Reactions of 4-bis(2-chloroethyl)aminophenylacetic acid (phenylacetic acid mustard) in physiological solutions

Abstract

4-Bis(2-chloroethyl)aminophenylacetic acid (phenylacetic acid mustard, 2) is the major metabolite of the cancer chemotherapeutic agent chlorambucil (1). Although its high antitumor activity and high toxicity to normal tissues have been known for a long time, no detailed chemical data on its reactions in aqueous media have been available. According to the present results 2 is decomposed in aqueous solutions by the same mechanism as other aromatic and aliphatic nitrogen mustards: an intramolecular, rate determining attack of the unprotonated nitrogen to form an aziridinium ion intermediate is followed by attack of an external nucleophile. Species 2 is considerably more stable in whole plasma than in plasma ultrafiltrate (t1/2 at 37 °C 10 h and 37 min, respectively). Also the product distribution is completely different: while in protein-depleted plasma the only reaction is hydrolysis, in plasma the predominant reactions are non-covalent and covalent binding of 2 to albumin. The present information is important when clinical evaluation of chlorambucil, or in vitro evaluation of phenylacetic acid mustard, is performed in order to determine efficacy and bioavailability of these compounds.