N-succinyl-(β-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin:: An extracellularly tumor-activated prodrug devoid of intravenous acute toxicity

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 LD50 of doxorubicin without inducing the acute toxic reaction, and they are active in vivo.