Unidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense, Plaza de Ramón y Cajal sn, 28040 Madrid, Spain.
Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Department of Biochemistry, School of Medicine, and Institute Teófilo Hernando for Drug Discovery, Universidad Autónoma de Madrid, 28029 Madrid, Spain.
J Med Chem. 2022 Feb 10;65(3):1867-1882. doi: 10.1021/acs.jmedchem.1c01255. Epub 2022 Jan 5.
Hybrid compounds containing structural fragments of the Rho kinase inhibitor fasudil and the NRF2 inducers caffeic and ferulic acids were designed with the aid of docking and molecular mechanics studies. Following the synthesis of the compounds using a peptide-coupling methodology, they were characterized for their ROCK2 inhibition, radical scavenging, effects on cell viability (MTT assay), and NRF2 induction (luciferase assay). One of the compounds () was selected in view of its good multitarget profile and good tolerability. It was able to induce the NRF2 signature, promoting the expression of the antioxidant response enzymes HO-1 and NQO1, via a KEAP1-dependent mechanism. Analysis of mRNA and protein levels of the NRF2 pathway showed that induced the NRF2 signature in control and -ALS lymphoblasts but not in sALS, where it was already increased in the basal state. These results show the therapeutic potential of this compound, especially for ALS patients with a mutation.
借助对接和分子力学研究，设计了含有 Rho 激酶抑制剂法舒地尔和 NRF2 诱导剂咖啡酸和阿魏酸结构片段的杂合化合物。采用肽偶联方法合成化合物后，对其 ROCK2 抑制作用、自由基清除作用、细胞活力（MTT 测定）和 NRF2 诱导作用（荧光素酶测定）进行了表征。鉴于其良好的多靶点特征和良好的耐受性，选择了一种化合物 ()。它能够通过 KEAP1 依赖性机制诱导 NRF2 特征，促进抗氧化反应酶 HO-1 和 NQO1 的表达。对 NRF2 通路的 mRNA 和蛋白水平的分析表明，在对照和 -ALS 淋巴母细胞中诱导 NRF2 特征，但在 sALS 中没有，因为在基础状态下已经增加。这些结果表明该化合物具有治疗潜力，特别是对于携带 突变的 ALS 患者。
