CYTOTOXICITY AND INTRACELLULAR BIOTRANSFORMATION OF N-BENZYLADRIAMYCIN-14-VALERATE (AD-198) ARE MODULATED BY CHANGES IN 14-O-ACYL CHAIN-LENGTH

N-benzyladriamycin-14-valerate (AD 198) is pharmacologically superior to Adriamycin (ADR) based upon comparable cytotoxicity, decreased card iotoxicity and the ability of AD 198 to circumvent multidrug resistanc e conferred by either P-glycoprotein overexpression or reduced topoiso merase II activity. AD 198, however, suffers from systemic lability of the 14-O-valerate moiety to enzymatic and non-enzymatic cleavage to y ield N-benzyladriamycin (AD 288), which is more similar to ADR in acti vity. The purpose of this study was to determine whether stability of the ester linkage could be achieved while preserving the favorable cha racteristics of AD 198 by using a series of N-benzylated ADR congeners containing 14-O-acyl substitutions of incrementally shorter carbon ch ain lengths. Results from this study indicate that the linear five-car bon valerate substitution is the minimum length necessary to circumven t P-glycoprotein and prevent inhibition of topoisomerase II activity. In addition, although AD 198 is not a pro-drug of AD 288, intracellula r 14-O-acyl cleavage appears to contribute to the cytotoxicity of AD 1 98. [(C) 1998 Rapid Science Ltd.].