Effect of fluorine substitution of α-and β-hydrogen atoms in ethyl phenylacetate and phenylpropionate on their stereoselective hydrolysis by cultured cancer cells

Article abstract of DOI:10.1016/S0022-1139(96)03485-9

(±)-Ethyl 2-fluoro-2-phenylacetate was stereoselectively hydrolyzed by cultured cells of several rat cancer cell lines to give the carboxylic acid rich in the R enantiomer. The stereoselectivity increased for (±)-ethyl 2-fluoro-2-phenylpropionate (2b) with all present cell lines and for (±)-ethyl 2-phenyl-3,3,3-trifluoropropionate (3b) with rat hepatoma McA-RH7777 cell line. The stereoselectivity was different for the different cell lines, as McA-RH7777 cells preferred (R)-2b in contrast with the preference towards (S)-2b by other cells such as ras oncogene-transformed rat liver Anr4 cells. These stereoselectivities were different from those for non-fluorinated (±)-ethyl 2-phenylpropionate. Thus fluorine atoms are recognized by ester hydrolases of cancer cells, and fluorine substitution on the acyl group will be useful for making ester-type anticancer prodrugs more specific to cancer cells.