An intramolecular cyclization reaction is responsible for the in vivo inefficacy and apparent pH insensitive hydrolysis kinetics of hydrazone carboxylate derivatives of doxorubicin

Cameron C. Lee, Andrew T. Cramer, Francis C. Szoka, Jean Frechet*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Contradictory reports concerning the pH sensitive hydrolysis kinetics of certain hydrazone carboxylates of doxorubicin have appeared in this journal (Kaneko et al., Bioconjugate Chem. 1991, 2, 133. Padilla De Jesús et al., Bioconjugate Chem. 2002, 13, 453). Since the pH stability of the drug-carrier linkage in macromolecular prodrugs has a significant bearing on pharmacological efficacy, the hydrolysis kinetics of low molecular weight and polymeric doxorubicin hydrazone carboxylates were therefore reinvestigated. As observed previously, the conjugates readily release native doxorubicin at pH 5. Unexpectedly, in neutral buffer the hydrazone carboxylate conjugates do not release native doxorubicin, but instead rapidly release a doxorubicin derivative substituted at C-9 by 3,6-dihydro-1,3,4-oxadiazin-2-one with first-order kinetics (t 1\2 = 2.5 h). The proposed intramolecular cyclization reaction involving doxorubicin's C-14 hydroxyl and the carboxylate-substituted hydrazone rationalizes the seemingly anomalous hydrolysis kinetics seen for hydrazone carboxylate linked doxorubicin, and provides a possible explanation for the poor antitumor activity exhibited by polymer-doxorubicin conjugates utilizing this specific type of linkage.

Original languageEnglish (US)
Pages (from-to)1364-1368
Number of pages5
JournalBioconjugate Chemistry
Volume17
Issue number5
DOIs
StatePublished - Sep 1 2006

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

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