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 alpha or for human DNA polymerase beta. 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.
Fraley
Andrew W
AW
Department of Chemistry, Boston College, 2609 Beacon Street, Chestnut Hill, Massachusetts 02467-3801, USA.
Chen
Dongli
D
Johnson
Kenneth
K
McLaughlin
Larry W
LW
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002417:Cattle; D004247:DNA / Q000378:metabolism; D006678:HIV / Q000187:drug effects / Q000201:enzymology*; D009705:Nucleosides / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D019380:Anti-HIV Agents; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; C473048:dd2APy; D004247:DNA