New Neplanocin Analogues. 1. Synthesis of 6'-modified Neplanocin A Derivatives as Broad-Spectrum Antiviral Agents

J Med Chem. 1992 Jan 24;35(2):324-31. doi: 10.1021/jm00080a018.

Abstract

Novel neplanocin A analogues modified at the 6'-position, i.e., 6'-deoxy analogues (2, 3, 6, 9, 20), 6'-O-methylneplanocin A (15), and 6'-C-methylneplanocin A's (22a and 22b) have been synthesized and evaluated for their antiviral activity in a wide variety of DNA and RNA virus systems. These compounds showed an activity spectrum that conforms to that of S-adenosylhomocysteine hydrolase inhibitors. They were particularly active against pox- (vaccinia), paramyxo-(parainfluenza, measles, respiratory syncytial), arena- (Junin, Tacaribe), rhabdo- (vesicular stomatitis), reo-, and cytomegalovirus. In order of (increasing) antiviral activity, the compounds ranked as follows: 3 less than 15 approximately 20 less than 6 less than 9 approximately 2 less than 22a. Of the two diastereomeric forms of 22, only 22a was active; 22a surpassed neplanocin A both in antiviral potency and selectivity. Compound 22a appears to be a promising candidate drug for the treatment of pox-, paramyxo-, arena-, rhabdo-, reo-, and cytomegalovirus infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemical synthesis
  • Adenosine / pharmacology
  • Adenosylhomocysteinase
  • Animals
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • Cell Line
  • Erythrocytes / enzymology
  • Hydrolases / antagonists & inhibitors
  • Mice
  • Rabbits
  • Stereoisomerism
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • neplanocin A
  • Hydrolases
  • Adenosylhomocysteinase
  • Adenosine