Phenolic peptides as antioxidant and anti-proliferative agents

Abstract

We report an efficient synthesis of phenolic peptides starting from 3,4-dihydroxyphenylacetic acid (DOPAC) and L-configured amino acid esters (glycine, phenylalanine, valine, serine, tryptophan, and cystine) using different coupling reagents. The combination of a phenolic scaffold with an amino acid residue might modulate the bioavailability and the therapeutic properties of title derivatives. Moreover, the incorporation of a catechol group, with inherent redox activity, can contribute to alter the redox status of the cancer cells, and therefore, provide anti-proliferative properties. Their activities as antioxidants (i.e. scavenging free radicals and H2O2 as well inhibition of lipid peroxidation) and as anti-proliferative agents against three human cervical carcinoma cell lines (HeLa, ViBo, and CaSki) and normal lymphocytes were evaluated. All compounds exhibited an excellent antioxidant activity; remarkably, the peptide derived from L-cystine exhibited the best antioxidant activity, displaying a 2.5-fold increase in radical-scavenging activity when compared with the natural 2-(3’,4’-dihydroxyphenyl)ethanol (hydroxytyrosol, HT). Moreover, this compound was also the most potent antitumor agent against the three human tumor cell lines (IC50 values 108-122 μM), with a 2-7-fold increase in activity when compared with natural DOPAC and HT, used as reference compounds. Importantly, the cytotoxic activity of these phenolic peptidomimetics against normal human lymphocytes was very low, hence confirming their selectivity towards tumor cells. Moreover, a disulfide-containing peptide also exhibited negligible cell necrosis and a high selectivity against tumor cells when compared to normal lymphocytes. Such derivative incorporates two fragments characterized with redox properties, the catechol moiety, and the disulfide linker. Thus, disulfide-containing phenolic peptidomimetics emerge as good lead candidates for the development of a novel family of anti-tumor agents.