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N-Succinyl-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin: an extracellularly tumor-activated prodrug devoid of intravenous acute toxicity.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2001 Oct 25; Vol. 44 (22), pp. 3750-3. - Publication Year :
- 2001
-
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.
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Antineoplastic Agents toxicity
Chromatography, High Pressure Liquid
Doxorubicin administration & dosage
Doxorubicin pharmacology
Doxorubicin toxicity
Drug Stability
Female
Humans
Injections, Intraperitoneal
Injections, Intravenous
Lethal Dose 50
Male
Mice
Mice, Inbred BALB C
Oligopeptides administration & dosage
Oligopeptides pharmacology
Oligopeptides toxicity
Prodrugs chemistry
Prodrugs pharmacology
Prodrugs toxicity
Solutions
Toxicity Tests, Acute
Tumor Cells, Cultured
Ultrafiltration
Xenograft Model Antitumor Assays
Antineoplastic Agents chemical synthesis
Doxorubicin analogs & derivatives
Doxorubicin chemical synthesis
Doxorubicin chemistry
Oligopeptides chemical synthesis
Oligopeptides chemistry
Prodrugs chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 44
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11606140
- Full Text :
- https://doi.org/10.1021/jm0108754