Chemo-enzymatic synthesis of a new type of enantiomerically pure carbocyclic nucleoside analogues with strong inhibitory effects on terminal deoxynucleotidyl transferase.
The synthesis of enantiomerically pure carbocyclic adenosine derivatives which have been prepared based on the kinetic resolution of a trans-2-(hydroxymethyl)cyclopentanol derivative is described. Their corresponding triphosphates were evaluated as inhibitors of DNA polymerase beta, terminal deoxynucleotidyl transferase (TdT), telomerase, Escherichia coli DNA polymerase I and reverse transcriptase of human immunodeficiency virus. Surprisingly, the triphosphate of (1S,2R)-1-(6-aminopurin-9-yl)-2-(hydroxymethyl)cyclopentane [(1S,2R)-6] and its enantiomer (1R,2S)-6 emerged as strong inhibitors of TdT (Ki = 0.5 and 1.9 mM, Kmapp dATP = 40 mM), whereas the activities of all other enzymes tested proved to be unaffected.
Theil
F
F
Institut für Angewandte Chemie Berlin-Adlershof, Germany. theil@liverpool.ac.uk
Ballschuh
S
S
Flatau
S
S
von Janta-Lipinski
M
M
Matthes
E
E
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016956:Burkholderia cepacia / Q000201:enzymology; D002417:Cattle; D004253:DNA Nucleotidylexotransferase / Q000037:antagonists & inhibitors*; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D006801:Humans; D007700:Kinetics; D008049:Lipase; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors
C114363:1-(6-aminopurin-9-yl)-2-(hydroxymethyl)cyclopentane triphosphate; D004791:Enzyme Inhibitors; D018894:Reverse Transcriptase Inhibitors; D004253:DNA Nucleotidylexotransferase; D054303:HIV Reverse Transcriptase; D019098:Telomerase; D004256:DNA Polymerase I; D019951:DNA Polymerase beta; D008049:Lipase; D000241:Adenosine