SYNTHESIS AND INHIBITORY ACTIVITY OF DIFLUOROKETONE SUBSTRATE-ANALOGS OF N-MYRISTOYLTRANSFERASE

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 IC50'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 IC50 of 7 nM. At 100 mu M in D2O, 3 was 59% hydrated and 2 was 88% hydrated.