Abstract
Fragment-based drug discovery (FBDD) is a well-established approach for the discovery of novel medicines, illustrated by the approval of two FBBD-derived drugs. This methodology is based on the utilization of small “fragment” molecules (<300 Da) as starting points for drug discovery and optimization. Organic synthesis has been identified as a significant obstacle in FBDD, however, in particular owing to the lack of novel 3-dimensional (3D) fragment collections that feature useful synthetic vectors for modification of hit compounds. Diversity-oriented synthesis (DOS) is a synthetic strategy that aims to efficiently produce compound collections with high levels of structural diversity and three-dimensionality and is therefore well-suited for the construction of novel fragment collections. This Mini-Review highlights recent studies at the intersection of DOS and FBDD aiming to produce novel libraries of diverse, polycyclic, fragment-like compounds, and their application in fragment-based screening projects.
Highlights
Within the biomedical community there remains a pressing need for new molecules to seed early stage drug discovery programs
In a similar vein to traditional drug discovery, deficiencies in commercially available fragment screening collections have been noted, in particular relating to the overrepresentation of sp2-rich flat molecules (Hajduk et al, 2011; Hung et al, 2011) that feature limited numbers of synthetic handles for fragment elaboration
With a growing demand for novel heterocycles and 3Dshaped molecules for use within Fragment-based drug discovery (FBDD) campaigns, many studies centering on the synthesis of 3D fragments around single heterocycles have been reported, for example using C-H activation methodologies (Davis et al, 2015; Palmer et al, 2016; Antermite et al, 2018)
Summary
Within the biomedical community there remains a pressing need for new molecules to seed early stage drug discovery programs. Diversity-oriented synthesis (DOS) emerged in the early 2000s in response to this challenge, a strategy which involves the efficient and deliberate construction of multiple scaffolds in a divergent manner (Lee et al, 2000; Schreiber, 2000; Spring, 2003; Burke and Schreiber, 2004) Nowadays, applications of this methodology span much of the spectrum of chemical space with examples describing the synthesis of fragment(Hung et al, 2011), small molecule (Wyatt et al, 2008; Lenci et al, 2015; Caputo et al, 2017), peptide (Kotha et al, 2013; Contreras-Cruz et al, 2017; Zhang et al, 2017) and macrocyclic (Isidro-Llobet et al, 2011; Kopp et al, 2012; Beckmann et al, 2013; Dow et al, 2017) collections all abundant within the literature. The majority of DOS successes have been achieved in high-throughput screening (HTS) contexts (Chou et al, 2011; Laraia et al, 2014; Aldrich et al, 2015; Kuo et al, 2015)
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