An HIV Reverse Transcriptase-Selective Nucleoside Chain Terminator

The synthesis of a 2‘,3‘-dideoxynucleoside cytidine analogue, but one that lacks the O2-carbonyl, is described from 2-aminopyridine in an overall yield of 60%. The synthesis of the 2-pyridone C-nucleoside relies upon the use of a Heck-type coupling between an appropriately protected sugar glycal and the 5-iodo derivative of 2-aminopyridone. Upon conversion of the dideoxynucleoside to the corresponding 5‘-triphosphate, the analogue ddNTP is observed to be a reasonable substrate with HIV reverse transcriptase (for a template dG residue), but is not a substrate for calf thymus DNA polymerase α or for human DNA polymerase β. With the human mitochondrial DNA polymerase the analogue functions as a poor substrate. The observed polymerase selectivities appear to arise from the absence of the O2-carbonyl, which either results in a destabilized Watson−Crick base pair or represents a critical contact for some polymerases.