新型吡唑啉衍生物作为COX-2和B-Raf双抑制剂用于治疗宫颈癌
Novel pyrazoline derivatives as bi-inhibitor of COX-2 and B-Raf in treating cervical carcinoma.
作者信息
Yu Minmin, Yang Hui, Wu Kaihua, Ji Ying, Ju Lili, Lu Xiaoyuan
机构信息
Department of Obstetrics and Gynecology, Second Affiliated Hospital of Southeast University, Nanjing 210003, China.
Department of Obstetrics and Gynecology, Huai'an Maternal and Child Health Hospital, 223002, China.
出版信息
Bioorg Med Chem. 2014 Aug 1;22(15):4109-18. doi: 10.1016/j.bmc.2014.05.059. Epub 2014 Jun 2.
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.
设计并合成了24种从塞来昔布衍生而来的吡唑啉衍生物，作为COX - 2和B - Raf的双抑制剂。对它们的COX - 1/COX - 2/B - Raf抑制活性和抗增殖活性进行了评估。化合物A3对COX - 2和HeLa细胞系表现出最强的活性（IC₅₀ = 0.008 μM；GI₅₀ = 19.86 μM），并显示出极好的COX - 1/COX - 2选择性（>500），比阳性对照塞来昔布或5 - 氟尿嘧啶更有效且更具选择性。化合物A5和B5表现出最佳的B - Raf抑制活性（分别为IC₅₀ = 0.15 μM和0.12 μM）。化合物A4对COX - 2和HeLa细胞系保持了极好的生物活性（IC₅₀ = 0.015 μM；GI₅₀ = 23.82 μM），并表现出中等的B - Raf抑制活性（IC₅₀ = 3.84 μM）。进行了对接模拟以给出结合模式。使用生物活性数据和优化构象建立了QSAR模型，以提供对COX - 2/B - Raf抑制剂的未来修饰。
Zotero 插件