Synthesis, Characterization, and Applications of a Melamine Based Dendrimer with Twelve Cysteine Groups on the Periphery

Abstract

A potential drug delivery vehicle based on a melamine dendrimer with twelve free thiols on the periphery for constructing bio-labile disulfides has been synthesized. Under ideal conditions for the native chemical ligation reaction, attempts for attaching the cell penetrating peptide TAT, via native chemical ligation proved difficult due to the low solubility of the dendrimer. A camptothecin derivative containing a reactive disulfide was prepared for disulfide exchange with the melamine dendrimer. Up to 7 exchange reactions were achieved as determined by mass spectroscopy. NMR and mass spectroscopy was used to characterize all of the intermediates. Capping groups to replace the hydrophobic piperidine with more water-soluble groups to aid the ligation reaction and optimization of the disulfide exchange step to give 12 substitutions have been proposed for future studies. The end target is a peptide dendrimer containing a cell penetrating peptide to mediate endocytosis and a bio-labile linker connecting an anti-tumor drug to the dendrimer, which would ultimately be released inside the cancerous cell.