The Antioxidant and Antiproliferative Activities of 1,2,3-Triazolyl-L-Ascorbic Acid Derivatives

Abstract

The novel 4-substituted 1,2,3-triazole L-ascorbic acid (L-ASA) conjugates with hydroxyethylene spacer as well as their conformationally restricted 4,5-unsaturated analogues were synthesized as potential antioxidant and antiproliferative agents. An evaluation of the antioxidant activity of novel compounds showed that the majority of the 4,5-unsaturated L-ASA derivatives showed a better antioxidant activity compared to their saturated counterparts. <i>m</i>-Hydroxyphenyl (<b>7j</b>), <i>p</i>-pentylphenyl (<b>7k</b>) and 2-hydroxyethyl (<b>7q</b>) substituted 4,5-unsaturated 1,2,3-triazole L-ASA derivatives exhibited very efficient and rapid (within 5 min) 2,2-diphenyl-1-picrylhydrazyl (DPPH^•) radical scavenging activity (<b>7j</b>, <b>7k</b>: IC₅₀ = 0.06 mM; <b>7q</b>: IC₅₀ = 0.07 mM). In vitro scavenging activity data were supported by in silico quantum-chemical modelling. Thermodynamic parameters for hydrogen-atom transfer and electron-transfer radical scavenging pathways of anions deprotonated at C2-OH or C3-OH groups of L-ASA fragments were calculated. The structure activity analysis (SAR) through principal component analysis indicated radical scavenging activity by the participation of OH group with favorable reaction parameters: the C3-OH group of saturated C4-C5(OH) derivatives and the C2-OH group of their unsaturated C4=C5 analogues. The antiproliferative evaluation showed that <i>p-</i>bromophenyl (<b>4e</b>: IC₅₀ = 6.72 μM) and <i>p-</i>pentylphenyl-substituted 1,2,3-triazole L-ASA conjugate (<b>4k</b>: IC₅₀ = 26.91 μM) had a selective cytotoxic effect on breast adenocarcinoma MCF-7 cells. Moreover, compound <b>4e</b> did not inhibit the growth of foreskin fibroblasts (IC₅₀ > 100 μM). In MCF-7 cells treated with <b>4e</b>, a significant increase of hydroxylated hypoxia-inducible transcription factor 1 alpha (HIF-1α) expression and decreased expression of nitric oxide synthase 2 (NOS2) were observed, suggesting the involvement of <b>4e</b> in the HIF-1α signaling pathway for its strong growth-inhibition effect on MCF-7 cells.