Chen Jia-Nian, Wu De-Wen, Li Ting, Yang Kang-Jian, Cheng Li, Zhou Zu-Ping, Pu Shi-Ming, Lin Wan-Hua
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Yucai Road 15, Guilin 541004, Guangxi, China.
Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Yucai Road 15, Guilin 541004, Guangxi, China.
Curr Top Med Chem. 2017 Nov 20;17(28):3099-3130. doi: 10.2174/1568026617666170707123553.
Arylurea derivatives, an important class of small molecules, have received considerable attention in recent years due to their wide range of biological applications. Various molecular targeted agents with arylurea scaffold as potential enzyme/receptor inhibitors were constructed with the successful development of sorafenib and regorafenib. This review focuses on those arylureas possessing anti-cancer activities from 2010 to date. According to their different mechanisms of action, these arylureas are divided into the following six categories: (1) Ras/Raf/MEK/ERK signaling pathway inhibitors; (2) tumor angiogenesis inhibitors, their targets include Vascular Endothelial Growth Factor Receptors (VEGFRs), Fibroblast Growth Factor Receptors (FGFRs), Platelet-Derived Growth Factor Receptors (PDGFRs), Epidermal Growth Factor Receptors (EGFRs), Insulin-Like Growth Factor 1 Receptor (IGF-1R), Fmslike Tyrosine Kinase 3 (FLT3), c-Kit, MET, and Smoothened (Smo); (3) PI3K/AKT/mTOR signaling pathway inhibitors; (4) cell cycle inhibitors, their targets include Checkpoint Kinases (Chks), Cyclin- Dependent Kinases (CDKs), Aurora, SUMO activating enzyme 1 (SUMO E1), tubulin, and DNA; (5) tumor differentiation, migration, and invasion inhibitors, their targets include Matrix Metalloproteinases (MMPs), LIM kinase (Limk), Nicotinamide Phosphoribosyltransferase (Nampt), and Histone Deacetylase (HDAC); (6) arylureas from the rational modification of natural products. This review focuses on the Structure-Activity Relationships (SARs) of these arylureas. The structural evolution and current status of some typical anti-cancer agents used in clinic and/or in clinical trials are emphasized.
芳基脲衍生物是一类重要的小分子化合物，近年来因其广泛的生物学应用而备受关注。随着索拉非尼和瑞戈非尼的成功研发，各种以芳基脲为骨架的分子靶向药物作为潜在的酶/受体抑制剂被构建出来。本综述聚焦于2010年至今具有抗癌活性的芳基脲类化合物。根据其不同的作用机制，这些芳基脲可分为以下六类：（1）Ras/Raf/MEK/ERK信号通路抑制剂；（2）肿瘤血管生成抑制剂，其靶点包括血管内皮生长因子受体（VEGFRs）、成纤维细胞生长因子受体（FGFRs）、血小板衍生生长因子受体（PDGFRs）、表皮生长因子受体（EGFRs）、胰岛素样生长因子1受体（IGF-1R）、Fms样酪氨酸激酶3（FLT3）、c-Kit、MET和平滑肌样蛋白（Smo）；（3）PI3K/AKT/mTOR信号通路抑制剂；（4）细胞周期抑制剂，其靶点包括检查点激酶（Chks）、细胞周期蛋白依赖性激酶（CDKs）、极光激酶、小泛素样修饰激活酶1（SUMO E1）、微管蛋白和DNA；（5）肿瘤分化、迁移和侵袭抑制剂，其靶点包括基质金属蛋白酶（MMPs）、LIM激酶（Limk）、烟酰胺磷酸核糖转移酶（Nampt）和组蛋白去乙酰化酶（HDAC）；（6）天然产物合理修饰得到的芳基脲类化合物。本综述重点关注这些芳基脲类化合物的构效关系。强调了一些用于临床和/或临床试验的典型抗癌药物的结构演变和现状。
