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1. Synthesis of Carbohydrate Based Macrolactones and Their Applications as Receptors for Ion Recognition and Catalysis

   https://doi.org/10.3390/molecules26113394  

   Adhikari, Surya B.; Chen, Anji; Wang, Guijun (June 2021, Molecules)

   null (Ed.)

   Glycomacrolactones exhibit many interesting biological properties, and they are also important in molecular recognitions and for supramolecular chemistry. Therefore, it is important to be able to access glycomacrocycles with different sizes and functionality. A new series of carbohydrate-based macrocycles containing triazole and lactone moieties have been designed and synthesized. The synthesis features an intramolecular nucleophilic substitution reaction for the macrocyclization step. In this article, the effect of some common sulfonate leaving groups is evaluated for macrolactonization. Using tosylate gave good selectivity for monolactonization products with good yields. Fourteen different macrocycles have been synthesized and characterized, of which eleven macrocycles are from cyclization of the C1 to C6 positions of N-acetyl D-glucosamine derivatives and three others from C2 to C6 cyclization of functionalized D-glucosamine derivatives. These novel macrolactones have unique structures and demonstrate interesting anion binding properties, especially for chloride. The macrocycles containing two triazoles form complexes with copper sulfate, and they are effective ligands for copper sulfate mediated azide-alkyne cycloaddition reactions (CuAAC). In addition, several macrocycles show some selectivity for different alkynes. 

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2. p ‐Chloropropynyl Phenylalanine, a Versatile Non‐Canonical Amino Acid for Co‐Translational Peptide Macrocyclization and Side Chain Diversification

   https://doi.org/10.1002/cbic.202300020  

   Osorio Franco, H. Estheban; Le, Anthony V.; Chang, Nathan Y.; Hartman, Matthew C. T. (May 2023, ChemBioChem)

   Abstract Macrocyclization has proven to be a beneficial strategy to improve upon some of the disadvantages of peptides as therapeutics. Nevertheless, many peptide cyclization strategies are not compatible with in vitro display technologies like mRNA display. Here we describe the novel amino acidp‐chloropropynyl phenylalanine (pCPF). pCPF is a substrate for a mutant phenylalanyl‐tRNA synthetase and its introduction into peptides via in vitro translation leads to spontaneous peptide macrocyclization in the presence of peptides containing cysteine. Macrocyclization occurs efficiently with a wide variety of ring sizes. Moreover, pCPF can be reacted with thiols after charging onto tRNA, enabling the testing of diverse ncAAs in translation. The versatility of pCPF should facilitate downstream studies of translation and enable the creation of novel macrocyclic peptide libraries. 

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3. N-Terminal cysteine mediated backbone-side chain cyclization for chemically enhanced phage display

   https://doi.org/10.1039/d2sc03241d  

   Zheng, Mengmeng; Haeffner, Fredrik; Gao, Jianmin (July 2022, Chemical Science)

   Phage display, an ingenious invention for evaluating peptide libraries, has been limited to natural peptides that are ribosomally assembled with proteinogenic amino acids. Recently, there has been growing interest in chemically modifying phage libraries to create nonnatural cyclic and multicyclic peptides, which are appealing for use as inhibitors of protein–protein interactions. While earlier reports largely focused on side-chain side-chain cyclization, we report herein a novel strategy for creating backbone-side chain cyclized peptide libraries on phage. Our strategy capitalizes on the unique reactivity of an N-terminal cysteine (NCys) with 2-cyanobenzothiazole (CBT) which, in conjugation with another thiol-reactive group, can elicit rapid cyclization between an NCys and an internal cysteine. The resulting library was screened against two model proteins, namely Keap1 and Sortase A. The screening readily revealed potent inhibitors for both proteins with certain Keap1 ligands reaching low nanomolar potency. The backbone-side chain cyclization strategy described herein presents a significant addition to the toolkit of creating nonnatural macrocyclic peptide libraries for phage display. 

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4. Near quantitative synthesis of urea macrocycles enabled by bulky N-substituent

   https://doi.org/10.1038/s41467-021-21678-3  

   Yang, Yingfeng; Ying, Hanze; Li, Zhixia; Wang, Jiang; Chen, Yingying; Luo, Binbin; Gray, Danielle L.; Ferguson, Andrew; Chen, Qian; Z, Y.; et al (March 2021, Nature Communications)

   Abstract Macrocycles are unique molecular structures extensively used in the design of catalysts, therapeutics and supramolecular assemblies. Among all reactions reported to date, systems that can produce macrocycles in high yield under high reaction concentrations are rare. Here we report the use of dynamic hindered urea bond (HUB) for the construction of urea macrocycles with very high efficiency. Mixing of equal molar diisocyanate and hindered diamine leads to formation of macrocycles with discrete structures in nearly quantitative yields under high concentration of reactants. The bulkyN-tert-butyl plays key roles to facilitate the formation of macrocycles, providing not only the kinetic control due to the formation of the cyclization-promotingcisC = O/tert-butyl conformation, but also possibly the thermodynamic stabilization of macrocycles with weak association interactions. The bulkyN-tert-butyl can be readily removed by acid to eliminate the dynamicity of HUB and stabilize the macrocycle structures. 

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5. Mismatched covalent and noncovalent templating leads to large coiled coil-templated macrocycles

   https://doi.org/10.1039/D3SC00231D  

   Stingley, Kyla J.; Carpenter, Benjamin A.; Kean, Kelsey M.; Waters, Marcey L. (May 2023, Chemical Science)

   Herein we describe the use of dynamic combinatorial chemistry to self-assemble complex coiled coil motifs. We amide-coupled a series of peptides designed to form homodimeric coiled coils with 3,5-dithiobenzoic acid (B) at the N-terminus and then allowed each B-peptide to undergo disulfide exchange. In the absence of peptide, monomer B forms cyclic trimers and tetramers, and thus we expected that addition of the peptide to monomer B would shift the equilibrium towards the tetramer to maximize coiled coil formation. Unexpectedly, we found that internal templation of the B-peptide through coiled coil formation shifts the equilibrium towards larger macrocycles up to 13 B-peptide subunits, with a preference for 4, 7, and 10-membered macrocycles. These macrocyclic assemblies display greater helicity and thermal stability relative to intermolecular coiled coil homodimer controls. The preference for large macrocycles is driven by the strength of the coiled coil, as increasing the coiled coil affinity increases the fraction of larger macrocycles. This system represents a new approach towards the development of complex peptide and protein assemblies. 

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