New Alkoxy- Analogues of Epoxyeicosatrienoic Acids Attenuate Cisplatin Nephrotoxicity In Vitro via Reduction of Mitochondrial Dysfunction, Oxidative Stress, Mitogen-Activated Protein Kinase Signaling, and Caspase Activation

Abstract

Application of cisplatin, a widely used and highly potent chemotherapeutic, is limited by its severe nephrotoxicity. Arachidonic acid (ARA)-derived epoxyeicosatrienoic acids (EETs), as well as soluble epoxide hydrolase (sEH) inhibitors, are promising therapeutics that can ameliorate this dose-limiting side effect, but both approaches have certain limitations. EET analogues are an alternative approach with distinct benefits, but the structural aspects of the current series of mimics have faced criticisms. Hence, in this study, regioisomer mixtures of four new ARA alkoxides were synthesized, characterized, and assessed as EET mimics against varying cisplatin doses and exposure durations in proximal tubular epithelial cells. All four ether groups displayed bioisostere activity, ranging from marginal for methoxy-, good for n-propoxy-, and excellent for ethoxy-and ipropoxy-. Cell protective potency of the ethoxy-and ipropoxymimics was comparable to that of EETs against high, acute exposures, but surpassed it against low to moderate, chronic exposures. The ethoxy-and ipropoxy-mimics exhibited their therapeutic effects through stabilization of the mitochondrial transmembrane potential and attenuation of reactive oxygen species generation, leading to reduced phosphorylation of mitogen-activated protein kinases p38 and JNK and decreased activation of caspase-9 and -3.The study elucidates linear ethers as potent and more metabolically stable bioisostere alternatives to the epoxide group within EETs, that concurrently enable ARA backbone preservation and sEH independent activity. It also illustrates the potential of alkoxy-mimics of EETs and other epoxy fatty acids to be promising nephroprotective agents to tackle the clinically relevant side effect of cisplatin.

Insect immune resolution with EpOME/DiHOME and its dysregulation by their analogs leading to pathogen hypersensitivity

“…Interestingly, A841 (= the methyl ester propoxy EpOME mimic) was the most potent among the eight alkoxides tested and even more potent than 12,13-EpOME itself. A similar screening of the oxylipin alkoxides using kidney cells was conducted to evaluate their role in protecting organs against reactive oxygen species during anticancer drug treatment using cisplatin [29]. The immunosuppressive activities of EpOMEs were evaluated using sEH inhibitors to upregulate the endogenous EpOME levels by blocking the conversion of EpOMEs to DiHOMEs.…”

“…were prepared as reported previously for the synthesis of urea-pharmacophore-based inhibitors of the sEH enzyme [30,42]. Four EpOME mimics (A839-A842) were generated via oxymercurationdemercuration, as previously described for the synthesis of arachidonic acid-derived epoxyeicosatrienoic acid (EET) mimics [29], using methyl LA with an appropriate alcohol as the solvent (methanol, ethanol, n-propanol or iso-propanol, respectively), followed by purification on silica gel to obtain the corresponding mono-alkoxide as a mixture of four regioisomers. The free acids (A843-A846) were obtained by basic hydrolysis of the corresponding methyl esters (A839-A842, respectively).…”

Inhibition of soluble epoxide hydrolase reduces paraquat neurotoxicity in rodents

“…To assess the efficacy of the sEH substrates on glial cell activation, 1 µM each of EETs (14,15-EET, 11,12-EET, 8,9-EET, or a 1:1:1 mixture ratio), all ±1 µM TPPU in 10% FBS DMEM with 0.1% sterile DMSO were applied to primary rat glial cells (DIV 10). EETs were synthesized and purified as recently discussed by Singh et al (Singh et al, 2021).…”