A noticeable increase in molecular complexity of drug targets has created an unmet need in the therapeutic agents that are larger than traditional small molecules. Macrocycles, which are cyclic compounds comprising 12 atoms or more, are now recognized as molecules that “are up to the task” to interrogate extended protein interfaces. However, because macrocycles (particularly the ones based on peptides) are equipped with large polar surface areas, achieving cellular permeability and bioavailability is anything but straightforward. While one might consider this to be the Achilles' heel of this class of compounds, the synthetic community continues to develop creative approaches toward the synthesis of macrocycles and their site-selective modification. This perspective provides an overview of both mechanistic and structural issues that bear on macrocycles as a unique class of molecules. The reader is offered a historical foray into some of the classic studies that have resulted in the current renaissance of macrocycles. In addition, an attempt is made to overview the more recent developments that give hope that macrocycles might indeed turn into a useful therapeutic modality.

/pdf/macrocycles-lessons-from-the-distant-past-recent-1fsfq3xwac.pdf

Macrocycles: lessons from the distant past, recent developments, and future directions

Organic compounds possessing S–S bonds, often called disulfides or more specifically disulfanes, have been widely applied in various fields ranging from biochemistry to different industrially important polymers, used as synthetic intermediates in other fine chemicals such as catenanes, rotaxanes, micelles, and also in areas like peptidomimetics, self-assembled monolayers (SAMs) etc. Such versatile applications have steered the development of several new methods for the preparation of organic disulfides. The present review has attempted to comprehensively summarize recent advances in the process of S–S bond formation, highlighting plausible mechanistic considerations, scope and limitations.

Recent advances in S–S bond formation

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.

Strategies for Fine-Tuning the Conformations of Cyclic Peptides.

Peptide neurotoxins from cone snails called conotoxins are renowned for their therapeutic potential to treat pain and several neurodegenerative diseases. Inefficient assay-guided discovery methods have been replaced by high-throughput bioassays integrated with advanced MS and next-generation sequencing, ushering in the era of 'venomics'. In this review, we focus on the impact of venomics on the understanding of cone snail biology as well as the application of venomics to accelerate the discovery of new conotoxins. We also discuss the continued importance of medicinal chemistry approaches to optimize conotoxins for clinical use, with a descriptive case study of MrIA featured.

Cone snail venomics: From novel biology to novel therapeutics

Abstract Isolation of cyclic (alkyl) amino carbenes (cAACs) in 2005 has been a major achievement in the field of stable carbenes due to their better electronic properties. cAACs and bicyclic(alkyl)(amino)carbene (BicAAC) in essence are the most electrophilic as well as nucleophilic carbenes are known till date. Due to their excellent electronic properties in terms of nucleophilic and electrophilic character, cAACs have been utilized in different areas of chemistry, including stabilization of low valent main group and transition metal species, activation of small molecules, and catalysis. The applications of cAACs in catalysis have opened up new avenues of research in the field of cAAC chemistry. This review summarizes the major results of cAAC chemistry published until August 2021.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/asia.202101301

Recent Advances in the Domain of Cyclic (Alkyl)(Amino) Carbenes

Loopy peptides: Peptide turn mimetics of a clinically relevant norepinephrine reuptake inhibitor were developed employing a high-throughput synthesis approach to generate peptide thioesters, with subsequent cyclization through native chemical ligation. The vicinal disulfide constrained cyclic peptidomimetics (see scheme) show high structural and functional similarity to the parent peptide, though with superior metabolic stability. Copyright

/pdf/vicinal-disulfide-constrained-cyclic-peptidomimetics-a-turn-o4coojb342.pdf

Vicinal Disulfide Constrained Cyclic Peptidomimetics: a Turn Mimetic Scaffold Targeting the Norepinephrine Transporter

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Vicinal Disulfide Constrained Cyclic Peptidomimetics: a Turn Mimetic Scaffold Targeting the Norepinephrine Transporter