A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds

Organic & Biomolecular Chemistry
Albert Isidro-LlobetDavid R Spring

Abstract

Macrocyclic peptidomimetics are associated with a broad range of biological activities. However, despite such potentially valuable properties, the macrocyclic peptidomimetic structural class is generally considered as being poorly explored within drug discovery. This has been attributed to the lack of general methods for producing collections of macrocyclic peptidomimetics with high levels of structural, and thus shape, diversity. In particular, there is a lack of scaffold diversity in current macrocyclic peptidomimetic libraries; indeed, the efficient construction of diverse molecular scaffolds presents a formidable general challenge to the synthetic chemist. Herein we describe a new, advanced strategy for the diversity-oriented synthesis (DOS) of macrocyclic peptidomimetics that enables the combinatorial variation of molecular scaffolds (core macrocyclic ring architectures). The generality and robustness of this DOS strategy is demonstrated by the step-efficient synthesis of a structurally diverse library of over 200 macrocyclic peptidomimetic compounds, each based around a distinct molecular scaffold and isolated in milligram quantities, from readily available building-blocks. To the best of our knowledge this represents an ...Continue Reading

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Citations

Jan 16, 2016·Angewandte Chemie·Christiana KitsiouWilliam P Unsworth
Mar 22, 2016·The Journal of Organic Chemistry·Garrett Thomas PotterJohn Michael Gardiner
May 18, 2016·Angewandte Chemie·Miguel Garcia-CastroKamal Kumar
Sep 21, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tze Han SumDavid R Spring
Oct 22, 2016·Angewandte Chemie·Daniel J FoleyStephen P Marsden
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Jul 18, 2017·Chemistry : a European Journal·Jörn SaupeChristian Mang
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Dec 10, 2016·Chemistry : a European Journal·Laetitia G BaudWilliam P Unsworth
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Naima AgouramAbdeslem Bentama
Mar 27, 2018·The Journal of Organic Chemistry·Mark B RichardsonGregory A Weiss
Jun 28, 2019·Chemical Reviews·Kim T MortensenDavid R Spring
Jun 4, 2019·Chemical Reviews·Ivan V SmolyarValentine G Nenajdenko
Nov 4, 2021·The Journal of Organic Chemistry·Wenqing XuJohn A Porco

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Methods Mentioned

BETA
column chromatography
PCA

Software Mentioned

DOS

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