STEREOSELECTIVE HYDROLYSIS OF XENOBIOTIC ESTERS BY DIFFERENT CELL-LINES FROM RAT-LIVER AND HEPATOMA AND ITS APPLICATION TO CHIRAL PRODRUGS FOR DESIGNATED GROWTH SUPPRESSION OF CANCER-CELLS

Stereoselectivity in the hydrolysis of racemic ethyl 2-phenylacetate d erivatives by cultured cells of noncancerous cell lines from rat liver (BRL, BRL 3A, Clone 9, and ARLJ301-3), spontaneously or oncogene tran sformed rat liver cell lines (ARLJ301-3TR1, Anr4, Anr9-1, and Anr13-1) , and cancer cell lines from rat hepatoma (H4-II-E, McA-RH7777, and MH (1)C(1)) and sarcoma (XC) was studied. A strong (R)-enantiomer prefere nce was found in the hydrolysis of ethyl 2-hydroxy- (2c) and 2-methoxy -2-phenylacetate (3c) by the noncancerous and oncogene-transformed cel ls and an (S)-enantiomer preference for ethyl N-acylphenylalaninates w ith all the present cell lines. These inclinations were, however, not recognized with ethyl 2-methoxy-2-phenylpropanoate and ethyl N-difluor oacetyl or N-trifluoroacetylphenylalaninate. Moreover, the R preferenc e for 3c was reversed in the reaction by hepatoma cells. Thus, the ste reoselectivity is influenced by both structure of acyl group and speci es of cell lines. The hepatoma cells were considerably different from the noncancerous or oncogene-transformed cells in stereoselectivity. T his fact was consistent with the order of colony formation in soft aga r cultures (index of malignancy) and the resemblance in actively stain ed esterase patterns in gel electrophoresis. The stereoselective hydro lysis leads to cell-specific activation of anticancer prodrugs. This h as been confirmed for the first time by the stereoselectivity of Anr4 and H4-II-E cells in the hydrolysis of a chiral mustard ester, bis(2-c hloroethyl)aminophenyl 2-methoxy-2-phenylacetate (14) and by the diffe rence of IC50 values of (R)- and (S)-14 against the two cell lines. (C ) 1995 Wiley-Liss, Inc.