5'-deoxy-5'-methylthioadenosine phosphorylase--IV. Biological activity of 2-fluoroadenine-substituted 5'-deoxy-5'-methylthioadenosine analogs

Biochem Pharmacol. 1987 Jun 15;36(12):1881-93. doi: 10.1016/0006-2952(87)90484-9.


5'-Deoxy-5'-methylthioadenosine phosphorylase (MTAPase) phosphorolyzes 5'-deoxy-5'-methylthioadenosine (MTA) generated during polyamine biosynthesis to adenine and 5-methylthioribose-1-phosphate. Two doubly-substituted, 2-fluoroadenine-containing analogs of MTA, 5'-deoxy-2-fluoroadenosine (5'-dFAdo) and 5'-deoxy-5'-iodo-2-fluoroadenosine (5'-IFAdo), were synthesized and studied as substrates of MTAPase: their reaction with this enzyme resulted in the liberation of the cytotoxic base, 2-fluoroadenine, as well as potentially cytotoxic analogs of 5-methylribose-1-phosphate. The activities of these MTA analogs were compared to that of the singly-substituted analog, 5'-deoxy-5'-methylthio-2-fluoroadenosine (5'-MTFAdo). The cytotoxic action of these MTA analogs depended primarily on their conversion to 2-fluoroadenine-containing nucleotides, as a cell line that contains both MTAPase and adenine phosphoribosyltransferase (APRT) activity (HL-60 human promyelocytic leukemia) readily converted these MTA analogs to 2-fluoroadenine-containing nucleotides (especially 2-fluoroadenosine triphosphate) and was highly sensitive to the growth-inhibitory effects of all three compounds (IC50 values in the 10(-8) M range), whereas cell lines lacking MTAPase (CCRF-CEM human T-cell leukemia) or APRT (HL-60/aprt1 cells) did not form analog nucleotides and were relatively insensitive to these compounds (IC50 values in the 10(-5) M range). The doubly-substituted analogs were not more growth inhibitory than 5'-MTFAdo in wild type HL-60 cells as the potent effects of 2-fluoroadenine may mask the activity of the 5-methylthioribose-1-phosphate analogs generated in the reaction of these compounds with MTAPase. 5'-dFAdo and 5'-IFAdo also were irreversible inhibitors of S-adenosylhomocysteine hydrolase, which may explain in part the weak but observable growth inhibitory action of these compounds against MTAPase-deficient cell lines.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenine Phosphoribosyltransferase / metabolism
  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Adenosine / therapeutic use
  • Cell Line
  • Chemical Phenomena
  • Chemistry
  • Chromatography, High Pressure Liquid
  • Deoxyadenosines / analogs & derivatives
  • Deoxyadenosines / metabolism
  • Deoxyadenosines / therapeutic use
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / enzymology
  • Pentosyltransferases / metabolism*
  • Purine-Nucleoside Phosphorylase / metabolism*
  • Structure-Activity Relationship
  • Thionucleosides / metabolism*
  • Thionucleosides / therapeutic use


  • Deoxyadenosines
  • Thionucleosides
  • 5'-methylthioadenosine
  • 2'-fluoro-2'-deoxyadenosine
  • Pentosyltransferases
  • Purine-Nucleoside Phosphorylase
  • 5'-methylthioadenosine phosphorylase
  • Adenine Phosphoribosyltransferase
  • Adenosine