KINETIC-ANALYSIS OF THE INTERACTION BETWEEN THE DIPHOSPHATE OF (S)-1-(3-HYDROXY-2-PHOSPHONYLMETHOXYPROPYL) CYTOSINE, DDCTP, AZTTP, AND FIAUTP WITH HUMAN DNA POLYMERASE-BETA AND POLYMERASE-GAMMA

The inhibitory effects of the diphosphate of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPCpp) toward human DNA polymerases beta and gamma were studied. The K-i values of HPMPCpp were compared with the K-i, values of the triphosphates of 5'-azidothymidine (AZTTP), 2',3'-dideoxycytidine (ddCTP) and 5-iodo-2'-fluoroarabinosyluridine (FIAUTP). The K-i values toward DNA polymerase beta in increasing order were 1.32, 1.43, 140, and 520 mu M for ddCTP, FIAUTP, AZTTP and HPMPCpp, respectively. The K-i values toward DNA polymerase gamma in increasing order were 0.034, 0.031, 18.3 and 299 mu M for ddCTP, FIAUTP, AZTTP and HPMPCpp, respectively. Therefore, HPMPC would be expected to have less inhibitory effects on DNA repair (DNA polymerase beta) and mitochondrial DNA synthesis (DNA polymerase gamma) than ddC, FIAU or AZT.