Chapter 2:The Application of Diversity-oriented Synthesis in Chemical Biology

Research into the applications of small molecules has proven to be a fruitful field for enabling both the investigation and understanding of biological systems and, thus, also forms the basis of many modern medicinal investigations. Indeed, the screening of small-molecule collections has been successfully used in chemical biology to identify and validate potential therapeutic targets (using chemical probes) as well as in drug discovery to identify novel bioactive compounds (hits). Despite this success, however, a key factor that impedes the efficient discovery of new small-molecule modulators is the availability of appropriate chemical modulators for challenging biological targets. A difficult question then arises regarding which molecules to synthesize and test, and how to ensure a broad coverage of chemical space. One powerful solution to this question is diversity-oriented synthesis (DOS), a chemical synthetic strategy that is focused on the rapid construction of complex and diverse compound collections covering a broad range of chemical space, using efficient synthetic transformations. This chapter aims to provide a brief overview of the central concepts of DOS, how DOS is used to construct complex and diverse small-molecule libraries and how the application of this strategy can be beneficial for the discovery of novel small-molecule modulators of important biological systems as probes or hit compounds. This chapter will highlight recent successful examples of the combination of DOS with different screening strategies to identify small-molecule modulators of biological processes involved in important disease areas such as antibacterials, anticancer agents and antiparasitics, ultimately enabling novel discoveries in biology and medicine and revealing new potential therapeutic strategies.