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

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.

• Authors: Andrijana Meščić Macan, Anja Harej, Ines Cazin, Marko Klobučar, Višnja Stepanić, Krešimir Pavelić, Sandra Kraljević Pavelić, Dominique Schols, Robert Snoeck, Graciela Andrei, Silvana Raić-Malić
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 184 Pg. 111739 (Dec 15 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 31586832 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Antiviral Agents
• Triazoles
• Ascorbic Acid

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Antiviral Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Ascorbic Acid (chemical synthesis, chemistry, pharmacology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Microbial Sensitivity Tests
• Molecular Structure
• Structure-Activity Relationship
• Triazoles (chemical synthesis, chemistry, pharmacology)
• Viruses (drug effects)