Mimicking the lipid peroxidation inhibitory activity of phospholipid hydroperoxide glutathione peroxidase (GPx4) by using fatty acid conjugates of a water-soluble selenolane.

A series of fatty acid conjugates of trans-3,4-dihydroxy-1-selenolane (DHS) were synthesized by reacting DHS with appropriate acid chlorides. The obtained monoesters were evaluated for their antioxidant capacities by the lipid peroxidation assay using a lecithin/cholesterol liposome as a model system. The observed antioxidant capacities against accumulation of the lipid hydroperoxide (LOOH) increased with increasing the alkyl chain length and became saturated for dodecanoic acid (C12) or higher fatty acid monoesters, for which the capacities were much greater than those of DHS, its tridecanoic acid (C13) diester, and PhSeSePh. On the other hand, the bacteriostatic activity of myristic acid (C14) monoester, evaluated through the colony formation assay using Bacillus subtilis, indicated that it has higher affinity to bacterial cell membranes than parent DHS. Since DHS-fatty acid conjugates would inhibit lipid peroxidation through glutathione peroxidase (GPx)-like 2e- mechanism, higher fatty acid monoesters of DHS can mimic the function of GPx4, which interacts with LOOH to reduce it to harmless alcohol (LOH). Importance of the balance between hydrophilicity and lipophilicity for the design of effective GPx4 mimics was suggested.

Fatty acid conjugates of water-soluble (±)-trans-Selenolane-3,4-diol: effects of alkyl chain length on the antioxidant capacity.

Fatty acid monoesters of the title compound (DHS(red) ), of variable carbon chain length (propionate, laurate, myristate, palmitate, and stearate), were synthesized, and their antioxidant capacities were evaluated by means of a lipid peroxidation assay with lecithin/cholesterol liposomes. The selenides with long alkyl chains exhibited significant antioxidant activity (IC50 =9-34 µM) against accumulation of lipid hydroperoxide. Incorporation of the myristate into the liposome was ≈50 % by EPMA analysis. Intermediacy of the selenoxide was examined by NMR. In addition, enhancement of interfacial redox catalytic activity was observed for the myristate, but not for PhSeSePh and edaravone, in a PhCl/H2 O biphasic peroxidation assay. These results suggested that a combination of a hydrophilic selenide moiety as a redox center with a long alkyl chain is an effective approach to selenium antioxidants with interfacial glutathione-peroxidase-like (GPx-like) activity. The activity can be controlled by the alkyl chain length.