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

Journal of medicinal chemistry ·Vol. 44 ·No. 22 ·2001-10-25 ·Pages 3750-3

Fernandez AM, Van Derpoorten K, Dasnois L, Lebtahi K, Dubois V, Lobl TJ, Gangwar S, Oliyai C, Lewis ER, Shochat D, Trouet A

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.

MeSH Terms

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

Chemicals

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

Authors & Affiliations

11 authors, click to expand affiliations / ORCID

Fernandez A M

Laboratory of Cell Biology, Université Catholique de Louvain, Place Croix du Sud 5, B-1348 Louvain-la-Neuve, Belgium. fernandez@bani.ucl.ac.be

Van Derpoorten K

Dasnois L

Lebtahi K

Dubois V

Lobl T J

Gangwar S

Oliyai C

Lewis E R

Shochat D

Trouet A

Article Info

Journal

Journal of medicinal chemistry

Abbr.

J Med Chem

ISSN

0022-2623

DOI

10.1021/jm0108754

fernandez@bani.ucl.ac.be

Published

2001-10-25

Pages

3750-3

Language

English

Region

United States

NLM ID

9716531

Subset

External Links

PubMed source DOI: 10.1021/jm0108754 View journal details

Analysis Services

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

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