title: Novel pyrazoline derivatives as bi-inhibitor of COX-2 and B-Raf in treating cervical carcinoma.
abstract: Twenty four pyrazoline derivatives modified from Celecoxib were designed and synthesized as bi-inhibitor of COX-2 and B-Raf. They were evaluated for their COX-1/COX-2/B-Raf inhibitory and anti-proliferation activities. Compound A3 displayed the most potent activity against COX-2 and HeLa cell line (IC₅₀=0.008 μM; GI₅₀=19.86 μM) and showed superb COX-1/COX-2 selectivity (>500), being more potent and selective than positive control Celecoxib or 5-fluorouracil. Compounds A5 and B5 were introduced best B-Raf inhibitory activities (IC₅₀=0.15 μM and 0.12 μM, respectively). Compound A4 retained superb bioactivity against COX-2 and HeLa cell line (IC₅₀=0.015 μM; GI₅₀=23.82 μM) and displayed moderate B-Raf inhibitory activity (IC₅₀=3.84 μM). Docking simulation was conducted to give binding patterns. QSAR models were built using bioactivity data and optimized conformations to provide a future modification of COX-2/B-Raf inhibitors.
authors.affiliation: Department of Obstetrics and Gynecology, Second Affiliated Hospital of Southeast University, Nanjing 210003, China. Electronic address: yuminmin324@126.com.
authors.forename: Minmin
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Obstetrics and Gynecology, Huai'an Maternal and Child Health Hospital, 223002, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, Second Affiliated Hospital of Southeast University, Nanjing 210003, China.
authors.forename: Kaihua
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Obstetrics and Gynecology, Second Affiliated Hospital of Southeast University, Nanjing 210003, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Obstetrics and Gynecology, Second Affiliated Hospital of Southeast University, Nanjing 210003, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Ju
authors.affiliation: Department of Obstetrics and Gynecology, Affiliated Hospital of Xuzhou Medical College, Xuzhou 221006, China. Electronic address: xy_lu68@aliyun126.com.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Lu
mesh_terms: D001665:Binding Sites; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D005260:Female; D006367:HeLa Cells; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D048493:Proto-Oncogene Proteins B-raf; D000068579:Celecoxib
keywords: 3D QSAR; B-Raf; Bi-inhibitor; COX-2; Celecoxib; Cervical carcinoma; Modification; Pyrazoline