ABSTRACT
One of the most powerful tools available to the combinatorial chemist is the process of split and mix in terms of the numbers of compounds that can be made and the economics of synthesis, with resin beads being used as the ultimate microreactor in synthesis. However, this method results in tiny amounts of compound being available with less than 1 nmol bead typically being available. This might be enough to identify an active bead, but it is not enough to conduct numerous biological assays or to validate the compound as a lead. More importantly, it is insufficient to determine the compound’s structure using conventional techniques such as 1H nuclear magnetic resonance (NMR). Such a low loading requires a tagging system to identify the compound and necessitates resynthesis on a larger scale either in solution or on the solid phase for rescreening. However, though elegant the introduction of a tag during the library synthesis is very time consuming. One solution to this problem is to increase the size of the beads. A larger bead will obviously bear more sites, although size is limited by bead stability, susceptibility to fracturing, and bead synthesis as well as poor reaction kinetics. Another approach is to multiply the functionalities on a bead by dendrimer-ization, using the hyperbranched nature of the dendrimer to amplify loading. Solid-phase lysine-based dendrimers were published by Tam [21] as a means of generating a high density of peptide functionality for antigen presentation (multiple antigen presentation system; MAPS), but resins with low loading were deliberately used to avoid possible steric problems. However, the development of solid-phase PAMAM dendrimers has provided a powerful tool to increase the loading of
single beads [22]. The development of highly symmetrical dendrimers allows an extremely high loading to be obtained on the resin beads.
