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

doi:10.1039/A903013A

Paper

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

Published 1999 · T. Pettersson-Fernholm, J. Vilpo, M. Kosonen

Journal of The Chemical Society-perkin Transactions 1

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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.

Study Snapshot

Phenylacetic acid mustard, the major metabolite of chlorambucil, decomposes in aqueous solutions through the same mechanism as other aromatic and aliphatic nitrogen mustards, with its stability and product distribution varying in whole plasma compared to plasma ultrafiltrate.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

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

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References

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Chlorambucil's alkylation of nucleophiles is limited by the aziridinium ion mechanism, making it difficult to alkylate a nucleophile extensively before it hydrolyzes, potentially explaining its inhibition of angiotensin-converting enzyme.

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Chlorambucil's formation of glutathione conjugates may contribute to the development of acquired drug resistance in humans.

Citations

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Immobilizing chlorambucil on magnetic nanoparticles significantly increases its cytotoxicity against cancerous cell lines compared to its unbound form.

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Phenylacetic acid mustard (PAM) is slightly more stable than chlorambucil (CLB) and may play a role in the cytotoxic and mutagenic properties of CLB.

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Modifying the B-steroidal ring to lactamic reduces anti-leukemic activity of chlorambucil's active metabolite, but increases toxicity, supporting the role of the steroidal part in their mechanism of action.

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SOT-19, I, is a potent anti-leukaemic agent with low toxicity and potential for further 3D-QSAR studies.