title: Modular assembly of purine-like bisphosphonates as inhibitors of HIV-1 reverse transcriptase.
abstract: Bisphosphonates can mimic the pyrophosphate leaving group of the nucleotidyl transfer reaction and effectively inhibit RNA/DNA polymerases. In a search of HIV-1 reverse transcriptase (RT) inhibitors, a new chemotype of nonhydrolyzable purine diphosphate mimic was synthesized. A modular synthetic protocol was developed, utilizing 2-amino-6-(methylthio)-4-(trimethylsilyl)nicotinonitrile as the key synthon in the preparation of highly substituted 2-aminonicotinonitriles. These building blocks were subsequently elaborated to the pyrido[2,3-d]pyrimidine bisphosphonates (PYPY-BPs). Biochemical screening identified analogs of PYPY-BPs that inhibit HIV-1 RT-catalyzed DNA synthesis.
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada.
authors.forename: Cyrus M
authors.initials: CM
authors.lastname: Lacbay
authors.forename: John
authors.initials: J
authors.lastname: Mancuso
authors.forename: Yih-Shyan
authors.initials: YS
authors.lastname: Lin
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bennett
authors.forename: Matthias
authors.initials: M
authors.lastname: Götte
authors.forename: Youla S
authors.initials: YS
authors.lastname: Tsantrizos
mesh_terms: D004164:Diphosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D008956:Models, Chemical; D015394:Molecular Structure; D009154:Mutation; D011687:Purines / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004164:Diphosphonates; D011687:Purines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C030985:purine