Slightly congested amino terminal dendrimers. The synthesis of amide-based stable structures on a large scale

Abstract

Nowadays, amino terminal dendrimers are appealing materials for biological applications due to their multivalence and the versatile conjugation of the amino groups. However, the high reactivity of these terminal groups can be decreased by steric hindrance, limiting their possible bioapplications. Herein, we report the divergent synthesis of slightly sterically hindered amino terminal polyamide dendrimers. A simple and unique AB2 scaffold has been chosen to build the dendritic structures, where only amide bonds have been used as the connecting unit. The 1–7 relative positions of the amino groups in the AB2 monomers avoid the steric congestion of the macromolecules, allowing the construction of robust dendrimers up to the fifth generation. The construction of the dendrimers is based on two well-established reactions, using simple and cheap reactants, with yields above 90% on a gram scale and easy purification procedures. This synthetic methodology constitutes an easy and efficient way for the preparation of stable and aqueous soluble dendrimers on a gram scale, representing a substantial improvement over the synthesis of this kind of aliphatic polyamide amino terminal dendrimer. The prepared structures were completely characterized and evaluated by size exclusion chromatography, diffusion ordered spectroscopy and atomic force microscopy to determine their size. Molecular dynamics simulations were also carried out and the values obtained were consistent with the experimentally determined values.

This work was supported by the Ministerio de Ciencia y Educación (PID2019-104293GB-I00), Ministerio de Ciencia e Innovación (Proyectos de I+D+I “Programación Conjunta Internacional”), EuroNanoMed 2019 (PCI2019-111825-2), Instituto de Salud Carlos III (ISCIII; RETIC ARADYAL RD16/0006/0012) and Junta de Andalucía and Universidad de Málaga (UMA18-FEDERJA-007). We gratefully acknowledge the computer resources provided by the SCBI (Supercomputing and Bioinformatics Center) of the University of Malaga. NMR experiments have been performed in the ICTS “NANBIOSIS”, in the U28 Unit at the Andalusian Centre for Nanomedicine and Biotechnology (BIONAND).