Antioxidant and neutrophil-inhibiting properties of new 2-O-methyl-6-(alkylthio)ascorbic acid derivatives

Abstract

A series of new 6-(alkylthio)ascorbic acids was synthesized, and their inhibitory effects on lipid peroxidation and the oxidative burst of human neutrophils were tested. Of 12 structurally different lipophilic ascorbic acid derivatives 6-S-n-hexadecyl-2-O-methyl-6-deoxy-6-thio-L-ascorbic acid (7b; B-003) inhibited the Fe2+/ADP-induced lipid peroxidation of rat liver microsomes with an IC50 value of 2 microM. In human neutrophils, 7b most potently inhibited the fMLP-induced oxidative burst in a cell density-dependent manner with an IC50 value of 0.6 microM at 5 x 10(5) cells/mL. Shorter alkyl chain lengths decreased the inhibitory potency for both lipid peroxidation and oxidative burst, but in general no correlation was found between the two parameters. Likewise, 6-S-n-hexadecyl-3-O-methyl-6-thio-L-ascorbic acid (7c; B-015), the regioisomer of 7b, was a potent antioxidant but did not affect the oxidative burst. Since superoxide anions generated by xanthine/xanthine oxidase were not quenched by 7b, it became evident that its target was somewhere between receptor stimulation and NADPH-oxidase activation. By measuring the cellular concentrations of 7b and 7c, an accumulation of the first was found explaining its potency and the dependence on cell density. Expecting a pKa value of 3.3 for 7b and 7.7 for 7c a protonophore action of 7b was likely and could be verified by the drop in intracellular pH (pHi) which did not occur with 7c. Ionophores such as nigericin, CCCP, or propionic acid also lowered the pHi but did not inhibit the oxidative burst, indicating that the pHi drop was not the cause for this inhibition. 7b also strongly inhibited the fMLP-induced secretion of azurophilic (IC50 = 7 microM) and specific (IC50 = 2.5 microM) granules.

Antioxidant Properties of Novel Lipophilic Ascorbic Acid Analogues

“…The autooxidation of Fe 2 aADPaascorbate causes massive lipid peroxidation in liver microsomes, and this can be monitored by the generation of malondialdehyde. When investigating the effects of the new ascorbic acid derivatives (series 3 and 5) on lipid peroxidation, compound 5f was found to signi®cantly reduce malondialdehyde production with an IC50 value of 4Á85 6 10 À4 M. Similarly, Schmid et al (1993) reported the synthesis of 2-Omethyl-6-(alkylthio)ascorbic acid derivatives, one of which (6-S-n-hexadecylthio derivative) inhibited the Fe 2 aADPaascorbate-induced lipid peroxidation of rat liver microsomes with an IC50 value of 2 mM. The results of the lipid-peroxidation assay con®rm the good activity of compound 5f in the test for reducing activity of DPPH.…”

Synthesis and pharmacological evaluation of novel derivatives of anti-inflammatory drugs with increased antioxidant and anti-inflammatory activities

“…It is well documented that uncontrolled release of ROS during inflammation may lead to severe tissue damage. Hence, considerable interest is directed towards developing agents capable of blocking the destructive effect of reactive oxidants in inflammatory conditions [Schmid et al, 1993;Kettle et al, 1993]. Antioxidants, e.g., low molecular weight thiols, have been applied to diminish damage caused by oxidative stress; thus, they have been used as antidotes in conditions such as paracetamol-intoxication [Prescott et al, 1976;Kourounakis et al, 1997].…”

Microbial Transformation of Mesterolone

“…This protection is based on the production of oxidative bursts [9] at the site of microbial invasion, and the mechanisms of the site-directed killing of microorganisms and tumorous and virus-infected cells have been extensively studied [10]. On the other hand, the uncontrolled release of reactive oxygen species (ROS) is…”