Dinucleotide analogues as inhibitors of thymidine kinase, thymidylate kinase, and ribonucleotide reductase.
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).
Davies
L C
LC
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, England.
Stock
J A
JA
Barrie
S E
SE
Orr
R M
RM
Harrap
K R
KR
D000227:Adenine Nucleotides; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D015226:Dinucleoside Phosphates; D007939:Leukemia L1210 / Q000201:enzymology; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology*; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013942:Thymine Nucleotides
D000227:Adenine Nucleotides; D015226:Dinucleoside Phosphates; D009841:Oligonucleotides; D013942:Thymine Nucleotides; D000255:Adenosine Triphosphate; D012264:Ribonucleotide Reductases; D010770:Phosphotransferases; D013937:Thymidine Kinase; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D013936:Thymidine