摘要
目的设计合成一系列环丙烷类B-Raf激酶抑制剂并测定其对人肝癌Hep G2细胞增殖的影响。方法以索拉非尼(sorafenib)为先导化合物,通过结构优化设计新型环丙烷类B-Raf激酶抑制剂,并以对羟基苯甲醛为起始原料经过苄基保护、缩合、酯化、环丙化、水解、酰胺化、脱苄、亲核取代等反应合成目标化合物。以索拉非尼为阳性对照物,采用MTT法测定目标化合物对人肝癌HepG2细胞增殖的影响。结果与结论合成了16个未见文献报道的新化合物,其结构经核磁共振氢谱鉴定。初步的体外活性评价结果表明,其中9个化合物表现出良好的肿瘤细胞抑制活性,优于阳性对照药索拉非尼,具有进一步研究的价值。
Raf kinase, a common serine/threonine kinase, is part of Raf/MEK/ERK signal transduction pathway that plays a critical role in cell growth, differentiation and proliferation. It is also associated with the development and progression of tumor. B-Raf kinase has the strongest base activity in subtypes of three Raf kinases（ A-Raf,B-Raf and C-Raf）. Therefore ,the development of B-Raf kinase inhibitors has been extensively studied in order to find some compounds as antineoplastic drugs. According to the mechanism, Raf kinase inhibitors can be divided into two categories, namely, type Ⅰand type Ⅱ. The former blocks the conduction of the signal by binding to the active conformation of the B-Raf kinase, which avoids the activation of the downstream MEK and ERK; the latter is bound to the inactive conformation of the B-Raf kinase,blocking the activation of the B-Raf kinase, resulting in direct inhibitory activity. Unfortunately, the anti-cancer activity produced by the current listing of Raf kinase inhibitors is mostly low. On the other hand, drug resistance, side effects ,high price and other shortcomings limit their application. In this study ,we designed 16 cyclopropane B-Raf kinase inhibitors, Ⅰ1- Ⅰ8 and Ⅱ 1- Ⅱ8, by a series of structural optimization with sorafenib as the lead compound. Starting with p-hydroxybenzaldehyde, we conduct a series of key chemical reactions to get the target compounds, including the functional group protection, aldol condensation reaction, cyclization reaction, nucleophilic substitution reaction, deprotection, et al. Sixteen new compounds were synthesized, which were not reported in the literatures. The structures were identified by NMR. MTT assay was used to evaluate the effect of the target compounds on the anti-proliferation of HepG2 cells. As a result, nine compounds showed good inhibitory activity in vitro, and the activity was better than that of the positive control. The results of structure-activity analysis show that：increasing the volume of the substituent on py
出处
《中国药物化学杂志》
CAS
CSCD
2017年第3期177-185,共9页
Chinese Journal of Medicinal Chemistry
基金
国家自然科学基金项目(30973616)
