Heterocycles: Versatile control elements in bioactive macrocycles

Soor, Harjeet S.; Appavoo, Solomon D.; Yudin, Andrei K.

doi:10.1016/j.bmc.2017.10.022

Cited by 26 publications

(13 citation statements)

References 47 publications

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“…We previously developed a chemoselective ligation for facile incorporation of reduced amides into linear peptides and, over the years, have been interested in augmenting the effect of these structural units through the use of heterocycles. Grafting heterocycles into macrocyclic backbones is an emerging modality to exercise conformational control over cyclic peptides . Some natural products offer a blueprint: for example, the thiazole ring in sanguinamide A leads to improved bioavailability over the corresponding all-amide congener .…”

Section: Introductionmentioning

confidence: 99%

Development of Endocyclic Control Elements for Peptide Macrocycles

et al. 2018

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Synthetic methods that provide control over macrocycle conformation represent valuable tools for the discovery of bioactive molecules. Incorporation of heterocycles into cyclic peptides may offer a way to stabilize their solution conformations. Herein, we used N-(isocyanimino)triphenylphosphorane (Pinc) to install an oxadiazole ring and an endocyclic amine into peptide macrocycles. To elucidate the conformational effect of this constellation of functionalities, we performed synthesis, variable temperature NMR analysis, and NOE-based molecular dynamics simulation of a range of macrocycles in DMSO. As part of this study, we conducted experiments to compare macrocycle conformation in aqueous and DMSO solutions. The obtained solution structures suggest that the reduced amide bond/heterocycle (RAH) motif can stabilize macrocycle conformations in both water and DMSO, which addresses an enduring challenge in molecular design. The conformational effect of the RAH was used in an effort to mimic the biologically relevant secondary structure of MAdCAM-1. This resulted in the discovery of a novel αβ integrin antagonist.

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Section: Introductionmentioning

confidence: 99%

Development of Endocyclic Control Elements for Peptide Macrocycles

et al. 2018

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“…It is well established in the medicinal chemistry literature that certain small heterocycles (e.g., oxazoles, oxazolines, thiazoles, thiazolines, triazoles, oxadiazoles) can successfully serve as isosteric replacements for amide groups. When such heterocyclic isosteric replacements are made in the context of a cyclic peptide architecture, there can be interesting flow-on effects on the overall molecular conformation. − …”

Section: The Effect Of Structural Modification On the Conformations O...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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“…Heterocyclic structural blocks can be found in various biologically active natural and non-natural products and are widely employed in the synthesis of pharmaceuticals, agrochemicals, dyes, and polymeric materials. [1][2][3][4][5][6][7][8] Numerous reviews and books on the synthesis and properties of heterocyclic compounds have been published. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] Five-membered heterocycles with nitrogen and oxygen atoms in the ring, such as oxazolines, oxazoles, isoxazolines, and isoxazoles, are particularly important in life-saving drugs, bioactive natural compounds, products of the pharmaceutical industry, synthetic building blocks, and as metal catalyst ligands.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Oxazoline and Oxazole Derivatives by Hypervalent-Iodine-Mediated Oxidative Cycloaddition Reactions

et al. 2020

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Organohypervalent iodine reagents are widely used for the preparation of various oxazolines, oxazoles, isoxazolines, and isoxazoles. In the formation of these heterocyclic compounds, hypervalent iodine species can serve as the activating reagents for various substrates, as well as the heteroatom donor reagents. In recent research, both chemical and electrochemical approaches toward generation of hypervalent iodine species have been utilized. The in situ generated active species can react with appropriate substrates to give the corresponding heterocyclic products. In this short review, we summarize the hypervalent-iodine-mediated preparation of oxazolines, oxazoles, isoxazolines, and isoxazoles starting from various substrates.1 Introduction2 Synthesis of Oxazolines3 Synthesis of Oxazoles4 Synthesis of Isoxazolines5 Synthesis of Isoxazoles6 Conclusion

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Heterocycles: Versatile control elements in bioactive macrocycles

Cited by 26 publications

References 47 publications

Development of Endocyclic Control Elements for Peptide Macrocycles

Development of Endocyclic Control Elements for Peptide Macrocycles

Strategies for Fine-Tuning the Conformations of Cyclic Peptides

Synthesis of Oxazoline and Oxazole Derivatives by Hypervalent-Iodine-Mediated Oxidative Cycloaddition Reactions

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