Structure–activity relationship of celecoxib and rofecoxib for the membrane permeabilizing activity

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) achieve their anti-inflammatory effect by inhibiting cyclooxygenase activity. We previously suggested that in addition to cyclooxygenase-inhibition at the gastric mucosa, NSAID-induced gastric mucosal cell death is required for the formation of NSAID-induced gastric lesions in vivo. We showed that celecoxib exhibited the most potent membrane permeabilizing activity among the NSAIDs tested. In contrast, we have found that the NSAID rofecoxib has very weak membrane permeabilizing activity. To understand the membrane permeabilizing activity of coxibs in terms of their structure-activity relationship, we separated the structures of celecoxib and rofecoxib into three parts, synthesized hybrid compounds by substitution of each of the parts, and examined the membrane permeabilizing activities of these hybrids. The results suggest that the sulfonamidophenyl subgroup of celecoxib or the methanesulfonylphenyl subgroup of rofecoxib is important for their potent or weak membrane permeabilizing activity, respectively. These findings provide important information for design and synthesis of new coxibs with lower membrane permeabilizing activity.

Isotope labelling by reduction of nitriles: Application to the synthesis of isotopologues of tolmetin and celecoxib

“…The iodinated celecoxib analogue 14 was prepared in a twostep process (Scheme 3). 20,21 Condensation of the iodoacetophenone 10 with ethyl trifluoroacetate 11 gave the 1,3-dicarbonyl 12, which cyclised regioselectively with the hydrazine 13 to give the iodinated intermediate 14.…”

An Integrated Continuous Flow Micro-Total Ultrafast Process System (μ-TUFPS) for the Synthesis of Celecoxib and Other Cyclooxygenase Inhibitors

“…0.33 mmol h –1 productivity (Table , entry 12). The reaction in μ-TPS was observed to be ∼90 times faster than the batch process ,− (see comparative Table , entries 1–4).…”

“…Notably, the alkyl-, fluoro-, alkoxy-, and phenyl-substituted diketones 2b , 2c , 2d , 2f , 2g , 2h , and 2i (Figure ) underwent cyclization in a short reaction time to afford the corresponding pyrazoles ( 3b – d , f–i ) in an excellent yield (75–85%) compared to bromo 3e , which was obtained in 65% yield. In general, for the synthesis of substituted pyrazoles, the batch process system involved longer reaction times and poor yields. ,− …”

Two-Step Synthesis of π-Expanded Maleimides from 3,4-Diphenylfuran-2(5H)-ones

“…The combined organic layers were dried over Mg 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica (ethyl acetate/petroleum ether, 1:15) to afford the corresponding products 1a (76.7 mg, 65%) . Similarly, compounds 1a – t were obtained with the same method as described above.…”

“…3,4-Diphenylfuran-2(5H)-one (1a). 26 Yield: 49%, 76.7 mg. 1 13 C{ 1 H} NMR (150 MHz, CDCl 3 ) δ (ppm) 173.0, 158.1, 134.0, 131.2, 130.9 (q, 2 J = 32.51 Hz), 130.4, 129.9, 129.4, 127.6, 125.8 (q, 3 J = 3.78 Hz), 125.0, 124.0 (q, 1 J = 270.97 Hz), 70.9; IR (KBr), ν (cm 3-(4-(tert-Butyl)phenyl)-4-(thiophen-2-yl)furan-2(5H)-one (1t). White solid.…”