Antitumor and antiviral activities of 4-substituted 1,2,3-triazolyl-2,3-dibenzyl-L-ascorbic acid derivatives

  • Eur J Med Chem. 2019 Dec 15:184:111739. doi: 10.1016/j.ejmech.2019.111739.
Andrijana Meščić Macan  1 ,  Anja Harej  2 ,  Ines Cazin  1 ,  Marko Klobučar  2 ,  Višnja Stepanić  3 ,  Krešimir Pavelić  4 ,  Sandra Kraljević Pavelić  2 ,  Dominique Schols  5 ,  Robert Snoeck  5 ,  Graciela Andrei  5 ,  Silvana Raić-Malić  6
Affiliations
  • 1. University of Zagreb, Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Marulićev Trg 20, HR-10000, Zagreb, Croatia.
  • 2. University of Rijeka, Department of Biotechnology, Centre for High-throughput Technologies Radmile Matejčić 2, HR-51000, Rijeka, Croatia.
  • 3. Ruđer Bošković Institute, Division of Molecular Medicine, Bijenička Cesta 54, 10 000, Zagreb, Croatia.
  • 4. Juraj Dobrila University of Pula, Zagrebačka 30, 52100, Pula, Croatia.
  • 5. Rega Institute for Medical Research, KU Leuven, Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, B-3000, Leuven, Belgium.
  • 6. University of Zagreb, Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Marulićev Trg 20, HR-10000, Zagreb, Croatia. Electronic address: [email protected].
PMID: 31586832 DOI: 10.1016/j.ejmech.2019.111739
Abstract

Two series of 6-(1,2,3-triazolyl)-2,3-dibenzyl-l-ascorbic acid derivatives with the hydroxyethylene (8a-8u) and ethylidene linkers (10c-10p) were synthesized and evaluated for their antiproliferative activity against seven malignant tumor cell lines and Antiviral activity against a broad range of viruses. Conformationally unrestricted spacer between the lactone and 1,2,3-triazole units in 8a-8u series had a profound effect on antitumor activity. Besides, the introduction of a long side chain at C-4 of 1,2,3-triazole that led to the synthesis of decyl-substituted 2,3-dibenzyl-l-ascorbic acid 8m accounted for a selective and potent antiproliferative activity on breast Cancer MCF-7 cells cells in the nM range. Further analysis showed that compound 8m strongly enhanced expression of hypoxia inducible transcription factor 1 α (HIF-1α) and to some extent decreased expression of nitric oxide synthase 2 (NOS2) suggesting its role in regulating HIF-1α signalling pathway. The p-methoxyphenyl-substituted derivative 10g displayed specific anti-cytomegalovirus (CMV) potential, whereas aliphatic-substituted derivatives 8l and 8m had the most potent, yet relatively non-specific, anti-varicella-zoster (VZV) activity.

Keywords
1,2,3-Triazole; Antitumoral; Antiviral activity; Butenolide; HIF-1; NOS2; Vitamin C.