Synthesis and Biological Activity of Sulfonamide Derivatives of Epipodophyllotoxin
| Autor: | Daniel Dauzonne, Pierre Renard, Chawki Boukarim, Claude Monneret, Paola B. Arimondo, Stephane Leonce, Bruno Pfeiffer, Dominique Guianvarc'h, Laurence Kraus-Berthier, Maria Duca, Alain Pierré |
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| Přispěvatelé: | Synthèse, Structure et Fonction de Molécules Bioactives (SSFMB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2004 |
| Předmět: |
Stereochemistry
Transplantation Heterologous Substituent Mice Nude Antineoplastic Agents Mice Structure-Activity Relationship chemistry.chemical_compound Epipodophyllotoxin Cell Line Tumor Drug Discovery medicine Animals Humans Topoisomerase II Inhibitors Structure–activity relationship ComputingMilieux_MISCELLANEOUS Etoposide Podophyllotoxin chemistry.chemical_classification Sulfonamides biology [CHIM.ORGA]Chemical Sciences/Organic chemistry Topoisomerase Biological activity Sulfonamide DNA Topoisomerases Type II chemistry biology.protein Molecular Medicine Drug Screening Assays Antitumor Topoisomerase-II Inhibitor Neoplasm Transplantation medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, American Chemical Society, 2004, 47 (9), pp.2365-2374 Journal of Medicinal Chemistry, 2004, 47 (9), pp.2365-2374 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A series of novel 4beta-substituted sulfonamide derivatives of 4'-O-demethyl-4-desoxypodophyllotoxin has been synthesized. Their effects on human DNA topoisomerase II and, in some cases, on tubulin polymerization were evaluated. Compounds 8a, 8c, 8f, 8g, 8n, 8q, 8r, and 8s and the synthetic precursor 4 are potent topoisomerase II poisons that induce double-stranded breaks in DNA, with either improved or similar activity compared to etoposide. Only the amino precursor, compound 5, was slightly active in tubulin polymerization inhibition assays. We observed that the derivatives bearing an aromatic ring on the 4beta-sulfonamide substituent were either less cytotoxic or equivalent to the parent drug, while the sulfonamides containing an aliphatic side chain and the amino-sulfonamide derivatives, except 8d and 8g, exhibited increased cytoxicity compared to etoposide. In vivo, against the P388 leukemia and the A-549 orthotopic model of lung carcinoma, the most promising compounds were the morpholino- and the piperazino-containing sulfonamides derivatives 8r and 8s. |
| Databáze: | OpenAIRE |
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