Total Synthesis and Structural Revision of the Antibiotic Tetrapeptide GE81112A

Jürjens, Gerrit; Schuler, Sören M. M.; Kurz, Michael; Petit, Sylvain; Couturier, Cédric; Jeannot, Frédéric; Nguyen, Fabian; Wende, Raffael C.; Hammann, Peter; Wilson, Daniel N.; Bacqué, Eric; Pöverlein, Christoph; Bauer, Armin

doi:10.1002/anie.201805901

“…Slow addition of 4 to a solution of 5, EDC, Oxyma and NaHCO3 cleanly afforded 22 as a single diastereomer in 66% isolated yield. 4 In line with our model hydrogenation, 22 was chemoselectively reduced to amine 23 in 66% yield under the action of H2 and PtO2. Subsequent methyl ester hydrolysis followed by global deprotection and HPLC purification yielded GE81112 B1 in 36% over two steps as the TFA salt.…”

supporting

confidence: 63%

“…The MIC obtained for 3 was in close agreement with previous data in the literature. 1,3,4 Analog 24 was found to be completely inactive. In conjunction with previous finding from Sanofi, this result suggests that the syn-b-hydroxy amino acid unit in AA1 is highly crucial for inhibitory activity.…”

mentioning

confidence: 97%

“…To date, there is only one reported total synthesis of the GE81112s (GE81112 A, 2018) though minimal structure-activity relationship (SAR) has been established for this tetrapeptide. 4 Additionally, the reported synthesis suffers from high stepcount (7-8 steps per fragment) and poor stereocontrol (Figure 1A). In light of these shortcomings, we sought to develop a tractable chemoenzymatic synthesis of GE81112 B1 that will also be amenable for analog generation for SAR analysis.…”

mentioning

confidence: 99%

“…10a,b These conditions presumably proceed through the intermediacy of a silyl carbamate, which is hydrolyzed upon work-up. The resulting amine 7 was carried on crude to peptide coupling with 6, yielding 4 after saponification (Scheme 1C). followed by saponification.…”

mentioning

confidence: 99%

“…Scheme 3. Peptide coupling of 4 and 5 followed by deprotection sequence to complete the synthesis of GE81112 B1.…”

mentioning

confidence: 99%

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Concise Chemoenzymatic Total Synthesis of GE81112 B1 and Simplified Analogs Enable Elucidation of Its Key Pharmaco-phores

Zwick¹,

Sosa²,

Renata

³

2020

Preprint

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Euglenatides, Potent Antiproliferative Cyclic Peptides Isolated from the Freshwater Photosynthetic Microalga Euglena gracilis

Ganesan

¹

,

Aldholmi

²

,

Ahmad

³

et al. 2022

Angewandte Chemie

2

0

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By limiting the nitrogen source to glutamic acid, we isolated cyclic peptides from Euglena gracilis containing asparagine and non-proteinogenic amino acids. Structure elucidation was accomplished through spectroscopic methods, mass spectrometry and chemical degradation. The euglenatides potently inhibit pathogenic fungi and cancer cell lines e.g., euglenatide B exhibiting IC 50 values of 4.3 μM in Aspergillus fumigatus and 0.29 μM in MCF-7 breast cancer cells. In an unprecedented convergence of non-ribosomal peptide synthetase and polyketide synthase assembly-line biosynthesis between unicellular species and the metazoan kingdom, euglenatides bear resemblance to nemamides from Caenorhabditis elegans and inhibited both producing organisms E. gracilis and C. elegans. By molecular network analysis, we detected over forty euglenatide-like metabolites in E. gracilis, E. sanguinea and E. mutabilis, suggesting an important biological role for these natural products.

show abstract

Euglenatides, Potent Antiproliferative Cyclic Peptides Isolated from the Freshwater Photosynthetic Microalga Euglena gracilis

Ganesan

¹

,

Aldholmi

²

,

Ahmad

³

et al. 2022

View full text Add to dashboard Cite

By limiting the nitrogen source to glutamic acid, we isolated cyclic peptides from Euglena gracilis containing asparagine and non-proteinogenic amino acids. Structure elucidation was accomplished through spectroscopic methods, mass spectrometry and chemical degradation. The euglenatides potently inhibit pathogenic fungi and cancer cell lines e.g., euglenatide B exhibiting IC 50 values of 4.3 μM in Aspergillus fumigatus and 0.29 μM in MCF-7 breast cancer cells. In an unprecedented convergence of non-ribosomal peptide synthetase and polyketide synthase assembly-line biosynthesis between unicellular species and the metazoan kingdom, euglenatides bear resemblance to nemamides from Caenorhabditis elegans and inhibited both producing organisms E. gracilis and C. elegans. By molecular network analysis, we detected over forty euglenatide-like metabolites in E. gracilis, E. sanguinea and E. mutabilis, suggesting an important biological role for these natural products.

show abstract

Total Synthesis and Structural Revision of the Antibiotic Tetrapeptide GE81112A

Cited by 13 publications

References 21 publications

Concise Chemoenzymatic Total Synthesis of GE81112 B1 and Simplified Analogs Enable Elucidation of Its Key Pharmaco-phores

Concise Chemoenzymatic Total Synthesis of GE81112 B1 and Simplified Analogs Enable Elucidation of Its Key Pharmaco-phores

Euglenatides, Potent Antiproliferative Cyclic Peptides Isolated from the Freshwater Photosynthetic Microalga Euglena gracilis

Euglenatides, Potent Antiproliferative Cyclic Peptides Isolated from the Freshwater Photosynthetic Microalga Euglena gracilis

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