Dendrimers

The term dendrimer is given in deference to the branched structure adopted by these molecules and the name comes from the prefix dendri- meaning treelike (from Greek dendron, tree) and the word polymer.

The first who reported a dendrimer synthesis was Fritz Vögtle in 1978, introducing the concept of cascade reaction: Michael type addition of an amine to acrylonitrile permitted the attachment of the initial two arms, or branches, subsequent reduction of the nitriles gave the desired diamine, which was subjected to the same synthetic sequence to afford 4-cascade:benzylamine[2-N,N]:(1-azabutylidene):propylamine (second generation, see image below).

Difficulties associated with nitrile reduction limited the continued growth of this cascade.

Dendrimers possess three distinguishing architectural components, namely an initial core, interior layers (generations), composed of repeating units, radially attached to the initiator core and exterior (terminal functionality) attached to the outermost interior generation.
Two main methods exist for the synthesis of dendrimers: a divergent approach, where the dendrimer is assembled in a totally linear manner, or a convergent method where fragments of the dendrimer are condensed together. These two methods both suffer from major problems when it comes to practical synthesis, in particular, the necessity for repeated and time-consuming purifications.

The solid-phase synthesis of dendrimers has many advantages: firstly, large excesses of reagents could be used without the problems usually associated with purification, which becomes only a matter of extensive washing; secondly, the use of differentially protected starting units would allow an avenue into the synthesis of unsymmetrical dendrimers under very clearly defined reaction conditions and allow the synthesised dendrimer to be specifically functionalised to other molecules of choice; thirdly, resin-bound dendrimers have the ability to enhance resin loading by at least one order of magnitude. At the present time, this seems extremely important, because of the huge demand for solid phase synthetic resins, usually suffering from relatively low loadings and high cost.

PAMAM (polyamidoamine) dendrimers were first synthesised by Tomalia et al. The general synthesis is a two-step process involving exhaustive Michael addition of a suitable amine initiator core with methyl acrylate and exhaustive amidation of the resulting esters with large excesses of 1,2-alkanediamines. In this way, dendrimers up to the ninth generation were produced (image below).

In 1997, Prof. Bradley published the first synthesis of PAMAM (polyamidoamine) dendrimer on solid phase.

The present research in this field involves:

Investigate the utility of these beads under a range of chemical conditions.
Study the mechanical stability and suitability of these beads for automated handling. Investigate the reaction kinetics on these higher loading beads. Utilise the multiple release techniques already developed by Prof. Bradley’s group for HTS using the high
loading dendrimerised beads. Synthesise novel dendrimers using solid-phase methodology.

Dendrimer SPS - Library Synthesis and Pharmaceutical Application

Dendrimers are macromolecules whose synthesis is generally based on a repetitive sequence of reaction steps, with each complete sequence creating a new generation of dendrimer. This class of polymers are highly symmetrical monodispersed molecules consisting of three distinct regions: a core, from which they generally emanate, successive branching units and a peripheral multivalent surface. Since the early work of Vögtle and Tomalia, research in the area has evolved to enable the development of engineered dendritic macromolecules with unique chemical and physical properties for applications in the fields of medicinal chemistry, supramolecular chemistry, catalysis and screening among others. Solid-phase synthesis has proven to be a powerful tool in making dendrimers as excess reagents can be used to ensure complete reaction of the surface functional groups and can be removed easily by simple washing of the resin-bound dendrimer. This methodology can be employed to prepare dendrimers which can be cleaved from the support via the use of a linker, or non-cleavable dendrimers which are covalently bound to a number of polymeric based supports. The former also allows the preparation of multivalent constructs which can be used to probe weak non-bonding interactions (‘cluster effect’) while the latter is useful for increasing single-bead loading capacities. Both of these approaches have been widely investigated within our group since we reported the first solid-phase synthesis of PAMAM dendrimer in 1997.

Isocyanate monomers of the AB3-type are advantageous building blocks both for the solid-phase synthesis of dendrimers due to their high branching multiplicity and the presence of a reactive isocyanate group, which allows fast dendrimer construction without using additional coupling reagents. Our research focused on the use of AB3-type monomers 1 and 3a developed by Newkome et al. and a series of novel monomers developed in our group (3b, 2a-b).
(S. Lebreton, S. How, M. Buchholz, B. Yingyongnarongkul, M. Bradley, Tetrahedron, 2003, 59, 3945-3953)

AB3-type monomers

Current studies focus on the synthesis of a dendrimer library and its conjugation with biologically active ligands to analyse multivalent interactions and to use dendrimer constructs for transfection and as drug delivery systems.