and their activities toward protein kinase C and topoisomerases I and II were tested together with their in vitro antitumor efficiency against murine B16 melanoma and P388 leukemia cells. Their antimicrobial activities were also examined against a Gram-negative bacterium (Escherichia coli), a yeast (Candida albicans), and three Gram-positive bacteria (Bacillus cereus, Streptomyces chartreusis, and Streptomyces griseus). To avoid side effects expected with protein kinase C inhibitors, we introduced substitution on the maleimide nitrogen and/or a sugar moiety linked to one of the indole nitrogens to obtain specific inhibitors of topoisomerase I with minimal activities on protein kinase C. As expected, these structures were inefficient on topoisomerase II, and some of them exhibited a strong activity against topoisomerase I. Generally, dechlorinated compounds were found to be more active than chlorinated analogues against both purified topoisomerase I and protein kinase C. On the other hand, opposite results were obtained in the cell antiproliferative assays. These results suggest lack of cell membrane permeability in the absence of the chlorine residue or cleavage of carbon-chlorine bonds inside the cell. |
| Databáze: | OpenAIRE |
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