title: Synthesis of dihydropyrazole sulphonamide derivatives that act as anti-cancer agents through COX-2 inhibition.
abstract: COX-2 has long been exploited in the treatment of inflammation and relief of pain; however, research increasingly suggests COX-2 inhibitors might possess potential benefits to thwart tumour processes. In the present study, we designed a series of novel COX-2 inhibitors based on analysis of known inhibitors combined with an in silico scaffold modification strategy. A docking simulation combined with a primary screen in vitro were performed to filter for the lead compound, which was then substituted, synthesized and evaluated by a variety of bioassays. Derivative 4d was identified as a potent COX-2 enzyme inhibitor and exerted an anticancer effect through COX-2 inhibition. Further investigation confirmed that 4d could induce A549 cell apoptosis and arrest the cell cycle at the G2/M phase. Moreover, treatment with 4d reduced A549 cell adhesive ability and COX-2 expression. The morphological variation of treated cells was also visualized by confocal microscopy. Overall, the biological profile of 4d suggests that this compound may be developed as a potential anticancer agent.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China.
authors.forename: Han-Yue
authors.initials: HY
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China.
authors.forename: Jun-Ting
authors.initials: JT
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China. Electronic address: wangxm07@nju.edu.cn.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China. Electronic address: yangyh@nju.edu.cn.
authors.forename: Yong-Hua
authors.initials: YH
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People's Republic of China. Electronic address: zhuhl@nju.edu.cn.
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D013449:Sulfonamides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human
keywords: Antitumor; COX-2 selectivity; Diarylheterocycle; Dihydropyrazole