Abstract
Cyclooxygenase-2 (COX-2) as a rate-limiting metabolism enzyme of arachidonic acid has been found to be implicated in tumor occurrence, angiogenesis, metastasis as well as apoptosis inhibition, regarded as an attractive therapeutic target for cancer therapy. In our research, a series of dihydropyrazole derivatives containing benzo oxygen heterocycle and sulfonamide moieties were designed as highly potent and selective COX-2 inhibitors by computer-aided drug analysis of known COX-2 inhibitors. A total of 26 compounds were synthesized and evaluated COX-2 inhibition and pharmacological efficiency both in vitro and in vivo with multi-angle of view. Among them, compound 4b exhibited most excellent anti-proliferation activities against SW620 cells with IC50 of 0.86 ± 0.02 µM than Celecoxib (IC50 = 1.29 ± 0.04 µM). The results favored our rational design intention and provides compound 4b as an effective COX-2 inhibitor available for the development of colon tumor therapeutics.
Highlights
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China; Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
The results suggest that we have identified a new class of COX-2 inhibitors available for the development of colon tumor therapeutics
The routes to synthesizing the novel dihydropyrazole derivatives containing benzo oxygen heterocycle and sulfonamide moieties 4a–4z are outlined in Scheme 1
Summary
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China; Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China. The results favored our rational design intention and provides compound 4b as an effective COX-2 inhibitor available for the development of colon tumor therapeutics. Cyclooxygenase (COX), known as prostaglandin oxidase reductase, is a bifunctional enzyme with cyclooxygenase and catalase activities, and plays a key rate-limiting role in the conversion of arachidonic acid into prostaglandin. The differences of COX-2 and other isozymes in structure, function, expression and distribution area lay a theoretical foundation for the design of selective COX-2 inhibitors, which will not affect the original physiological function of COX as much as possible [9,10,11]. With the deepening and development of drugs in recent years, the research on selective COX-2 inhibitors as specific anti-tumor drugs is increasing dramatically [13,14]
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