Effect of Fluorine Substitution of α‐ and β‐Hydrogen Atoms in Ethyl Phenylacetate and Phenylpropionate on Their Stereoselective Hydrolysis by Cultured Cancer Cells.

Abstract ( ±) -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 oncogenetransformed 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 estertype anticancer prodrugs more specific to cancer cells.