title: 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.
authors.affiliation: Research Laboratories, Biota Inc., Carlsbad, California, USA. naboyle@hotmail.com
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Boyle
authors.forename: Patrick
authors.initials: P
authors.lastname: Fagan
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Brooks
authors.forename: Marija
authors.initials: M
authors.lastname: Prhavc
authors.forename: John
authors.initials: J
authors.lastname: Lambert
authors.forename: P Dan
authors.initials: PD
authors.lastname: Cook
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016566:Organoselenium Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D016566:Organoselenium Compounds; D018894:Reverse Transcriptase Inhibitors; D013440:Sulfides; D054303:HIV Reverse Transcriptase