Macromolecular derivatives of N, N-di-(2-chloroethyl)-4-phenylenediamine mustard. 1. Synthesis and in vitro hydrolytic stability

Abstract

Polymeric prodrugs of N, N-di(2-chloroethyl)-4-phenylenediamine mustard (PDM) were prepared by coupling the drug via an oligopeptide spacer onto poly[ N 5-(2-hydroxyethyl)- l-glutamine] (PHEG). In a first step PDM was linked to the peptide spacer and subsequently the low molecular weight peptidyl-PDM derivatives were coupled to 4-nitrophenyl chloroformate activated PHEG. Hydrolytic stability studies clearly demonstrated an improved stability for the polymeric derivatives compared to the parent drug. Dynamic laser light scattering measurements indicated the formation of aggregates. The influence of the amino acid sequence of the spacer on the enzymatic stability of the macromolecular drug conjugate was investigated under different conditions. Accordingly, the conjugates were incubated in buffers of lysosomal or physiological pH and in the presence of lysosomal or tumor-associated enzymes. The gly-phe-ala-leu based derivative proved to be a promising candidate for further biological evaluations.