De novo branching cascades for structural and functional diversity in small molecules.

Miguel Garcia-Castro,Christopher D Reinkemeier,Lea Kremer,Slava Ziegler,Kamal Kumar,Christian Unkelbach,Claude Ostermann,Carsten Strohmann

doi:10.1038/ncomms7516

Miguel Garcia-Castro, Christopher D Reinkemeier + Show 6 more

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https://doi.org/10.1038/ncomms7516

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Abstract

The limited structural diversity that a compound library represents severely restrains the discovery of bioactive small molecules for medicinal chemistry and chemical biology research, and thus calls for developing new divergent synthetic approaches to structurally diverse and complex scaffolds. Here we present a de novo branching cascades approach wherein simple primary substrates follow different cascade reactions to create various distinct molecular frameworks in a scaffold diversity phase. Later, the scaffold elaboration phase introduces further complexity to the scaffolds by creating a number of chiral centres and incorporating new hetero- or carbocyclic rings. Thus, employing N-phenyl hydroxylamine, dimethyl acetylenedicarboxylate and allene ester as primary substrates, a compound collection of sixty one molecules representing seventeen different scaffolds is built up that delivers a potent tubulin inhibitor, as well as inhibitors of the Hedgehog signalling pathway. This work highlights the immense potential of cascade reactions to deliver compound libraries enriched in structural and functional diversity.

Highlights

The limited structural diversity that a compound library represents severely restrains the discovery of bioactive small molecules for medicinal chemistry and chemical biology research, and calls for developing new divergent synthetic approaches to structurally diverse and complex scaffolds
Different approaches have been developed to incorporate structural diversity to a compound collection, for instance, in the build-couple-pair strategies[12,13], folding[14] and branching pathways[15,16,17], structural variations either in the building blocks or the reacting partners of common substrates derive the formation of new scaffolds
Terpenes and sesquiterpenes represent interesting examples of de novo biosynthesis designs where compound collections are generated in two important phases; the first cyclase phase builds up scaffolds from simple acyclic substrates with the help of cyclase enzymes and the phase elaborates these scaffolds, for instance, with oxidative modifications, to generate a number of diversely functionalized molecules (Fig. 1a)[25,26]

Summary

Introduction

The limited structural diversity that a compound library represents severely restrains the discovery of bioactive small molecules for medicinal chemistry and chemical biology research, and calls for developing new divergent synthetic approaches to structurally diverse and complex scaffolds. Terpenes and sesquiterpenes represent interesting examples of de novo biosynthesis designs where compound collections are generated in two important phases; the first cyclase phase builds up scaffolds from simple acyclic substrates with the help of cyclase enzymes and the phase elaborates these scaffolds, for instance, with oxidative modifications, to generate a number of diversely functionalized molecules (Fig. 1a)[25,26]. A de novo cascade reaction design is chosen in which simple acyclic substrates, N-phenylhydroxylamine, acetylenedicarboxylates and allene esters undergo branching cascades reactions under different reaction conditions to provide seven distinct scaffolds in SD phase. Cell-based screenings identify potent and novel bioactive molecules, representing four different structural classes, as inhibitors of tubulin polymerization or hedgehog signalling, and thereby validate the notion that functional diversity is bequeathed to a compound collection by scaffold diversity

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