Farnesyl Diphosphate Analogues with omega-Bioorthogonal Azide and Alkyne Functional Groups for Protein Farnesyl Transferase-Catalyzed Ligation Reactions

GUILLERMO R. LABADIE; RAJESH VISWANATHAN; C. DALE POULTER

JOURNAL OF ORGANIC CHEMISTRY

American Chemical Society

Lugar: Washington; Año: 2007 vol. 72 p. 9291 - 9297

0022-3263

Eleven farnesyl diphosphate analogues, which contained omega-azide or alkyne substituents suitable for bioorthogonal Staudinger and Huisgen [3 + 2] cycloaddition coupling reactions, were synthesized. The analogues were evaluated as substrates for the alkylation of peptide cosubstrates by yeast protein farnesyl transferase. Five of the diphosphates were good alternative substrates for farnesyl diphosphate (FPP). Steady-state kinetic constants were measured for the active compounds, and the products were characterized by HPLC and LC-MS. Two of the analogues gave steady-state kinetic parameters (kcat and Km) very similar to those of the natural substrate.