Pyrazole-related nucleosides. Synthesis and antiviral/antitumor activity of some substituted pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides

J Med Chem. 1992 Mar 6;35(5):917-24. doi: 10.1021/jm00083a017.

Abstract

Several pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one ribonucleosides were prepared and tested for antiviral/antitumor activities. Appropriate heterocyclic bases were prepared by standard methodologies. Glycosylation of pyrazoles 6a-e,g,i and of pyrazolo[4,3-d]-1,2,3-triazin-4-ones 12f-1 mediated by silylation with hexamethyldisilazane, with 1-beta-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose, gave in good yields the corresponding glycosides 7a-e,g, 8g,i, 13f,h,k, and 14f, but could not be applied to compounds 12g,i,j,l. To overcome this occurrence, a different strategy involving the preparation, diazotization, and in situ cyclization of opportune pyrazole glycosides 9 and 10 was required. Moreover derivatives having the general formula 5 were considered not only as synthetic intermediates in the synthesis of 3 but also as carbon bioisosteres of ribavirin 4. All compounds were evaluated in vitro for cytostatic and antiviral activity. The pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides that resulted were substantially devoid of any activity; only 15h,k showed a moderate cytostatic activity against T-cells. However, pyrazole nucleosides 9b,c,e were potent and selective cytotoxic agents against T-lymphocytes, whereas 9e showed a selective, although not very potent, activity against coxsackie B1.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • B-Lymphocytes / drug effects
  • Cell Division / drug effects
  • Cyclization
  • Enterovirus / drug effects
  • Glycosylation
  • HIV-1 / drug effects
  • Humans
  • Leukemia L1210 / pathology
  • Mice
  • Molecular Structure
  • Nucleosides / chemical synthesis*
  • Nucleosides / pharmacology
  • Organosilicon Compounds*
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacology
  • Silicon
  • Structure-Activity Relationship
  • T-Lymphocytes / drug effects
  • Tumor Cells, Cultured
  • Vero Cells

Substances

  • Antineoplastic Agents
  • Antiviral Agents
  • Nucleosides
  • Organosilicon Compounds
  • Pyrazoles
  • hexamethylsilazane
  • Silicon