Design,Synthesis And Biological Evaluation Of Anticancer Agents Targeting COX-2

Cancer is classified as noncommunicable disease as cardiovascular diseases,chronic respiratory diseases and diabetes are.They are mostly chronic diseases of long duration and generally slow development.While they are assumed to develop from aging,urbanization,environmental pollution,and unhealthy lifestyles,malignant tumor is one of the diseases that seriously threaten human life.Recent studies have demonstrated that inflammation has emerged as a major factor promoting cancer development.Inflammatory mediators are chemical agents that participate in inflammatory responses and then change the intracellular microenvironment,activate a variety of proteins and inflammatory factors involved in the endognous or exogenous signal pathway.Prostaglandin E2 which acted as inflammatory mediators influence many mechanisms that played a significant role in tumor cell proliferation,angiogenesis,apoptosis,metastasis and immunosuppression,such as induction of mutations and epigenetic modifications,suppressing natural killer cells and inhibiting CD8+ T cell anti-tumour functions.Prostaglandins including PGE2 were derived from arachidonic acid catalyzed by two isoforms cyclooxygenase:the constitutive COX-1 and the inducible COX-2.COX-2 overexpression was a characteristic feature of most malignant tumor and contributed to poor outcomes in multiple malignancies.These researches caused mechanisms of cyclooxygenase-dependent tumor and COXs inhibitors become a new target and hotpot for anticancer drug research.Our research focuses on the identification and modification of a variety of active group from references using 1,5-diarylpyrazoles as the basic skeleton.We use the method of Computer Aided Drug Design including docking operation analysis,comparative moleular field analysis to design and synthesize two novel series of sulfonamide-substituted 1,5-diarylpyrazoles derivatives and evaluated for their biological activities as selective COX-2 inhibitor with anticancer potential.All target compounds are characterized by utilizing 1H NMR,ESI-MS and 13C NMR.Meanwhile,single crystal X-ray diffraction structure analysiswas further identified A2 and A20 compounds to determine the specific type of compound structure.In first step study,44 novel COX-2 inhibitors has been designed and synthesized;their biological activities have been evaluated which suggest these compounds possess moderate to potent antiproliferative activities against A549 cells,HepG2,HeLa,F10 cells and COX-2 inhibitory activities.Among these compounds,compound A28 showed the most powerful antiproliferative activity(IC50=0.78?M for A549 cell)and COX-2 inhibitory activity(IC50 =0.37?M).In addition,compound A28 can induce cancer cell apoptosis effectively and employing human kidney epithelial cell 293T also indicates high safety.The probable binding mode proposed by the docking simulation indicated that A28 binds well with COX-2 through four hydrogen bonds,Sigma-Pi and Pi bond.It can be concluded that the idea of introduction of the active fragment on the diarylpyrazole skeleton is feasible.On the basis of preceding work,we have further modified the structure to optimize and synthesize a series of 1,5-diarylpyrazoles coumarin containing sulfonamide derivatives.Their pharmacological activities have been evaluated which suggest compound B20 showed most powerful selective inhibitory and antiproliferative activity(IC50=0.09±0.01?M for COX-2,IC50=0.36±0.05?M against HeLa cells,0.85 ± 0.08?M against HepG2 cells),comparable to the control positive compound Celecoxib(0.31±0.12?M,20.79±1.84?M?27.03±2.04?M).Cancer cell apoptosis assay were performed and results indicated that compound B20 effectively fuels HeLa cells apoptosis in a dose and time-dependent manner.Moreover,B20 could significantly suppress cancer cell adhesion,migration and invasion which were essential process of cancer metastasis.These results suggest that 1,5-diarylpyrazoles coumarin derivatives are promising leads for further study as potential anticancer agents.Moreover,A QSAR model was built to provide a reliable tool for the rational design of novel COX-2 inhibitors in the future.