2',3'-dideoxynucleoside 5'-beta, gamma-(difluoromethylene) triphosphates with alpha-P-thio or alpha-P-seleno modifications: synthesis and their inhibition of HIV-1 reverse transcriptase

Abstract

Nucleoside reverse transcriptase inhibitors (NRTIs) are prodrugs which require three intracellular phosphorylation steps to yield their corresponding, biologically active, nucleoside triphosphate. In order to circumvent this often inefficient phosphorylation cascade, a plausible approach is to provide the active species directly in the form of a stabilized nucleoside triphosphate mimic. We have previously shown that such a mimic, namely 5'-alpha-Rp-borano-beta,gamma-(difluoromethylene)triphosphate (5'-alphaBCF2TP) is a generic triphosphate mimic that is biologically stable and can render antiviral ddNs with potent inhibitory activity against HIV-1 RT. Herein we report the synthesis and activity against HIV-1 RT of several ddN 5'-alpha-modified-beta,gamma(difluoromethylene)triphosphate mimics with either a non-bridging calphaP-thio (5'-alphaSCF2TP) or alpha-P-seleno (5'-alpha SeCF2TP) modification. One compound, namely, AZT-5'-alpha-P-seleno-beta,gamma-(difluoromethylene)triphosphate (diastereomer I), was identified as a potent inhibitor of HIV-1 RT (Ki = 64 nM) and represents the first report of HIV-1 RT inhibition data for a nucleotide bearing an alpha-P-seleno modification. These triphosphate mimics may be useful in the investigation of enzyme mechanism and may have interesting properties with respect to drug resistance and polymerase selectivity.