ENCODED COMBINATORIAL CHEMISTRY : BINARY CODING USING CHEMICALLY ROBUST SECONDARY AMINE TAGS

Publisher Summary Synthetic chemical libraries produced by combinatorial synthesis have rapidly become the important tools for pharmaceutical lead discovery and compound optimization. Many of the approaches devised to prepare such libraries rely on solid-phase synthesis techniques and exploit the efficient “split/pool” method to assemble all possible combinations of a set of chemical building blocks. Elucidation of the chemical structure of biologically active library members has represented a major challenge, because the quantity of material available for chemical analysis from a complex library is frequently miniscule. A general solution to this structure elucidation problem has been proposed here that exploits a set of surrogate analytes or identifier tags that can be detected, with either greater ease or sensitivity than the chemical entities that they represent. Through their concurrent appendage to the synthesis supports, these tags provide an unambiguous record of the chemical reaction history or chronology of monomer (building block) additions to each support in the library. This method that has become known as “encoded combinatorial synthesis” has broad scope and utility, and conceptually may be applied to the construction of any collection of compounds that can be produced through a multistep scheme of synthesis on solid supports. Two conceptually different approaches to encoding a combinatorial synthesis have been described in this chapter. In the first mode, the sequence of monomer addition steps is recorded by the parallel and alternating assembly of a polymeric molecule that is itself amenable to chemical sequence analysis. In the second coding method, sets of readily identifiable markers are attached to the supports that specify the monomer coupling reaction that is visited, in which step of the ligand synthesis.