Probing the cysteine-34 position of endogenous serum albumin with thiol-binding doxorubicin derivatives. Improved efficacy of an acid-sensitive doxorubicin derivative with specific albumin-binding properties compared to that of the parent compound

Tools

Item Type:	Article
Title:	Probing the cysteine-34 position of endogenous serum albumin with thiol-binding doxorubicin derivatives. Improved efficacy of an acid-sensitive doxorubicin derivative with specific albumin-binding properties compared to that of the parent compound
Creators Name:	Kratz, F., Warnecke, A., Scheuermann, K., Stockmar, C., Schwab, J., Lazar, P., Drueckes, P., Esser, N., Drevs, J., Rognan, D., Bissantz, C., Hinderling, C., Folkers, G., Fichtner, I. and Unger, C.
Abstract:	We have recently proposed a macromolecular prodrug strategy for improved cancer chemotherapy based on two features (Kratz, F.; et al. J. Med. Chem 2000, 43, 1253-1256.): (a) rapid and selective binding of thiol-reactive prodrugs to the cysteine-34 position of endogenous albumin after intravenous administration and (b) release of the albumin-bound drug in the acidic environment at the tumor site due to the incorporation of an acid-sensitive bond between the drug and the carrier. To investigate this therapeutic strategy in greater depth, four (maleinimidoalkanoyl)hydrazone derivatives of doxorubicin were synthesized differing in the length of the aliphatic spacer (1, -(CH2)2-; 2, -(CH2)3-; 3, -(CH2)5-; 4, -(CH2)7-). The albumin-binding doxorubicin prodrugs, especially the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (3), are rapidly and selectively bound to the cysteine-34 position of endogenous albumin. 3 was distinctly superior to the parent compound doxorubicin in three animal tumor models (RENCA, MDA-MB 435, and MCF-7) with respect to antitumor efficacy and toxicity.
Keywords:	Antineoplastic Agents, Antitumor Drug Screening Assays, Cultured Tumor Cells, Cysteine, Doxorubicin, Heterologous Transplantation, Hydrazones, Kidney Neoplasms, Inbred BALB C Mice, Molecular Models, Neoplasm Transplantation, Nude Mice, Prodrugs, Protein Binding, Renal Cell Carcinoma, Serum Albumin, Animals, Mice
Source:	Journal of Medicinal Chemistry
ISSN:	0022-2623
Publisher:	American Chemical Society
Volume:	45
Number:	25
Page Range:	5523-5533
Date:	5 December 2002
Official Publication:	https://doi.org/10.1021/jm020276c
PubMed:	View item in PubMed

Repository Staff Only: item control page