| Autor: |
Harej A; Centre for High-throughput Technologies, Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia. aharej@biotech.uniri.hr., Macan AM; Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, 10000 Zagreb, Croatia. amescic@fkit.hr., Stepanić V; Division of Electronics, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia. Visnja.Stepanic@irb.hr., Klobučar M; Centre for High-throughput Technologies, Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia. mklobucar@biotech.uniri.hr., Pavelić K; Faculty of medicine, Juraj Dobrila University of Pula, Zagrebačka 30, 52100 Pula, Croatia. kresimir.pavelic@unipu.hr., Pavelić SK; Centre for High-throughput Technologies, Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia. sandrakp@biotech.uniri.hr., Raić-Malić S; Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, 10000 Zagreb, Croatia. sraic@fkit.hr. |
| Abstrakt: |
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 : IC 50 = 0.06 mM; 7q : IC 50 = 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 : IC 50 = 6.72 μM) and p- pentylphenyl-substituted 1,2,3-triazole L-ASA conjugate ( 4k : IC 50 = 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 (IC 50 > 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. |
