Siamese Depsipeptides: Constrained Bicyclic Architectures

Ruiz-Rodríguez, Javier; Spengler, Jan; Alberício, Fernando

doi:10.1002/ange.200904135

Angewandte Chemie

2009

DOI: 10.1002/ange.200904135

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Siamese Depsipeptides: Constrained Bicyclic Architectures

Javier Ruiz-Rodríguez¹,

Jan Spengler²,

Fernando Alberício³

Abstract: Die ersten Vertreter einer neuen Klasse von Depsipeptiden mit Weinsäure als zentraler Einheit – bezeichnet als siamesische Depsipeptide – wurden aus einer verzweigten Vorstufe in einem einzigen Cyclisierungsschritt erhalten. Strukturmodifikationen eines natürlichen bioaktiven Depsipeptids (Sansalvamid A) liefern Analoga mit höherer Aktivität und damit Zusatzinformationen über Struktur‐Aktivitäts‐Beziehungen (siehe Formeln).

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Cited by 2 publications

References 29 publications

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Ribosomal Synthesis of Natural‐Product‐Like Bicyclic Peptides in Escherichia coli

Bionda

Fasan

2015

ChemBioChem

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Methods to access natural product-like macrocyclic peptides can disclose new opportunities for the exploration of this important structural class for chemical biology and drug discovery applications. Here, the scope and mechanism of a novel strategy for directing the biosynthesis of thioether-bridged bicyclic peptides in bacterial cells was investigated. This method entails split intein-catalyzed head-to-tail cyclization of a ribosomally produced precursor peptide combined with inter-side-chain cross-linking via a genetically encoded cysteine-reactive amino acid. This study demonstrates how this strategy can be successfully applied to achieve the formation of structurally diverse bicyclic peptides with high efficiency and selectivity in E. coli. Insights into the sequence of reaction underlying the peptide bicyclization process were gained from time course experiments. Finally, the potential utility of this methodology toward the discovery of macrocyclic peptides with enhanced functional properties was illustrated through the isolation of a bicyclic peptide with submicromolar affinity for streptavidin.

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Ribosomal Synthesis of Natural‐Product‐Like Bicyclic Peptides in Escherichia coli

Bionda

Fasan

2015

ChemBioChem

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Structural Diversity using Hyp “Customizable Units”: Proof‐of‐Concept Synthesis of Sansalvamide‐Related Antitumoral Peptides

et al. 2021

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The potential of “customizable units” to generate structural diversity for biological screenings is highlighted in this proof‐of‐concept synthesis of new peptides related to the potent antitumoral Sansalvamide A. Using L‐4‐hydroxyproline (Hyp) as a customizable unit in a linear parent peptide, an improved procedure for selective peptide modification was developed. A divergent Hyp scission‐reductive amination process was carried out, affording five linear peptides with cationic residues, and notably, an N‐alkyl moiety that affected the conformation of the peptide. After two steps (saponification and macrocyclization), sixteen differently N1‐substituted linear and cyclic peptides were obtained. For the first time, the activity of the linear and cyclic compounds was compared. Not only some linear analogs but also cyclic compounds with scarcely studied cationic residues were active against MCF7 breast cancer line. Thus, the structural diversity generated from customizable units can be valuable in drug discovery.

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Siamese Depsipeptides: Constrained Bicyclic Architectures

Cited by 2 publications

References 29 publications

Ribosomal Synthesis of Natural‐Product‐Like Bicyclic Peptides in Escherichia coli

Ribosomal Synthesis of Natural‐Product‐Like Bicyclic Peptides in Escherichia coli

Structural Diversity using Hyp “Customizable Units”: Proof‐of‐Concept Synthesis of Sansalvamide‐Related Antitumoral Peptides

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