Towards drugging the ‘undruggable’: enhancing the scaffold diversity of synthetic small molecule screening collections using diversity-oriented synthesis

Abstract

Medicinal chemistry research has traditionally focused upon a limited set of biological targets. Many other human disease-related targets have been termed ‘undruggable’ as they have proved largely impervious to modulation by small molecules. However, it is becoming increasingly evident that such targets can indeed be modulated; they are simply being challenged with the wrong types of molecules. Traditionally, screening libraries were composed of large numbers of structurally similar compounds. However, library size is not everything; the structural diversity of the library, which is largely dictated by the range of molecular scaffolds present, is crucial. Diversity-oriented synthesis (DOS) generates small molecule libraries with high levels of scaffold, and thus structural, diversity. Such collections should provide hits against a broad range of targets with high frequency, including ‘undruggable’ targets. Examples in the area of scaffold diversity generation taken from the author’s laboratories are given.

Sustainable Practices in Medicinal Chemistry Part 2: Green by Design

“…DOS has been defined as deliberate, simultaneous, and efficient synthesis of libraries in a diversity-driven approach. The libraries yielded are normally smaller in size than their commercially available libraries but are typically structurally more complex, with a greater variety of core scaffolds and richer stereochemical variation . Diversity-oriented synthesis (DOS) generates small molecule libraries with high levels of structural diversity with examples highlighting green chemistry in the literature. ,− …”

“…The libraries yielded are normally smaller in size than their commercially available libraries but are typically structurally more complex, with a greater variety of core scaffolds and richer stereochemical variation. 63 Diversityoriented synthesis (DOS) generates small molecule libraries with high levels of structural diversity with examples highlighting green chemistry in the literature. 28,63−66 DOS can take into account both standard drug-like chemical space and "natural-product"-like space with most DOS library design strategies leveraging information about existing biologically active small molecules to generate compounds that similarly target these regions.…”

Scaffold Diversity Synthesis with Branching Cascades Strategy

“…Often, scaffolds are directly involved in interactions with protein targets or receptors, either by hydrogen bonds or hydrophobic interactions. Scaffold diversity is therefore a very important parameter to characterize compound libraries and to identify diverse ligands that could interact with diverse protein targets [34,35]. However; a balance between the diversity of core frameworks or scaffolds within a library and the density of representation of each scaffold is nevertheless required.…”

Air-Stable Pd Catalytic Systems for Sequential One-Pot Synthesis of Challenging Unsymmetrical Aminoaromatics

“…During our initial study, we developed a convenient Pd-catalyzed methodology for the preparation of push–pull dyes starting from 7-bromo-9,9-dimethylfluorene-2-carbaldehyde. We now wish to report an appendage diversity-oriented synthesis (DOS) ,, of functionalized aromatic compounds using air-stable palladium catalytic systems (Scheme ).…”