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RESEARCH PRODUCT

Synthesis, Anti-Inflammatory Activity, and in Vitro Antitumor Effect of a Novel Class of Cyclooxygenase Inhibitors: 4-(Aryloyl)phenyl Methyl Sulfones

Giovanni CasulaSalvatore PlesciaRamon PouplanaJoan BassetY. HarrakGlòria RosellMaria Grazia CusimanoDemetrio RaffaMaria Dolors Pujol

subject

Models MolecularIndolesMolecular modelCell SurvivalStereochemistrymedicine.drug_classAntineoplastic AgentsAnti-inflammatoryStructure-Activity RelationshipIn vivoCell Line TumorDrug DiscoverymedicineAnimalsHumansCyclooxygenase InhibitorsSulfonesBinding siteIC50Cell ProliferationIndole testCyclooxygenase 2 InhibitorsbiologyChemistryStereoisomerismSettore CHIM/08 - Chimica FarmaceuticaIn vitroRats4-(Aryloyl)phenyl methyl sulfones anti-inflammatory activity antitumor effect COX-1/COX-2 selectivityCyclooxygenase 1biology.proteinThermodynamicsMolecular MedicineCyclooxygenaseDrug Screening Assays AntitumorHydrophobic and Hydrophilic Interactions

description

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.

yearjournalcountryeditionlanguage
2010-08-30Journal of Medicinal Chemistry
https://doi.org/10.1021/jm100398z