Synthesis, DFT Calculations, and In Vitro Antioxidant Study on Novel Carba-Analogs of Vitamin E

Abstract

Vitamin E is the most active natural lipophilic antioxidant with a broad spectrum of biological activity. α-Tocopherol (α-T), the main representative of the vitamin E family, is a strong inhibitor of lipid peroxidation as a chain-breaking antioxidant. Antioxidant and antiradical properties of vitamin E result from the presence of a phenolic hydroxyl group at the C-6 position. Due to stereoelectronic effects in the dihydropyranyl ring, the dissociation enthalpy for phenolic O–H bond (BDEOH) is reduced. The high chain-breaking reactivity of α-T is mainly attributed to orbital overlapping of the 2p-type lone pair on the oxygen atom (O1) in para position to the phenolic group, and the aromatic π-electron system. The influence of the O1 atom on the antioxidant activity of vitamin E was estimated quantitatively. The all-rac-1-carba-α-tocopherol was synthesized for the first time. Along with model compounds, 1-carba-analog of Trolox and its methyl ester were screened for their in vitro antioxidant activity by inhibition of styrene oxidation, and for the radical-reducing properties by means of 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH) scavenging assay. To study the antioxidant activity, density functional theory (DFT) was also applied. Reaction enthalpies related to HAT (hydrogen atom transfer), SET–PT (sequential electron transfer—proton transfer), and SPLET (sequential proton loss—electron transfer) mechanisms were calculated.

Phase Transitions and Structural Changes in DPPC Liposomes Induced by a 1-Carba-Alpha-Tocopherol Analogue

“…For the CT sample, after 15 min of incubation, the absorbance value decreased compared to the control sample, but its activity was much less effective than that observed for the original α-T sample. A similar observation for the carba analogues of Trolox was reported in our previous studies [ 8 ]. For both α-T and CT, longer incubation did not significantly affect the absorbance value.…”

“…Regarding potential applications of this CT analogue, it has been shown that its antioxidant properties are much less effective as a scavenging agent and much less effective as an antioxidant than its parent compounds [ 8 ]. Biological activity is related to transport across membranes, which depends on many factors, including fluidity or surface charge [ 52 ].…”

“…However, among them, the most interesting seems to be a new molecule of 1-carba-α-tocopherol (CT) since, in this molecule, the heterocyclic oxygen O1 present in chromanol ring of α-tocopherol (α-T) was replaced with a methylene group. This modification changed the electronic effects in the chroman-6-ol system (important for antioxidant function), which has recently been recognized quantitatively [ 8 ]. The obtained results of calculating the concentration required causing 50% of maximum effect (EC 50 ), the antioxidant activity toward peroxyl radicals (ROO·), and the ability of the studied compounds to reduce the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical using EPR spectroscopy confirmed that 1-carba analogues are much less effective scavenging agents than the parent chroman-6-ols.…”

“…However, it has been confirmed that the head groups and attached moieties also influence the membrane phase behavior [ 1 ]. Thus, taking into account already presented results [ 8 ] and possible interactions of modified chromanol ring with fatty-acid chains, we applied fluorescent probes embedded in a 1,2-dipalmitoyl- sn -glycero-3-phosphocholine (DPPC) liposome as reporters of changes in the biophysical properties of the membrane [ 12 , 13 , 14 ].…”

Tannic Acid as a Natural Ferroptosis Inhibitor: Mechanisms and Beneficial Role of 3’‐O‐Galloylation

“…Figure S2 and Table 1, the two gallotannins efficiently trap PTIO . , suggesting that there is an electron transfer (ET) plus proton transfer (PT) [41–43] . Fer‐1 was not evaluated for its insolubility (Table 1).…”