N-Succinyl-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin: an extracellularly tumor-activated prodrug devoid of intravenous acute toxicity.

Abstract

Intravenous administration of N-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin (4) induces an acute toxic reaction, killing animals in a few minutes. This results from its positive charge at physiological pH combined with its propensity to form large aggregates in aqueous solutions. Negatively charged N-capped versions of 4 such as the succinyl derivative 5 can be administered by the iv route at more than 10 times the LD(50) of doxorubicin without inducing the acute toxic reaction, and they are active in vivo.

• Authors: A M Fernandez, K Van Derpoorten, L Dasnois, K Lebtahi, V Dubois, T J Lobl, S Gangwar, C Oliyai, E R Lewis, D Shochat, A Trouet
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 44 Issue 22 Pg. 3750-3 (Oct 25 2001) ISSN: 0022-2623 [Print] United States
• PMID: 11606140 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• N-(succinyl-beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin
• N-alanyl-leucyl-alanyl-leucyl-doxorubicin
• Oligopeptides
• Prodrugs
• Solutions
• Doxorubicin

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology, toxicity)
• Chromatography, High Pressure Liquid
• Doxorubicin (administration & dosage, analogs & derivatives, chemical synthesis, chemistry, pharmacology, toxicity)
• Drug Stability
• Female
• Humans
• Injections, Intraperitoneal
• Injections, Intravenous
• Lethal Dose 50
• Male
• Mice
• Mice, Inbred BALB C
• Oligopeptides (administration & dosage, chemical synthesis, chemistry, pharmacology, toxicity)
• Prodrugs (chemical synthesis, chemistry, pharmacology, toxicity)
• Solutions
• Toxicity Tests, Acute
• Tumor Cells, Cultured
• Ultrafiltration
• Xenograft Model Antitumor Assays