Hydrolysis of Pro-Ala dipeptides by lysosomal hydrolases. Models for the study of lysosomotropic amino acid prodrugs of penicillins

Abstract

Peptidic lysosomotropic prodrugs of antibiotics and antitumoral agents could be of advantage in chemotherapy, providing that free, active drug is released at, or close to, the desired site of action. Thus, aminoacyl derivatives of doxorubicin, e.g., where the drug is attached to the amino acid by a primary amino function, are sensitive to lysosomal hydrolases. We have examined whether a similar approach can be used for drugs carrying a carboxyl group such as beta-lactam antibiotics. Because the C adjacent to the carboxyl group in beta-lactams has the D configuration, we have examined and report here the synthesis and susceptibility of model peptides, namely Boc-D-Pro-L-Ala and Boc-L-Pro-L-Ala to lysosomal hydrolases. Hydrolysis of the D isomer proceeds considerably more slowly than that of the L isomer. Lysosomal carboxypeptidase(s) and/or amidases appear therefore to have a much narrower specificity than aminopeptidase(s), which will severely limit the applicability of the concept of peptidic lysosomotropic prodrugs.

Influence of conversion of penicillin G into a basic derivative on its accumulation and subcellular localization in cultured macrophages

“…The amide linkage realized in this study was not hydrolyzed by lysosomal amidases. Substitution of the carboxyl group by amino acids is also unsatisfactory because lysosomal carboxy peptidases do not split peptidic bounds in which the carbon atom adjacent to the carbonyl is of the D-configuration (35), as would be the case for penicillinamino acid derivatives. Conversely, most ester linkages are quickly hydrolyzed extracellularly by unspecific esterases.…”