title: New COX-2/5-LOX inhibitors: apoptosis-inducing agents potentially useful in prostate cancer chemotherapy.
abstract: The arachidonic acid metabolizing enzymes cyclooxygenase-2 (COX-2) and lipoxygenases (LOXs) have been found to be implicated in a variety of cancers, including prostate cancer. To develop new therapeutic treatments, it therefore seemed interesting to design dual COX-2/5-LOX inhibitors. We report here the synthesis and in vitro pharmacological properties of diarylpyrazole derivatives that have in their structure key pharmacophoric elements to obtain optimal interaction with subsites of active pockets in both enzyme systems. Using a molecular modeling approach, a set of SAR data is proposed, highlighting the importance of the sulfonyl group of one of the aryl moieties in terms of proliferation inhibition and/or apoptosis induction.
authors.affiliation: Institut de Chimie Pharmaceutique Albert Lespagnol, EA 2692, Université de Lille 2, BP 83, 59006 Lille, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pommery
authors.forename: Thierry
authors.initials: T
authors.lastname: Taverne
authors.forename: Aurélie
authors.initials: A
authors.lastname: Telliez
authors.forename: Laurence
authors.initials: L
authors.lastname: Goossens
authors.forename: Caroline
authors.initials: C
authors.lastname: Charlier
authors.forename: Jean
authors.initials: J
authors.lastname: Pommery
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Goossens
authors.forename: Raymond
authors.initials: R
authors.lastname: Houssin
authors.forename: François
authors.initials: F
authors.lastname: Durant
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hénichart
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry; D016466:CHO Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D051546:Cyclooxygenase 2; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016859:Lipoxygenase Inhibitors; D008297:Male; D008565:Membrane Proteins; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011720:Pyrazoles; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases