An Intramolecular Cyclization Reaction Is Responsible for the in Vivo Inefficacy and Apparent pH Insensitive Hydrolysis Kinetics of Hydrazone Carboxylate Derivatives of Doxorubicin

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• 作者：Cameron C. Lee ; Andrew T. Cramer ; Francis C. Szoka ; Jr. ; Jean M. J. Fr&eacute ; chet
• 刊名：Bioconjugate Chemistry
• 出版年：2006
• 出版时间：September 2006
• 年：2006
• 卷：17
• 期：5
• 页码：1364 - 1368
• 全文大小：105K
• 年卷期：v.17,no.5(September 2006)
• ISSN：1520-4812

文摘

Contradictory reports concerning the pH sensitive hydrolysis kinetics of certain hydrazone carboxylates ofdoxorubicin have appeared in this journal (Kaneko et al., Bioconjugate Chem. 1991, 2, 133. Padilla De Jesús etal., Bioconjugate Chem. 2002, 13, 453). Since the pH stability of the drug-carrier linkage in macromolecularprodrugs has a significant bearing on pharmacological efficacy, the hydrolysis kinetics of low molecular weightand polymeric doxorubicin hydrazone carboxylates were therefore reinvestigated. As observed previously, theconjugates readily release native doxorubicin at pH 5. Unexpectedly, in neutral buffer the hydrazone carboxylateconjugates do not release native doxorubicin, but instead rapidly release a doxorubicin derivative substituted atC-9 by 3,6-dihydro-1,3,4-oxadiazin-2-one with first-order kinetics (t_1/2 = 2.5 h). The proposed intramolecularcyclization reaction involving doxorubicin's C-14 hydroxyl and the carboxylate-substituted hydrazone rationalizesthe seemingly anomalous hydrolysis kinetics seen for hydrazone carboxylate linked doxorubicin, and provides apossible explanation for the poor antitumor activity exhibited by polymer-doxorubicin conjugates utilizing thisspecific type of linkage.