3-Deazaneplanocin: a new and potent inhibitor of S-adenosylhomocysteine hydrolase and its effects on human promyelocytic leukemia cell line HL-60

Biochem Biophys Res Commun. 1986 Mar 13;135(2):688-94. doi: 10.1016/0006-291x(86)90048-3.

Abstract

3-Deazaneplanocin, a new carbocyclic analog of adenosine, was synthesized as an inhibitor of S-adenosylhomocysteine hydrolase. The Ki of 3-deazaneplanocin for a purified hamster liver preparation of S-adenosylhomocysteine hydrolase was 5 X 10(-11) M, making this inhibitor 250-fold more potent than the previously known most potent inhibitor of this enzyme, 3-deazaaristeromycin. Inhibition was competitive with the substrate adenosine. Human promyelocytic leukemia (HL-60) cells treated with 10(-5) M 3-deazaneplanocin showed a pronounced elevation in S-adenosylhomocysteine which was 4-fold greater than that produced by an equimolar concentration of 3-deazaaristeromycim. This effect preceded a moderate reduction in cell growth and viability following continuous exposure for 6 days. Cellular differentiation as monitored by the reduction of nitroblue tetrazolium was not markedly affected except after 4 days exposure to 10(-5) M 3-deazaneplanocin where 60% of the viable cells were positive. These results indicate that 3-deazaneplanocin may have therapeutic potential as an anticancer or antiviral drug.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacology
  • Adenosylhomocysteinase
  • Animals
  • Cell Division / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Cricetinae
  • Humans
  • Hydrolases / antagonists & inhibitors*
  • Leukemia, Myeloid, Acute / enzymology*
  • Leukemia, Myeloid, Acute / pathology
  • Liver / enzymology

Substances

  • 3-deazaneplanocin
  • 3-deazaaristeromycin
  • neplanocin A
  • Hydrolases
  • Adenosylhomocysteinase
  • Adenosine