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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. 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 ?M) and p-pentylphenyl-substituted 1,2,3-triazole L-ASA conjugate (4k: IC50 = 26.91 ?M) had a selective cytotoxic effect on breast adenocarcinoma MCF-7 cells. Moreover, compound 4e did not inhibit the growth of foreskin fibroblasts (IC50 > 100 ?M). In MCF-7 cells treated with 4e, a significant increase of hydroxylated hypoxia-inducible transcription factor 1 alpha (HIF-1?) expression and decreased expression of nitric oxide synthase 2 (NOS2) were observed, suggesting the involvement of 4e in the HIF-1? signaling pathway for its strong growth-inhibition effect on MCF-7 cells.

SUBMITTER: Harej A

PROVIDER: S-EPMC6801448 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Harej Anja A Macan Andrijana Meščić AM Stepanić Višnja V Klobučar Marko M Pavelić Krešimir K Pavelić Sandra Kraljević SK Raić-Malić Silvana S

International journal of molecular sciences 20190924 19

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-pent ...[more]

PMID: 31554245

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Project description:Reactive oxygen species (ROS) are constantly produced by metabolically active plant cells. The concentration of ROS may determine their role, e.g., they may participate in signal transduction or cause oxidative damage to various cellular components. To ensure cellular homeostasis and minimize the negative effects of excess ROS, plant cells have evolved a complex antioxidant system, which includes ascorbic acid (AsA). AsA is a multifunctional metabolite with strong reducing properties that allows the neutralization of ROS and the reduction of molecules oxidized by ROS in cooperation with glutathione in the Foyer-Halliwell-Asada cycle. Antioxidant enzymes involved in AsA oxidation and reduction switches evolved uniquely in plants. Most experiments concerning the role of AsA have been performed on herbaceous plants. In addition to extending our understanding of this role in additional taxa, fundamental knowledge of the complex life cycle stages of woody plants, including their development and response to environmental factors, will enhance their breeding and amend their protection. Thus, the role of AsA in woody plants compared to that in nonwoody plants is the focus of this paper. The role of AsA in woody plants has been studied for nearly 20 years. Studies have demonstrated that AsA is important for the growth and development of woody plants. Substantial changes in AsA levels, as well as reduction and oxidation switches, have been reported in various physiological processes and transitions described mainly in leaves, fruits, buds, and seeds. Evidently, AsA exhibits a dual role in the photoprotection of the photosynthetic apparatus in woody plants, which are the most important scavengers of ozone. AsA is associated with proper seed production and, thus, woody plant reproduction. Similarly, an important function of AsA is described under drought, salinity, temperature, light stress, and biotic stress. This report emphasizes the involvement of AsA in the ecological advantages, such as nutrition recycling due to leaf senescence, of trees and shrubs compared to nonwoody plants.

Dataset Information

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

Publications

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

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