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Article

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

1
Centre for High-throughput Technologies, Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia
2
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, 10000 Zagreb, Croatia
3
Division of Electronics, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia
4
Faculty of medicine, Juraj Dobrila University of Pula, Zagrebačka 30, 52100 Pula, Croatia
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(19), 4735; https://doi.org/10.3390/ijms20194735
Received: 30 August 2019 / Revised: 17 September 2019 / Accepted: 19 September 2019 / Published: 24 September 2019
(This article belongs to the Special Issue Modulation of Oxidative Stress: Molecular and Pharmacological Aspects)
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. View Full-Text
Keywords: vitamin C; 1,2,3-triazole; antioxidant; quantum-chemical modelling; antitumor; HIF-1 vitamin C; 1,2,3-triazole; antioxidant; quantum-chemical modelling; antitumor; HIF-1
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MDPI and ACS Style

Harej, A.; Macan, A.M.; Stepanić, V.; Klobučar, M.; Pavelić, K.; Pavelić, S.K.; Raić-Malić, S. The Antioxidant and Antiproliferative Activities of 1,2,3-Triazolyl-L-Ascorbic Acid Derivatives. Int. J. Mol. Sci. 2019, 20, 4735. https://doi.org/10.3390/ijms20194735

AMA Style

Harej A, Macan AM, Stepanić V, Klobučar M, Pavelić K, Pavelić SK, Raić-Malić S. The Antioxidant and Antiproliferative Activities of 1,2,3-Triazolyl-L-Ascorbic Acid Derivatives. International Journal of Molecular Sciences. 2019; 20(19):4735. https://doi.org/10.3390/ijms20194735

Chicago/Turabian Style

Harej, Anja, Andrijana M. Macan, Višnja Stepanić, Marko Klobučar, Krešimir Pavelić, Sandra K. Pavelić, and Silvana Raić-Malić. 2019. "The Antioxidant and Antiproliferative Activities of 1,2,3-Triazolyl-L-Ascorbic Acid Derivatives" International Journal of Molecular Sciences 20, no. 19: 4735. https://doi.org/10.3390/ijms20194735

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