Enantioselective cytotoxic activity of bromine-substituted analogues of ifosfamide. A microsomal implication

Nine investigated chlorobromine-, bromine-, and dibromine-ifosfamide analogues including 3 racemates and 6 enantiomers, caused about 10-fold increase in in vitro cytotoxic activity, similar to reference standards ifosfamide and cyclophosphamide in HeLa (KB) human tumor cell culture systems with the addition of rat liver microsomal preparations (ED50 = 0.11 - 0.27 x 10(-3) mole/l) as compared to microsomally non induced samples. The chlorobromine-analogues (ED50 = 0.11 - 0.20 x 10(-3) mole/l) demonstrated the highest cytotoxicity in comparison with bromine-, or dibromine-analogues (SAR). Their levorotatory (-)-(S)- enantiomers (ED50 = 0.11 : 0.21 : 0.24 x 10(-3) mole/l) appear to be more active than their dextrorotatory (+)-(R)-antipodes (ED50 = 0.20 : 0.26 : 0.27 x 10(-3) mole/l, respectively) (ESAR). The stereodifferentiated enhancement of their in vitro cytotoxicity, correlated with the decreasing of in vivo L1210 antileukemic effect following phenobarbital metabolic induction in terms of a whole--strong antitumor activity, indicate that their cytostatic activity depends enantioselectively on the mixed function oxidases-system activity, and presumably on the efficacy of the rate of drug metabolic transformation to their cytostatically active metabolites/intermediates.