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.

Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII

“…The classical Claisen condensation of acetophenone (1) with diethyl oxalate in the presence of sodium ethoxide gave ethyl 2,4-dioxo-4-phenylbutanoate (2). The regioselective cyclization of butanoate 2 with 4-aminosulfonylphenylhydrazine [24] was achieved in acetic acid, yielding ethyl 5-phenyl-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate (3) which was then reacted with hydrazine hydrate to afford hydrazide 4. Hydrazones 5aed were obtained by refluxing hydrazide 4 with the appropriate isatin derivative in ethanol, in the presence of catalytic amounts of acetic acid.…”

Synthesis, cyclooxygenase inhibition, anti-inflammatory evaluation and ulcerogenic liability of new 1,5-diarylpyrazole derivatives

“…Cyclocondensation of the appropriate enaminone (8a-d) with 4-hydrazinylbenzenesulfonamide hydrochloride (9a) 22 , methanesulfonylphenylhydrazine hydrochloride (9b) 23,24 or 4-hydrazinobenzoic acid (9c) 25 in aqueous ethanol afforded the respective 1,5-diarylpyrazoles (10a-l) in good yields (56-88%) (Scheme 1). …”

Synthesis and biological evaluation of 2,5-disubstituted 1,3,4-oxadiazole derivatives with both COX and LOX inhibitory activity

“…Therefore, dual inhibition of COX and LOX is an interesting alternative to provide safer NSAIDs 1 . Compounds with dual COX/LOX inhibitory activity have recently emerged as potential anticancer agents 19,20 . Five-membered heterocyclic compounds like oxazole, pyrazole, indole, triazole, oxadiazole have been widely explored for their biological activities especially for antiinflammatory activity, for example, celecoxib bears pyrazole nucleus, phenyl butazones have pyrazole-2,5-dione, rofecoxib has furanone, and valdecoxib has isoxazole nucleus.…”