1. Synthesis, Anti-Inflammatory Activity, and in Vitro Antitumor Effect of a Novel Class of Cyclooxygenase Inhibitors: 4-(Aryloyl)phenyl Methyl Sulfones
- Author
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Giovanni Casula, Salvatore Plescia, Ramon Pouplana, Joan Basset, Y. Harrak, Glòria Rosell, Maria Grazia Cusimano, Demetrio Raffa, Maria Dolors Pujol, Harrak, Y, Casula, G, Basset, J, Rosell, G, Plescia, S, Raffa, D, Cusimano, MG, Pouplana, R, and Pujol, MD
- Subjects
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 - Abstract
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.
- Published
- 2010