Synthesis, Structure, and Cytotoxicity of Urukthapelstatin A Polyazole Cyclopeptide Analogs

Analogs of the natural product urukthapelstatin A that belongs to the rare family of polyazole cyclopeptides were synthesized and their cytotoxic activities were determined to gather data toward structure–activity relationships. Crucial steps within the convergent syntheses were a macrothiolactoniza...

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Bibliographic Details
Published in:European journal of organic chemistry 2019-07, Vol.2019 (27), p.4320-4326
Main Authors: Oberheide, Ansgar, Schwenk, Sebastian, Ronco, Cyril, Semmrau, Lisa Maria, Görls, Helmar, Arndt, Hans‐Dieter
Format: Article
Language:English
Subjects:
Analogs
Biocompatibility
Chemical Sciences
Conformation analysis
Crystallography
Cyclopeptides
Cytotoxicity
Heterocycles
Heterocyclic compounds
Hydrogen bonds
Natural products
Oxazole
Structure–activity relationship
Toxicity
X‐ray crystallography
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Summary:Analogs of the natural product urukthapelstatin A that belongs to the rare family of polyazole cyclopeptides were synthesized and their cytotoxic activities were determined to gather data toward structure–activity relationships. Crucial steps within the convergent syntheses were a macrothiolactonization and a subsequent aza‐Wittig reaction to install the heterocyclic backbone. The synthesis design was proven to be generally suitable for the formation of these azole containing cyclopeptides. Two analogs were structurally characterized by X‐ray crystallography which unveiled the planar assembly of the five catenated azoles as well as a unique hydrogen bond network. A conformational comparison to the known natural products was conducted. Cytotoxicity data showed the importance of key structural features with respect to the bioactivity including the phenyl ring attached to the eastern oxazole and the rigid, lipophilic tripeptide section. Polyazole cyclopeptides related to the natural product urukthapelstatin A were synthesized by using efficient macrothiolactonization and aza‐Wittig ring contraction. Their solid‐state conformations were analyzed based on X‐ray crystallography and key structural features were unveiled with respect to the cytotoxicity of these cyclopeptides.
ISSN:1434-193X
1099-0690
DOI:10.1002/ejoc.201900206