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

Miguel Garcia-Castro, Lea Kremer, Christopher D. Reinkemeier, Christian Unkelbach, Carsten Strohmann, Slava Ziegler, Claude Ostermann and Kamal Kumar ()
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Miguel Garcia-Castro: Max-Planck-Institut für Molekulare Physiologie
Lea Kremer: Max-Planck-Institut für Molekulare Physiologie
Christopher D. Reinkemeier: Max-Planck-Institut für Molekulare Physiologie
Christian Unkelbach: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie
Carsten Strohmann: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie
Slava Ziegler: Max-Planck-Institut für Molekulare Physiologie
Claude Ostermann: Compound Management and Screening Center (COMAS), Max-Planck-Institut für Molekulare Physiologie
Kamal Kumar: Max-Planck-Institut für Molekulare Physiologie

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7516

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