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. m-Hydroxyphenyl (7j), p-pentylphenyl (7k) and 2-hydroxyethyl (7q) 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 (7j, 7k: IC50 = 0.06 mM; 7q: 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 p-bromophenyl (4e: IC50 = 6.72 μM) and p-pentylphenyl-substituted 1,2,3-triazole L-ASA conjugate (4k: IC50 = 26.91 μM) had a selective cytotoxic effect on breast adenocarcinoma MCF-7 cells. Moreover, compound 4e did not inhibit the growth of foreskin fibroblasts (IC50 > 100 μM). In MCF-7 cells treated with 4e, 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 4e in the HIF-1α signaling pathway for its strong growth-inhibition effect on MCF-7 cells.
Highlights
Biochemical processes in our body, including aerobic metabolism and inflammatory responses, as well as exposure to the environment, result in the generation of unstable and highly reactive free radicals, such as reactive oxygen (ROS) and nitrogen (RNS) species [1,2,3,4]
The C-6 substituted 1,2,3-triazole 4,5-unsaturated L-ascorbic acid (L-ASA) derivatives (7c−7g and 7i−7q) showed no antiproliferative effect on the tested cell panel at concentrations lower than 100 μM (Table S1, Supplementary Information), which implies that the linker connecting the lactone ring and the 1,2,3-triazole moiety has an influence on the antitumor activity of tested compounds, which is in accordance with the previously shown antitumor effects of 2,3-O,O-dibenzylated L-ASA derivatives [40]
An explanation of the observed differences in the DPPH radical scavenging activities of the L-ASA−triazole conjugates has been obtained using in silico analysis, which showed that the triazole conjugates have an analogous radical scavenging mechanism to L-ASA and that the most significant difference between saturated C4-C5(OH) and unsaturated C4=C5 derivatives is in acidity of C2-OH group
Summary
Biochemical processes in our body, including aerobic metabolism and inflammatory responses, as well as exposure to the environment, result in the generation of unstable and highly reactive free radicals, such as reactive oxygen (ROS) and nitrogen (RNS) species [1,2,3,4]. While L-ASA has an antioxidant property and protects the cell from damage caused by free radicals, when used in pharmacological (millimolar) concentrations achieved through intravenous administration L-ASA shows pro-oxidant activity [13,23,24,25]. Recent findings showed that high levels of vitamin C selectively kill colorectal cancer cells with KRAS and BRAF mutations by increasing ROS production, which blocks glucose metabolism and subsequently causes the energy crisis and cell death [27,28]. High-doses of vitamin C showed a cytotoxic effect on breast adenocarcinoma (MCF7) and colon cancer (HT29) cells by inducing metabolic changes, which caused insufficient ATP formation and cell death [29]. SScchheemmee 11..RReeaaggeenntstsanadndcocnodnidtiiotniosn: s(i:)(Ci)uC, 1u,M1cMoppceorp(IpIe) rs(uIIl)phsautleph(CauteSO(C4)u,StOer4t)-,butetratn-boul,tDanMoFl,, wDaMteFr,, awnadtear,maincdrowa amviecrroewacatovre; (rieia) c1toMr; b(oiir)o1n Mtricbholororindetr(iBchCllo3r)idane d(BdCryl3)daicnhdlodrorymedtihcahnloer;o(miiie)tchoapnpee; r((iIiIi)) accoeptpateer((ICI)ua(cOeAtact)e2)(Caun(dOmAect)h2)aannodl. methanol
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