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

Nature Communications
Miguel Garcia-CastroKamal Kumar

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.

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Citations

Apr 7, 2016·Accounts of Chemical Research·David TejedorFernando García-Tellado
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May 18, 2016·Angewandte Chemie·Miguel Garcia-CastroKamal Kumar
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Jun 1, 2016·Chemical Science·Niels HammerKarl Anker Jørgensen
Apr 1, 2021·Journal of the Royal Society, Interface·Madhur Mangalam, Damian G Kelty-Stephen
Dec 14, 2018·Organic Letters·Uttam K MishraS S V Ramasastry

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