Novel 1,2,4-triazole and Purine Acyclic Cyclopropane Nucleoside Analogues: Synthesis, Antiviral and Cytostatic Activity Evaluations

Background: Several published studies indicate that the acyclic guanine nucleoside analogues possessing bis(1,2-hydroxymethyl) substituted cyclopropane rings mimicking the sugar moiety are potent inhibitors of replication of several herpes viruses. Methods: Established synthetic methods and antivira...

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Veröffentlicht in:Antiviral chemistry & chemotherapy 2011-08, Vol.21 (6), p.221-230
Hauptverfasser: Benci, Krešimir, Suhina, Tomislav, Mandić, Leo, Pavelić, Sandra Kraljević, Paravić, Andrea Tomljenović, Pavelić, Krešimir, Balzarini, Jan, Wittine, Karlo, Mintas, Mladen
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Sprache:eng
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Zusammenfassung:Background: Several published studies indicate that the acyclic guanine nucleoside analogues possessing bis(1,2-hydroxymethyl) substituted cyclopropane rings mimicking the sugar moiety are potent inhibitors of replication of several herpes viruses. Methods: Established synthetic methods and antiviral and cytostatic activity assays were used for the evaluation of new 1,2,4-triazole and purine acyclic nucleoside analogues. Results: The synthesis of new types of acyclic nucleoside analogues which incorporate 1,2,4-triazole or purine moiety bound via flexible methylenic spacer to the bis(1,2-hydroxymethyl) cyclopropane ring. None of the new compounds showed pronounced antiviral activities at subtoxic concentrations on a broad panel of DNA and RNA viruses. Evaluation of their affinity for herpes simplex type 1 (HSV-1) and varicella-zoster virus-encoded thymidine kinases (VZV TK) also showed that none of the compounds was able to significantly inhibit 1 μM deoxythymidine phosphorylation by HSV-1 and VZV TK at 500 μM concentrations. The in vitro cytostatic activity evaluation results indicated a weak antiproliferative activity for all tested compounds. Only 6-pyrrolylpurine derivative bearing a carboxylic group substituted cyclopropane ring produced a rather slight inhibitory effect at higher micromolar concentrations on a breast carcinoma cell line (MCF-7) and no cytotoxic effect on human normal fibroblasts (WI 38). Conclusions: The lack of antiherpetic activity may be due to poor, if any, recognition of the compounds by virus-induced nucleoside kinases as an alternative substrate to become metabolically activated.
ISSN:2040-2066
0956-3202
2040-2066
DOI:10.3851/IMP1762