Dinucleotide analogues as inhibitors of thymidine kinase, thymidylate kinase, and ribonucleotide reductase

J Med Chem. 1988 Jul;31(7):1305-8. doi: 10.1021/jm00402a008.

Abstract

P1-(Adenosine-5')-Pn-(thymidine-5') tri-, tetra-, penta-, and hexaphosphates (ApnT) plus the analogues with a methylene group alpha, beta to the thymidine residue (ApncpT) were synthesized by coupling the appropriate two nucleotides, having activated one by morpholine. These were tested as potential dinucleotide inhibitors of thymidine kinase, thymidylate kinase, and ribonucleotide reductase. All three enzymes bind ATP and thymidine or its nucleotides and therefore might be inhibited by dinucleotides containing adenosine and thymidine. Ap5T and Ap6T strongly inhibited all three enzymes (IC50 = 2.4-20 microM). Ap4cpT and Ap5cpT also strongly inhibited the two kinases (IC50 = 4-20 microM) but were much weaker inhibitors of the reductase (IC50 = 130 and 230 microM).

Publication types

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

MeSH terms

  • Adenine Nucleotides
  • Adenosine Triphosphate / metabolism
  • Animals
  • Chemical Phenomena
  • Chemistry
  • Dinucleoside Phosphates
  • Leukemia L1210 / enzymology
  • Nucleoside-Phosphate Kinase / antagonists & inhibitors*
  • Nucleoside-Phosphate Kinase / metabolism
  • Oligonucleotides / pharmacology*
  • Phosphotransferases / antagonists & inhibitors*
  • Ribonucleotide Reductases / antagonists & inhibitors*
  • Ribonucleotide Reductases / metabolism
  • Structure-Activity Relationship
  • Thymidine / metabolism
  • Thymidine Kinase / antagonists & inhibitors*
  • Thymidine Kinase / metabolism
  • Thymine Nucleotides

Substances

  • Adenine Nucleotides
  • Dinucleoside Phosphates
  • Oligonucleotides
  • Thymine Nucleotides
  • Adenosine Triphosphate
  • Ribonucleotide Reductases
  • Phosphotransferases
  • Thymidine Kinase
  • Nucleoside-Phosphate Kinase
  • dTMP kinase
  • Thymidine