White cj yudin akcontemporary strategies for peptide macrocyclizationnat chem 2011 3 509 − 524 Peptide macrocyclization is a crucial technique in modern chemistry, enabling the creation of constrained peptide structures with enhanced pharmacological properties and bioactivity. This field has seen significant advancements, moving beyond traditional methods to embrace diverse, state-of-the-art macrocyclization methodologies. Contemporary strategies aim to address the major challenges in synthesizing these complex molecules, offering innovative solutions for peptide sequence-level optimization and the development of novel therapeutic agents.
The formation of a peptide macrocycle involves creating a covalent bond that closes a linear peptide chain into a ring.作者：TR Oppewal·2022·被引用次数：59—We report anefficient two-step strategyto access MPs via the programmed modification of a unique cysteine residue and an N-terminal amine. This structural constraint is often employed to fix specific bioactive conformations, which can lead to improved receptor binding affinity, increased metabolic stability, and enhanced cell permeability. Consequently, macrocyclic peptides are gaining prominence in drug discovery and development, serving as scaffolds for a new generation of therapeutics.Here we describe thesynthetic strategy of peptide macrocyclizationthrough late-stage palladium-catalyzed C-H activation. These methods utilize endogenous ... The drive to develop more efficient and versatile macrocyclization techniques is a testament to their growing significance.
Historically, peptide macrocyclization relied heavily on classical lactamization, forming amide bonds between the N-terminus and a C-terminal carboxyl group, or between side chains.作者：É Biron·2017·被引用次数：8—In many cases, thesolution-phase strategyis the best choice for performing the macrocyclization step, especially when larger quantities of ... While effective, these methods can be challenging due to conformational preferences of the peptide backbone and potential side reactions.Contemporary strategies for peptide macrocyclization The field has since expanded dramatically, incorporating a wide array of modern organic chemistry approaches.
Recent developments include sophisticated cyclization strategies that leverage various functional groups and reaction mechanisms.Contemporary strategies for peptide macrocyclization. · Peptide macrocyclization through amide-to-amide transpeptidation · Chemoselective cyclization of ... These contemporary strategies often focus on creating linkages other than simple amide bonds, such as those formed through imine and imine analogue formation, or through palladium-catalyzed reactions like C-H activation. Such approaches offer greater control over regioselectivity and can be applied to a broader range of peptide substrates.
A significant area of innovation lies in the development of "new cyclization strategies for peptide macrocyclization" that move beyond established protocols.作者：P Fang·2024·被引用次数：46—In this tutorial review,diverse state-of-the-art macrocyclization methodologies and techniquesfor peptides and peptidomimetics are surveyed and discussed. These include:
* Metal-Catalyzed Cyclizations: Palladium-catalyzed reactions, for instance, have emerged as powerful tools for constructing peptide macrocycles. These methods often involve intramolecular C-H activation or cross-coupling reactions, allowing for the formation of carbon-carbon or carbon-heteroatom bonds within the peptide chain作者：P Fang·2024·被引用次数：46—In this tutorial review,diverse state-of-the-art macrocyclization methodologies and techniquesfor peptides and peptidomimetics are surveyed and discussed.. This offers a high degree of synthetic flexibility and can be applied in late-stage functionalization作者：C Nitsche·2019·被引用次数：72—3. White, C. J.; Yudin, A. K.,Contemporary strategies for peptide macrocyclization. Nat. Chem. 2011, 3, 509–524..
* Click Chemistry Approaches: Reactions such as the azide-alkyne cycloaddition provide efficient and biocompatible routes to macrocyclic structures. These methods are known for their high yields, specificity, and tolerance of various functional groups, making them attractive for complex peptide synthesis.
* Biomimetic and Biosynthetic Strategies: Inspired by natural product biosynthesis, researchers are developing strategies that mimic enzymatic processes.2024年11月19日—Owing to their special spatial structures,peptide-based macrocycles have recently shown tremendous promise in multidisciplinary research ... This includes leveraging specific amino acid residues, such as cysteine, for facile and biocompatible cyclization through reactions like disulfide bond formation or Michael additions.Contemporary strategies for peptide macrocyclization The development of efficient two-step strategies often draws from these principles作者：TR Oppewal·2022·被引用次数：59—We report anefficient two-step strategyto access MPs via the programmed modification of a unique cysteine residue and an N-terminal amine..
* Solution-Phase vs. Solid-Phase Synthesis: While solid-phase peptide synthesis (SPPS) has been a cornerstone of peptide chemistry, solution-phase strategies remain vital, particularly for macrocyclization steps involving larger quantities or when specific reaction conditions are required. The choice between these approaches depends on the specific peptide sequence and desired macrocycle.Biocompatible macrocyclization between cysteine and 2- ...
Despite the significant progress, challenges persist in peptide macrocyclization.Biocompatible macrocyclization between cysteine and 2- ... These include achieving regioselectivity, controlling conformational outcomes, and improving the efficiency of cyclization for longer or more complex peptide sequences. Furthermore, transitioning macrocyclic peptides to cell-permeable drugs requires strategies that enhance their pharmacokinetic properties, a goal that macrocyclization itself helps to achieve.
The ongoing exploration of "diverse state-of-the-art macrocyclization methodologies and techniques" continues to push the boundaries of what is possible.作者：W Wang·2021·被引用次数：21—Macrocyclizationhas become a common approach for improving the pharmacological properties and bioactivity ofpeptides. A variety of ribosomal-derived and non- ... Future research is likely to focus on developing more sustainable and environmentally friendly methods, expanding the repertoire of accessible macrocyclic scaffolds, and integrating computational design with experimental synthesis to accelerate the discovery of novel peptide-based therapeutics.作者：P Fang·2024·被引用次数：46—In this tutorial review,diverse state-of-the-art macrocyclization methodologies and techniquesfor peptides and peptidomimetics are surveyed and discussed. The pursuit of innovative synthetic strategies enabling efficient macrocyclization will remain a key driver in this dynamic field.
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