Role of Sulphur and Heavier Chalcogens on the Antioxidant Power and Bioactivity of Natural Phenolic Compounds

Abstract

The activity of natural phenols is primarily associated to their antioxidant potential, but is ultimately expressed in a variety of biological effects. Molecular scaffold manipulation of this large variety of compounds is a currently pursued approach to boost or modulate their properties. Insertion of S/Se/Te containing substituents on phenols may increase/decrease their H-donor/acceptor ability by electronic and stereo-electronic effects related to the site of substitution and geometrical constrains. Oxygen to sulphur/selenium isosteric replacement in resveratrol or ferulic acid leads to an increase in the radical scavenging activity with respect to the parent phenol. Several chalcogen-substituted phenols inspired by Vitamin E and flavonoids have been prepared, which in some cases prove to be chain-breaking antioxidants, far better than the natural counterparts. Conjugation of catechols with biological thiols (cysteine, glutathione, dihydrolipoic acid) is easily achieved by addition to the corresponding ortho-quinones. Noticeable examples of compounds with potentiated antioxidant activities are the human metabolite 5-S-cysteinyldopa, with high iron-induced lipid peroxidation inhibitory activity, due to strong iron (III) binding, 5-S-glutathionylpiceatannol a most effective inhibitor of nitrosation processes, and 5-S-lipoylhydroxytyrosol, and its polysulfides that proved valuable oxidative-stress protective agents in various cellular models. Different methodologies have been used for evaluation of the antioxidant power of these compounds against the parent compounds. These include kinetics of inhibition of lipid peroxidation alkylperoxyl radicals, common chemical assays of radical scavenging, inhibition of the OH• mediated hydroxylation/oxidation of model systems, ferric- or copper-reducing power, scavenging of nitrosating species. In addition, computational methods allowed researchers to determine the Bond Dissociation Enthalpy values of the OH groups of chalcogen modified phenolics and predict the best performing derivative. Finally, the activity of Se and Te containing compounds as mimic of glutathione peroxidase has been evaluated, together with other biological activities including anticancer action and (neuro)protective effects in various cellular models. These and other achievements are discussed and rationalized to guide future development in the field.

Keywords: Bond Dissociation Energy; DFT calculations; S/Se/Te-substituted phenols; alkylperoxyl radicals; antioxidant chemical assays; dihydrolipoic acid; glutathione peroxidase-like activity; glutathionyl/cysteinylcatechols; kinetic constant; lipid peroxidation; thia/selenotocopherols.

Scheme 1

H-donation, electronic and intramolecular H-bond effects in substituted phenols (a–g).

Scheme 2

Stereo-electronic effects of chalcogen-containing substituents, in para (a) or ortho (b–d) positions, on the reactivity of phenols with free radicals (X•).

Scheme 3

Effect of the insertion of a selenium atom into the molecular scaffold of resveratrol on the BDE of the OH groups and on the rate constant of the reaction with ROO• radicals.

Figure 1

(A) Stereo-electronic effects of a hypothetical ortho-SCH₃ substituent on the BDE of a phenol. In red are shown the Ar-SMe dihedral angles. (B) Active site of the enzyme Galactose Oxidase, featuring a covalent Tyr-Cys linkage.

Figure 2

Resveratrol-related 4-mercaptostilbenes and their radical scavenging mechanisms.

Figure 3

Chemical structures of natural flavonoid (e.g., chrysin and quercetin) and their sulphur and selenium derivatives.

Scheme 4

Thiatocopherols, selenotocopherol and related antioxidants modified by insertion of sulphur.

Scheme 5

Ditocopherols featuring -S- and -S-S- functions, and representation of the possibilities for intramolecular H-bonding of sulfides (a–c) and difulfides (d).

Scheme 6

Se- and Te-containing antioxidants endowed with catalytic or additional mechanisms of antioxidant activity.

Figure 4

Schematic representation of shogaol conjugates formation (M2) and their ability to inhibit colony formation in human colon cancer cell (HCT-116) with doses ranging from 0 to 40 μM over 2 weeks.

Figure 5

Antioxidant activity of methyl caffeate, methyl dihydrocaffeate, myricetin or catechin with or without equimolar amounts of N-benzoylcysteine methyl ester against 2,2′-azobis (2,4-dimethylvaleronitrile)-induced lipid oxidation for 4 h.

Figure 6

Effect of 5-S-cysteinyldopa (CD) on: deoxyribose degradation and salicylic acid hydroxylation induced by the Fenton reagent; conjugated diene formation in the 2,2′-azobis (2-amidinopropane) (ABAP)-induced oxidation of linoleic acid and malondialdehyde formation from Fe²⁺-induced 15-HPETE degradation. For comparative purposes the effects of DOPA, ascorbic acid (AA) and GSH were examined at the same concentration.

Figure 7

Effect of polycysteinyldopamine (PCDA) or polydopamine (PDA) thin films on the autoxidation of GSH after 3 h incubation in phosphate buffer pH 7.4. The redox cycling mechanism supposedly involved in PCDA prooxidant properties toward GSH is also shown.

Figure 8

(A) Schematic overview of the flavan-3-ol thio-conjugates (1–3) formation by depolymerization of grape polymeric flavanols in the presence of cysteine, captopril or tiopronin under acidic conditions; (B) Free radical scavenging activity of the thio-conjugates in the DPPH• assay. The scavenging ability of Trolox, catechin and epicatechin is also reported for comparison.

Scheme 7

Schematic overview of the regiochemistry of thiol/ortho-quinone reactions.

Figure 9

Schematic overview of the glutathionyl adduct formation (A–C) and (D) effects of catechols and their glutathionyl conjugates on DAN nitrosation at pH 4.0 measured as fluorescence emission at 450 nm of naphtho [2,3-d]triazole.

Figure 10

Synthesis and evaluation of the antioxidant activity of 5-S-lipoylhydroxytyrosol and its derivatives with sulphide chain. Cytoprotective effects of Lipo-HT and HTy on Hg-induced oxidative alterations in red blood cells.