The search for small molecules that can be used as chemical probes or drugs requires casting a wide net for diverse structures. Stuart L. Schreiber and his coworkers at Harvard University and the Broad Institute have developed an oligomer-based approach to introduce such diversity in small-molecule synthesis (J. Am. Chem. Soc. 2006, 128, 14766). The researchers synthesized reactive oligomers from readily available olefinic and acetylenic monomers and then transformed the oligomers into distinct three-dimensional structures by using ring-closing reactions. The 1,3-diene products from this first round of reactions could be further diversified via Diels-Alder reactions, they note. Overall, starting with only three monomers coupled into linear 2-mers or 3-mers, the researchers have synthesized 12 unique skeletons of five- and six-membered heterocycles and polycyclic compounds. "Methods which allow genuine combinatorial variation of ligand skeleton are extremely rare," notes Adam Nelson of the University of Leeds, in England. "With a larger number of building blocks, libraries of molecules with hundreds of distinct molecular architectures may be accessible for the first time."