The novel C-5 aryl, alkenyl, and alkynyl substituted uracil derivatives of L-ascorbic acid: synthesis, cytostatic, and antiviral activity evaluations

Bioorg Med Chem. 2007 Jan 15;15(2):749-58. doi: 10.1016/j.bmc.2006.10.046. Epub 2006 Oct 25.

Abstract

The novel C-5 substituted uracil derivatives of l-ascorbic acid were synthesized by coupling of 5-iodouracil-4,5-didehydro-5,6-dideoxy-l-ascorbic acid with unsaturated stannanes under Stille reaction conditions. The new compounds were evaluated for their antitumoral and antiviral activities. Among all compounds evaluated the 5-propynyl substituted uracil derivative of l-ascorbic acid (7) exhibited the most pronounced cytostatic activities against all examined tumor cell lines (IC(50): 0.2-0.78 microM). However, this compound was also cytotoxic to human normal fibroblasts WI 38. The 5-(phenylethynyl)uracil-2,3-di-O-benzylated l-ascorbic acid derivative (4) exhibited an albeit slight (IC(50): 55-108 microM), but selective inhibitory effect toward all tumor cell lines except for cervical carcinoma (HeLa), pancreatic carcinoma (MiaPaCa-2), laryngeal carcinoma (Hep-2), and colon carcinoma (SW 620), and no cytotoxicity to normal human fibroblast (WI 38). Compound 7 showed some, not highly specific, inhibitory potential against vesicular stomatitis virus, Coxsackie B4 virus, and Sindbis viruses (EC(50): 1.6 microM).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology*
  • Ascorbic Acid / analogs & derivatives*
  • Ascorbic Acid / chemical synthesis*
  • Ascorbic Acid / pharmacology
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical
  • Drug Screening Assays, Antitumor
  • Fibroblasts / drug effects
  • Humans
  • Indicators and Reagents
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Mice
  • Pyrimidines / chemistry
  • Structure-Activity Relationship
  • Uracil / chemistry*
  • Viruses / drug effects

Substances

  • Antineoplastic Agents
  • Antiviral Agents
  • Indicators and Reagents
  • Pyrimidines
  • Uracil
  • Ascorbic Acid