Diversity-oriented synthesis screening

Multicomponent reactions (MCRs) are one-pot processes combining three or more substrates simultaneously [1], MCR processes are of great interest, not only because of their atom economy but also for their application in diversity-oriented synthesis and in preparing libraries for the screening of functional molecules. Catalytic asymmetric multicomponent processes are particularly valuable but demanding and only a few examples have been realized so far. Here we provide an overview of this exciting and rapidly growing area. 

Chemical Libraries Screening for Biologically Active Small Molecules Diversity-Oriented Synthesis of Small Molecules Reverse Chemical Genetics... 

In many cases, small molecules are found for a TF of interest through assays developed with known protein partners. Structures of the interacting protein domains also have been invaluable for drug discovery. For several important TFs, however, the specific cellular partners with which they interact are unknown. In this case, using small molecule screens on solid supports is an extremely useful tool for dmg discovery. In one such screen, diversity-oriented synthesis (DOS (129) was used to identify a small molecule binder of Hap3p, a yeast protein... 

Most commonly, a commercial library, containing a subset of compounds that matches a desired set of properties (if known), is screened in an initial study. Once hits are obtained and verified, a small library of compounds is synthesized to produce a set of compounds in the same chemical-stmctural space as the original hit stmcture. This process allows for hits with higher potency and elucidates information of the structure-activity relationship within the system of interest. Such synthetic libraries of chemically diverse compounds have been made possible through combinatorial chemistry (52-56) and diversity-oriented synthesis (52). 

Fig. 6-20 Forward chemical-genetic screen for inhibitors of protein deacetylation (data from Ref. 80). (a) Overview of cell-based screens of the 1,3-dioxane-based, diversity-oriented synthesis-derived library using antibodies to measure tubulin and histone acetylation, (b) Relative position of selected active compounds in a three-dimensional principal component model computed from five cell-based assay descriptors. AcTubulin-selective (red),...

Figure 6.26 Principal component analysis of chemical space properties for groups of compounds categorized as drugs, bioactives, natural products, fragments, diversity oriented synthesis (DOS) and Rule-of-Five. Numbered compounds representative of the various categories are given in the reference. (Reprinted with permission from Shelat, A. A., Guy, R.K. The interdependence between screening methods and screening libraries. Curr. Opin. Chem. Biol. 2007, 11, 244-251, copyright 2007, Elsevier.)...

Towards drugging the undrug-gable enhancing the scaffold diversity of synthetic small molecule screening collections using diversity-oriented synthesis. Divers. Oriented Synth., 1, 21-28. 

Peuchmaiu- M, Wong Y-S (2008) Expanding the chemical space in practice diversity-oriented synthesis. Comb Chem High Throughput Screen 11 587-601... 

F. De Moliner, L. Banfi, R. Riva, A. Basso, Comb. Chem. High Throughput Screen. 2011, 14, 782-810. Beyond Ugi and Passerini reactions. Multicomponent approaches based on isocyanides and alkynes as an efficient tool for diversity oriented synthesis. 

Generation of New Screening Compounds l09 Diversity-oriented synthesis... 

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