title: Novel 1,2,4-triazole and purine acyclic cyclopropane nucleoside analogues: synthesis, antiviral and cytostatic activity evaluations.
abstract: 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.
authors: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Zagreb, Croatia.
authors: Krešimir
authors: K
authors: Benci
authors: Tomislav
authors: T
authors: Suhina
authors: Leo
authors: L
authors: Mandić
authors: Sandra Kraljević
authors: SK
authors: Pavelić
authors: Andrea Tomljenović
authors: AT
authors: Paravić
authors: Krešimir
authors: K
authors: Pavelić
authors: Jan
authors: J
authors: Balzarini
authors: Karlo
authors: K
authors: Wittine
authors: Mladen
authors: M
authors: Mintas
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D054697:Cytostatic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004267:DNA Viruses / Q000187:drug effects; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000201:enzymology; D014645:Herpesvirus 3, Human / Q000201:enzymology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010766:Phosphorylation; D011684:Purine Nucleosides / Q000737:chemistry* / Q000494:pharmacology; D012328:RNA Viruses / Q000187:drug effects; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D054697:Cytostatic Agents; D004791:Enzyme Inhibitors; D011684:Purine Nucleosides; D014230:Triazoles; C045575:1,2,4-triazole; D013937:Thymidine Kinase; D013936:Thymidine