Synthetic Epoxyeicosatrienoic Acid Mimics Protect Mesangial Cells from Sorafenib-Induced Cell Death.

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.