Novel 1,2,4-triazole and imidazole derivatives of L-ascorbic and imino-ascorbic acid: synthesis, anti-HCV and antitumor activity evaluations.

Abstract

Several novel 1,2,4-triazole and imidazole L-ascorbic acid (1, 2, 3, 5, 6 and 9) and imino-ascorbic acid (4, 7 and 8) derivatives were prepared and evaluated for their inhibitory activity against hepatitis C virus (HCV) replication and human tumour cell proliferation. Compounds 6 and 9 exerted the most pronounced cytostatic effects in all tumour cell lines tested, and were highly selective for human T-cell acute lymphoblastic leukaemia cells (CEM/0) with IC(50)s of 10 ± 4 and 7.3 ± 0.1 μM, respectively. Unlike compound 9, compound 6 showed no toxicity in human diploid fibroblasts. One of the possible mechanisms of action of compound 6 accounting for observed cytostatic activity towards haematological malignancies might be inhibition of inosine monophosphate dehydrogenase (IMPDH) activity, a key enzyme of de novo purine nucleotide biosynthesis providing the cells with precursors for DNA and RNA synthesis indispensable for cell growth and division, which has emerged as an important target for antileukemic therapy. In addition, this compound proved to be the most potent inhibitor of the hepatitis C virus replication as well. However, observed antiviral effect was most likely associated with the effect that the compound exerted on the host cell rather than with selective effect on the replication of the virus itself. In conclusion, results of this study put forward compound 6 as a potential novel antitumor agent (IMPDH inhibitor) for treating leukaemia. Its significant biological activity and low toxicity in human diploid fibroblasts encourage further development of this compound as a lead.

• Authors: Karlo Wittine, Maja Stipković Babić, Damjan Makuc, Janez Plavec, Sandra Kraljević Pavelić, Mirela Sedić, Krešimir Pavelić, Pieter Leyssen, Johan Neyts, Jan Balzarini, Mladen Mintas
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 11 Pg. 3675-85 (Jun 01 2012) ISSN: 1464-3391 [Electronic] England
• PMID: 22555152 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Antiviral Agents
• Imidazoles
• Triazoles
• 1,2,4-triazole
• IMP Dehydrogenase
• Ascorbic Acid

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Antiviral Agents (chemical synthesis, chemistry, pharmacology)
• Ascorbic Acid (analogs & derivatives, chemistry)
• Cell Line, Tumor
• Dogs
• Drug Evaluation, Preclinical
• Drug Screening Assays, Antitumor
• Fibroblasts (drug effects)
• Hepacivirus (drug effects, physiology)
• Humans
• IMP Dehydrogenase (antagonists & inhibitors)
• Imidazoles (chemistry, pharmacology)
• Magnetic Resonance Spectroscopy
• Molecular Structure
• Triazoles (chemistry)
• Virus Replication (drug effects)