Am. Fernandez et al., N-succinyl-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin: An extracellularly tumor-activated prodrug devoid of intravenous acute toxicity, J MED CHEM, 44(22), 2001, pp. 3750-3753
Intravenous administration of N-(beta -alanyl-L-leucyl-L-alanyl-L-leucyl)do
xorubicin (4) induces an acute toxic reaction, killing animals in a few min
utes. This results from its positive charge at physiological pH combined wi
th its propensity to form large aggregates in aqueous solutions. Negatively
charged N-capped versions of 4 such as the succinyl derivative 5 can be ad
ministered by the iv route at more than 10 times the LD50 of doxorubicin wi
thout inducing the acute toxic reaction, and they are active in vivo.