Discovery of thienopyrimidine-based inhibitors of the human farnesyl pyrophosphate synthase--parallel synthesis of analogs via a trimethylsilyl ylidene intermediate

Chun-Yuen Leung; Adrienne M Langille; John Mancuso; Youla S Tsantrizos

doi:10.1016/j.bmc.2013.02.006

Discovery of thienopyrimidine-based inhibitors of the human farnesyl pyrophosphate synthase--parallel synthesis of analogs via a trimethylsilyl ylidene intermediate

Bioorg Med Chem. 2013 Apr 15;21(8):2229-2240. doi: 10.1016/j.bmc.2013.02.006. Epub 2013 Feb 18.

Authors

Chun-Yuen Leung¹, Adrienne M Langille¹, John Mancuso², Youla S Tsantrizos³

Affiliations

¹ Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, Canada H3A 0B8.
² 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.
³ 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: [email protected].

PMID: 23477945
DOI: 10.1016/j.bmc.2013.02.006

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cyclization
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Geranyltranstransferase / antagonists & inhibitors*
Humans
Models, Molecular
Nitriles / chemistry
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Nitriles
Pyrimidines
thienopyrimidine
dicyanmethane
Geranyltranstransferase