de Bourg Marcus, Mishra Abhishek, Mohammad Rawand S, Morisseau Christophe, Hammock Bruce D, Imig John D, Vik Anders
Department of Pharmacy, Section for Pharmaceutical Chemistry, University of Oslo, N-0316 Oslo, Norway.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Molecules. 2025 Mar 24;30(7):1445. doi: 10.3390/molecules30071445.
Nineteen potential mimics of 8,9-epoxyeicosatrienoic acid (8,9-EET), a natural bioactive oxylipin, were synthesized and evaluated for their ability to protect renal mesangial cells against sorafenib-induced cell death in a water-soluble tetrazolium (WST-8) assay. All compounds were also evaluated as inhibitors of soluble epoxide hydrolase. As expected of a potent pan-kinase inhibitor the drug sorafenib caused a significant decrease in cell viability in HRMCs. Several analogs containing amide and oxamide groups in place of the epoxide showed efficacy in reducing sorafenib induced human renal mesangial cell (HRMC) death. Oxamide containing analogs proved particularly effective, with the most promising analog increasing cell viability five-fold over control at 1 µM. These analogs, containing an oxamide group as a bioisostere for the epoxide in 8,9-EET, did not display significant inhibitory activity towards soluble epoxide hydrolase. This preliminary structure-activity relationship analysis reveals the oxamide group as a promising bioisostere for the epoxide in the 8,9-position of the fatty acid chain, producing protective effects against sorafenib-induced cell death in HRMCs. Collectively, these findings demonstrate the potential for using epoxide mimics and particularly oxamides as 8,9-EET analogs as bioisosteres of the corresponding epoxide in a therapeutic strategy against sorafenib-induced glomerular nephrotoxicity.
合成了19种天然生物活性氧脂8,9-环氧二十碳三烯酸（8,9-EET）的潜在模拟物，并在水溶性四氮唑（WST-8）试验中评估了它们保护肾系膜细胞免受索拉非尼诱导的细胞死亡的能力。所有化合物还被评估为可溶性环氧化物水解酶的抑制剂。正如强效泛激酶抑制剂所预期的那样，药物索拉非尼导致人肾系膜细胞（HRMCs）的细胞活力显著下降。几种用酰胺和草酰胺基团取代环氧化物的类似物在减少索拉非尼诱导的人肾系膜细胞（HRMC）死亡方面显示出疗效。含草酰胺的类似物被证明特别有效，最有前景的类似物在1µM时使细胞活力比对照提高了五倍。这些含有草酰胺基团作为8,9-EET中环氧化物生物电子等排体的类似物，对可溶性环氧化物水解酶没有显著的抑制活性。这种初步的构效关系分析表明，草酰胺基团是脂肪酸链8,9位环氧化物的一种有前景的生物电子等排体，对索拉非尼诱导的HRMC细胞死亡具有保护作用。总的来说，这些发现证明了使用环氧化物模拟物，特别是草酰胺作为8,9-EET类似物作为相应环氧化物的生物电子等排体，在对抗索拉非尼诱导的肾小球肾毒性的治疗策略中的潜力。
