Amide‐to‐Ester Substitution Allows Fine‐Tuning of the Cyclopeptide Conformational Ensemble

Cupido, Tommaso; Spengler, Jan; Ruiz-Rodríguez, Javier; Adán, Jaume; Mitjans, Francesc; Piulats, Jaume; Alberício, Fernando

doi:10.1002/anie.200907274

Cited by 18 publications

(17 citation statements)

References 38 publications

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“…Since small cyclic peptides still have considerable mobility of their backbones, [36–39] it is reasonable to expect that the ester-to-amide substitution in our case will also lead to significant conformational changes. Therefore, we should expect different CD spectra of depsipeptide 6 and amide analog 14 in water and less polar TFE, due to their different conformational flexibility and the ability of TFE to promote intramolecular H-bonds and stabilize preferential conformation.…”

Section: Resultsmentioning

confidence: 99%

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Effects of Cyclic Lipodepsipeptide Structural Modulation on Stability, Antibacterial Activity, and Human Cell Toxicity

et al. 2012

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Bacterial infections are becoming increasingly difficult to treat due to the development and spread of antibiotic resistance. Therefore, identifying novel antibacterial targets and new antibacterial agents capable of treating infections from drug-resistant bacteria is of vital importance. Structurally simple, yet potent fusaricidin or LI-F class of natural products represents a particularly attractive source of candidates for the development of new antibacterial agents. We have synthesized eighteen fusaricidin/LI-F analogs and investigated the effect of their structure modification on conformation, serum stability, antibacterial activity and human cell toxicity. Our findings show that substitution of an ester bond in depsipeptides with an amide bond may afford equally potent analogs with improved stability and greatly decreased cytotoxicity. Lower overall hydrophobicity/amphiphilicity of amide analogs in comparison to their parent depsipeptides, as indicated by the HPLC retention times, may explain dissociation of antibacterial activity and human cell cytotoxicity. These results indicate that amide analogs may have significant advantages over fusaricidin/LI-F natural products and their depsipeptide analogs as lead structures for the development of new antibacterial agents.

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Section: Resultsmentioning

confidence: 99%

“…[36, 71–73] In general, replacement of a hydrogen-donating NH-group by the oxygen atom in depsipeptides results in removal of the backbone H-bond, affecting therefore conformation of peptides. As long as the side chains are not altered, intramolecular hydrogen bonds affect the equilibrium distribution of peptide conformers.…”

Section: Discussionmentioning

confidence: 99%

Effects of Cyclic Lipodepsipeptide Structural Modulation on Stability, Antibacterial Activity, and Human Cell Toxicity

et al. 2012

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“…[25,36] Reportedly,m acrolactamization of 19 b with 10 equiv of EDC•HCl( r.t.,o vernight)a fforded the desired 20 b in approximately 38 %y ield (Scheme 2). [37] On the other hand, our developed conditions afforded the desired 20 a in 72 %y ield from 19 a (for preparation details, see Supporting Information) in only 10 s, although 20 a contains an acid-labile N-methyl amide structure (Scheme 2).…”

Section: Resultsmentioning

confidence: 99%

Rapid and Mild Lactamization Using Highly Electrophilic Triphosgene in a Microflow Reactor

Fuse

Komuro

Otake

et al. 2021

Chemistry A European J

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Lactams are cyclic amides that are indispensable as drugs and as drug candidates. Conventionall actamization includes acid-mediated and coupling-agent-mediated approaches that suffer from narrow substrate scope,m uch waste, and/orh igh cost. Inexpensive, less-wasteful approaches mediated by highly electrophilic reagents are attractive, but there is an imminent risk of side reactions. Herein,amethods using highly electrophilic triphosgene in am icroflow reactor that accomplishesr apid (0.5-10s), mild, inexpensive, and less-wasteful lactamizationare described. Methods Aa nd B, which use N-methylmorpholine and Nmethylimidazole, respectively, were developed. Various lactams and ac yclic peptide containing acid-and/orh eat-labile functional groups were synthesized in good to high yields without the need for tedious purification. Undesired reactions were successfully suppressed, and the risk of handling triphosgene was minimizedb yt he use of microflow technology.

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“…The constraints inherent to the macrocycle (e.g., the need to minimize steric and electrostatic repulsions) are usually more important. 65,66…”

Section: Typical Structures Of Homodetic Cyclic Tetra- Penta- and Hex...mentioning

confidence: 99%

Strategies for Fine-Tuning the Conformations of Cyclic Peptides

2020

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Cyclic peptides are promising scaffolds for drug development, attributable in part to their increased conformational order compared to linear peptides. However, when optimizing the target-binding or pharmacokinetic properties of cyclic peptides, it is frequently necessary to “fine-tune” their conformations, e.g., by imposing greater rigidity, by subtly altering certain side chain vectors, or by adjusting the global shape of the macrocycle. This review systematically examines the various types of structural modifications that can be made to cyclic peptides in order to achieve such conformational control.

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Amide‐to‐Ester Substitution Allows Fine‐Tuning of the Cyclopeptide Conformational Ensemble

Cited by 18 publications

References 38 publications

Effects of Cyclic Lipodepsipeptide Structural Modulation on Stability, Antibacterial Activity, and Human Cell Toxicity

Effects of Cyclic Lipodepsipeptide Structural Modulation on Stability, Antibacterial Activity, and Human Cell Toxicity

Rapid and Mild Lactamization Using Highly Electrophilic Triphosgene in a Microflow Reactor

Strategies for Fine-Tuning the Conformations of Cyclic Peptides

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