Chemo-enzymatic synthesis of a new type of enantiomerically pure carbocyclic nucleoside analogues with strong inhibitory effects on terminal deoxynucleotidyl transferase

Abstract 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 β, terminal deoxynucleotidyl transferase (TdT), telomerase, Escherichia coli DNA polymerase I and reverse transcriptase of human immunodeficiency virus. Surprisingly, the triphosphate of (1 S ,2 R )-1-(6-aminopurin-9-yl)-2-(hydroxymethyl)cyclopentane [(1 S ,2 R )- 6 ] and its enantiomer (1 R ,2 S )- 6 emerged as strong inhibitors of TdT ( K i =0.5 and 1.9 mM, K mapp dATP=40 mM), whereas the activities of all other enzymes tested proved to be unaffected.