Synthesis, Anti-Inflammatory Activity, and in Vitro Antitumor Effect of a Novel Class of Cyclooxygenase Inhibitors: 4-(Aryloyl)phenyl Methyl Sulfones
| Autor: | Giovanni Casula, Salvatore Plescia, Ramon Pouplana, Joan Basset, Y. Harrak, Glòria Rosell, Maria Grazia Cusimano, Demetrio Raffa, Maria Dolors Pujol |
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| Přispěvatelé: | Harrak, Y, Casula, G, Basset, J, Rosell, G, Plescia, S, Raffa, D, Cusimano, MG, Pouplana, R, Pujol, MD |
| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Indoles Molecular model Cell Survival Stereochemistry medicine.drug_class Antineoplastic Agents Anti-inflammatory Structure-Activity Relationship In vivo Cell Line Tumor Drug Discovery medicine Animals Humans Cyclooxygenase Inhibitors Sulfones Binding site IC50 Cell Proliferation Indole test Cyclooxygenase 2 Inhibitors biology Chemistry Stereoisomerism Settore CHIM/08 - Chimica Farmaceutica In vitro Rats 4-(Aryloyl)phenyl methyl sulfones anti-inflammatory activity antitumor effect COX-1/COX-2 selectivity Cyclooxygenase 1 biology.protein Thermodynamics Molecular Medicine Cyclooxygenase Drug Screening Assays Antitumor Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Journal of Medicinal Chemistry. 53:6560-6571 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm100398z |
| Popis: | Following our previous research on anti-inflammatory drugs (NSAIDs), we report on the design and synthesis of 4-(aryloyl)phenyl methyl sulfones. These substances were characterized for their capacity to inhibit cyclooxygenase (COX-1 and COX-2) isoenzymes. Molecular modeling studies showed that the methylsulfone group of these compounds was inserted deep in the pocket of the human COX-2 binding site, in an orientation that precludes hydrogen bonding with Arg120, Ser353, and Tyr355 through their oxygen atoms. The N-arylindole 33 was the most potent inhibitor of COX-2 and also the most selective (COX-1/COX-2 IC(50) ratio was 262). The indole derivative 33 was further tested in vivo for its anti-inflammatory activity in rats. This compound showed greater inhibitory activity than ibuprofen. Other compounds (20, 26, 9, and 30) showed strong activity against carrageenan-induced inflammation. The latter compounds showed a weak capacity to inhibit the proliferation of human cell lines K562, NCI-H460, and HT-29 in vitro. |
| Databáze: | OpenAIRE |
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