title: Discovery of thienopyrimidine-based inhibitors of the human farnesyl pyrophosphate synthase--parallel synthesis of analogs via a trimethylsilyl ylidene intermediate.
abstract: Thienopyrimidine-based bisphosphonates were identified as a new class of nitrogen-containing bisphosphonate (N-BP) inhibitors of the human farnesyl pyrophosphate synthase (hFPPS). Analogs were prepared via cyclization of 2-(1-(trimethylsilyl)ethylidene)malononitrile to 2-amino-4-(trimethylsilyl)thiophene-3-carbonitrile in the presence of elemental sulfur. Direct ipso-iododesilylation of this intermediate led to selective iodination at Cβ of the sulfur atom in high efficiency. The synthetic protocols developed were used in the parallel synthesis of structurally diverse thieno[2,3-d]pyrimidin-4-amine-based bisphosphonate inhibitors of hFPPS.
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, Canada H3A 0B8.
authors.forename: Chun-Yuen
authors.initials: CY
authors.lastname: Leung
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, Canada H3A 0B8.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Langille
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, Canada H3A 0B8; Tranzyme Pharma, 3001 12th Avenue North, Sherbrooke, QC, Canada J1H 5N4.
authors.forename: John
authors.initials: J
authors.lastname: Mancuso
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, Canada H3A 0B8; Department of Biochemistry, McGill University, 3649 Promenade Sir William Osler, Montreal, QC, Canada H3G 0B1. Electronic address: youla.tsantrizos@mcgill.ca.
authors.forename: Youla S
authors.initials: YS
authors.lastname: Tsantrizos
mesh_terms: D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D009570:Nitriles; D011743:Pyrimidines; C476003:thienopyrimidine; C000945:dicyanmethane; D051228:Geranyltranstransferase