Synthesis and inhibitory activity of difluoroketone substrate analogs of N-myristoyltransferase.

Abstract Two fluorinated nonhydrolyzable analogs of myristoyl-coenzyme A were synthesized and tested for inhibitory activity against N -myristoyltransferase (NMT). S -(2,2-Difluoro-3-oxohexadecyl)-coenzyme A ( 3 ) and S -(3,3-difluoro-2-oxopentadecyl)-coenzyme A ( 2 ) were prepared by alkylation of coenzyme A and were purified by reverse phase chromatography. Inhibition of NMT was observed with 3 and 2 , with IC 50 's of 110 nM and 80 nM, respectively, in an in vitro assay developed in our laboratory. The known unfluorinated analog S -(2-oxopentadecyl)-coenzyme A ( 1 ) was found to have an IC 50 of 7 nM. At 100 μM in D 2 O, 3 was 59% hydrated and 2 was 88% hydrated.