Chemical probes and drug leads from advances in synthetic planning and methodology

Abstract

Screening of small-molecule libraries is a productive method for identifying both chemical probes of disease-related targets and potential starting points for drug discovery. In this article, we focus on strategies such as diversity-oriented synthesis that aim to explore novel areas of chemical space efficiently by populating small-molecule libraries with compounds containing structural features that are typically under-represented in commercially available screening collections. Drawing from more than a decade's worth of examples, we highlight how the design and synthesis of such libraries have been enabled by modern synthetic chemistry, and we illustrate the impact of the resultant chemical probes and drug leads in a wide range of diseases.

Impact of NDI‐Core Substitution on the pH‐Responsive Nature of Peptide‐Tethered Luminescent Supramolecular Polymers

“…A change in the substitution of the NDI core from ethoxy to isopropylamino group altered the hydrophobic to hydrophilic balance in the molecular design and the electrostatic repulsion between the charged lysine moieties no longer overruled the strong hydrophobic desolvation, hydrogen bonding and π‐π stacking between chromophores. This is in agreement with the calculated logP (partition coefficient) values using online calculation service at www.molinspiration.com which gives a higher logP value for NDI‐OEtiPa‐cat core (2.46) than that of NDI‐diOEt‐cat core (1.69) (Figure SI6) . This suggests an increased hydrophobicity for NDI‐OEtiPa‐cat than that of NDI‐diOEt‐cat .…”

A Chemical Biology View of Bioactive Small Molecules and a Binder‐Based Approach to Connect Biology to Precision Medicines

“…[26] Compounds arising from modern asymmetric synthesis, and proven to have a novel mechanism of action, stand in contrast to the typical compounds thus far incorporated into DELs, even more so than the compounds that populate commercial vendor libraries for traditional screening. A reasonable proposal is that the value of DELs would be enhanced if a far greater range of candidate binders could be synthesized within the constraints of DEL technology, which include the need to perform synthetic transformations that are compatible with DNA and water.…”

Harnessing the Chemistry of the Indole Heterocycle to Drive Discoveries in Biology and Medicine

“…Diversity‐oriented synthesis (DOS) is an approach that aims to rapidly generate skeletally and stereochemically diverse small molecules to explore and interrogate biological systems of relevance to human disease and medicine . Both reagent‐based differentiation and substrate‐based folding approaches have been used in DOS to create novel and diverse compounds.…”