Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, Davis, One Shields Avenue, Davis, CA 95616-8584, USA.
Bioorg Med Chem Lett. 2013 Jul 1;23(13):3732-7. doi: 10.1016/j.bmcl.2013.05.011. Epub 2013 May 15.
To reduce the pro-angiogenic effects of sEH inhibition, a structure-activity relationship (SAR) study was performed by incorporating structural features of the anti-angiogenic multi-kinase inhibitor sorafenib into soluble epoxide hydrolase (sEH) inhibitors. The structural modifications of this series of molecules enabled the altering of selectivity towards the pro-angiogenic kinases C-RAF and vascular endothelial growth factor receptor-2 (VEGFR-2), while retaining their sEH inhibition. As a result, sEH inhibitors with greater potency against C-RAF and VEGFR-2 were obtained. Compound 4 (t-CUPM) possesses inhibition potency higher than sorafenib towards sEH but similar against C-RAF and VEGFR-2. Compound 7 (t-CUCB) selectively inhibits sEH, while inhibiting HUVEC cell proliferation, a potential anti-angiogenic property, without liver cancer cell cytotoxicity. The data presented suggest a potential rational approach to control the angiogenic responses stemming from sEH inhibition.
为了降低可溶性环氧化物水解酶（sEH）抑制的促血管生成作用，通过将多激酶抑制剂索拉非尼的抗血管生成结构特征纳入可溶性环氧化物水解酶抑制剂中，进行了构效关系（SAR）研究。该系列分子的结构修饰使对促血管生成激酶 C-RAF 和血管内皮生长因子受体-2（VEGFR-2）的选择性发生改变，同时保留了对 sEH 的抑制作用。结果，获得了对 C-RAF 和 VEGFR-2 抑制活性更高的 sEH 抑制剂。化合物 4（t-CUPM）对 sEH 的抑制活性高于索拉非尼，但对 C-RAF 和 VEGFR-2 的抑制活性相似。化合物 7（t-CUCB）选择性抑制 sEH，同时抑制 HUVEC 细胞增殖，这是一种潜在的抗血管生成特性，而对肝癌细胞无细胞毒性。所提供的数据表明，控制源自 sEH 抑制的血管生成反应的一种潜在合理方法。
