Kilogram Scale Synthesis of a Triazine-based Dendrimer and the Development of a General Strategy for the Installation of Pharmacophores to Yield Potential Drug Delivery Agents

Abstract

Diverse dendrimer peripheries are often produced through convergent synthesis with multiple protection-deprotection steps. Achieving such diversity while maintaining monodispersity, has previously proven problematic. Interception of an electrophilic poly(monochlorotriazine) dendrimer with a molecule of interest bearing a reactive, nucleophilic group presents an efficient method to achieve large quantities of dendrimers with biologically relevant peripheries. Kilogram-scale synthesis of a triazine-based dendrimer relies on reaction of the dichlorotriazine monomer with the amine terminated dendrimer to afford a poly(monochlorotriazine) dendrimer. Normally, the dendrimer is then reacted with piperidine, an inexpensive ?cap? due to its chemically inert nature after reaction. The dendrimer then undergoes a global deprotection to afford an amine-terminated dendrimer. Subsequent iterations with the dichlorotriazine monomer affords higher generation architectures. Intercepting the poly(monochlorotriazine) dendrimer with biologically relevant molecules containing reactive amines enables the development of a drug delivery vehicle. Desferrioxamine B, an iron chelate, and camptothecin, and anticancer drug, are two clinically approved drugs of interest investigated for macromolecular drug delivery. Upon acylation of each drug with BOC-isonipecotic acid, substitution on the dendrimer may occur with varying levels of success depending on the drug in question. Upon successful substitution to afford the desired product,biological studies may be performed. Each synthetic approach will be discussed along with alternative routes leading to this general strategy.