High loading beads for single bead screening in combinational chemistry

Abstract

Combinatorial chemistry and solid-phase synthesis have revolutionised the process of drug discovery in the last decade. Ever since the concept of split and mix synthesis was introduced in 1988, and in particular the concept of one bead one compound. this approach has been associated with the possibility of generating thousands or millions of compounds in only a relatively small number of synthetic steps. With the miniaturisation of screening assays the amount of compound released by a single resin bead has become sufficient for biological test. However, if multiple screenings, IC₅₀ determination or direct structure characterisation are required, commercially available resins are not suitable. Therefore the demand for high-loading resins has drastically increased over the last years.

The research reported here is focussed on bead-loading enhancement, via a dendrimerisation process. Two different types of high loading dendrimer resins have been synthesised.

Polyamidoamine (PAMAM) dendrimer resin has been used for the solid phase synthesis of various classes of compounds, involving many different chemical conditions. Robustness, swelling properties and suitability for single bead screening have also been investigated.

Polyether dendrimer resin has been synthesised for the first time and again chemical inertness and mechanical properties have been explored.

Both dendrimer resins can be conveniently and efficiency synthesised starting from commercially available resins, they are inert under severe chemical conditions and the final loading is sufficient for multiple single bead screenings.

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