Novel (P)under-baroly((ET)under-barhylene(A)under-barmido(A)under-barmine) (PETAA) dendrimers produced through a unique and highly efficient synthesis

Polyamidoamine (PAMAM) dendrimers have unique attributes that have led to their use in a wide variety of biomedical applications. However, the complex synthesis of this polymer leads to variations in the structure and consistency of the final product, and makes scale-up of manufacturing difficult. This has limited the clinical translation of PAMAM-based materials. Here we describe a rapid and highly efficient two-step method for the synthesis of novel (P) under bar oly((ET) under bar hylene (A) under bar mido (A) under bar mine) (PETAA) dendrimers that have many of the favorable characteristics of PAMAM dendrimers. Generation 0 (G0) to 5 (G5) PETAA dendrimers were synthesized using a 3-(bis(2-(2,2,2,-trifluoroacetamido)ethyl)amino)propanoic acid AB(2) (compound 1) building block via a divergent approach. An ethylenediamine core was coupled with the AB(2) building block via O-(7-Azabenzotriazol-1-yl)N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) in the presence of diisopropylethyl amine to give a G0 trifluoroacetamide surface dendrimer. The G0 amine surface dendrimer was then obtained by treating the G0 trifluoroacetamide surface dendrimer with potassium carbonate. Repetitions of these two coupling/deprotection reactions were then used to build the dendrimer by coupling the surface amino groups to the carboxyl moiety of the AB(2) building block, followed by the deprotection step with potassium carbonate. The resulting PETAA dendrimers have the same number of surface primary amino groups, the same number of chemical bonds between the dendrimer core and the surface, and the same number of tertiary amino groups throughout the structures as similar generations of PAMAM dendrimers. In contrast, the structure of the PETAA dendrimers is more complete and more uniform than PAMAM dendrimers, especially at higher generations. This unique synthetic process for PETAA dendrimers also offers the potential for large-scale production, therefore providing inherently more uniform and complete structures for exacting biomedical applications. (C) 2011 Elsevier Ltd. All rights reserved.