The antioxidant and antiproliferative activities of 1, 2, 3-triazolyl-L-ascorbic acid derivatives

Harej, Anja; Meščić Macan, Andrijana; Stepanić, Višnja; Klobučar, Marko; Pavelić, Krešimir; Kraljević Pavelić, Sandra; Raić-Malić, Silvana (2019) The antioxidant and antiproliferative activities of 1, 2, 3-triazolyl-L-ascorbic acid derivatives. International Journal of Molecular Sciences, 20 (19). ISSN 1661-6596

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Official URL: https://www.mdpi.com/1422-0067/20/19/4735

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.

Item Type:

Article

Uncontrolled Keywords:

vitamin C ; 1, 2, 3-triazole ; antioxidant ; quantum-chemical modelling ; antitumor ; HIF-1

Subjects:

NATURAL SCIENCES > Chemistry

Divisions:

Division of Electronics

Projects:

Project title	Project leader	Project code	Project type
Novi spojevi temeljeni na bioizosterima purina za ispitivanje njihovih antitumorskih i antipatogenih djelovanja-PurBioCaPa	Silvana Raić-Malić	IP-2018-01-4682	HRZZ
UNSPECIFIED	UNSPECIFIED	uniri-biomed-18-133	UNSPECIFIED
BioProspecting Jadranskog mora-BioProspecting Jadranskog mora	Rozelinda Čož-Rakovac	KK.01.1.1.01.0002	EK