Synthesis of Halogenated α‐Amino Acids

Strickland, Madeleine; Willis, Christine L.

doi:10.1002/9783527631766.ch10

Cited by 4 publications

(2 citation statements)

References 96 publications

(63 reference statements)

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“…The synthesis of halogenated amino acids has already been reviewed and the excellent chapter by Strickland and Willis remains an important reference [ 104 ], as well as the methods of preparation of brominated tryptophan ( 15 – 19 ) reported by Bittner et al [ 67 ]. The fermentative production of the halogenated amino acid 7-chloro-L-tryptophan from sugars, ammonium and chloride salts has also been achieved.…”

Section: Halo-amino Acids and Halogenated Non-ribosomal Peptidesmentioning

confidence: 99%

Natural and Synthetic Halogenated Amino Acids—Structural and Bioactive Features in Antimicrobial Peptides and Peptidomimetics

Mardirossian

Rubini

Adamo³

et al. 2021

Molecules

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The 3D structure and surface characteristics of proteins and peptides are crucial for interactions with receptors or ligands and can be modified to some extent to modulate their biological roles and pharmacological activities. The introduction of halogen atoms on the side-chains of amino acids is a powerful tool for effecting this type of tuning, influencing both the physico-chemical and structural properties of the modified polypeptides, helping to first dissect and then rationally modify features that affect their mode of action. This review provides examples of the influence of different types of halogenation in amino acids that replace native residues in proteins and peptides. Examples of synthetic strategies for obtaining halogenated amino acids are also provided, focusing on some representative compounds and their biological effects. The role of halogenation in native and designed antimicrobial peptides (AMPs) and their mimetics is then discussed. These are in the spotlight for the development of new antimicrobial drugs to counter the rise of antibiotic-resistant pathogens. AMPs represent an interesting model to study the role that natural halogenation has on their mode of action and also to understand how artificially halogenated residues can be used to rationally modify and optimize AMPs for pharmaceutical purposes.

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Section: Halo-amino Acids and Halogenated Non-ribosomal Peptidesmentioning

confidence: 99%

Natural and Synthetic Halogenated Amino Acids—Structural and Bioactive Features in Antimicrobial Peptides and Peptidomimetics

Mardirossian

Rubini

Adamo³

et al. 2021

Molecules

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“…In addition, numerous synthetically accessible amino acids have been described in the literature, in particular derivatives of the proteinogenic amino acids phenylalanine, tyrosine, tryptophan, and histidine. 16 , 17 …”

Section: Introductionmentioning

confidence: 99%

Synthesis of Amino Acids Bearing Halodifluoromethyl Moieties and Their Application to p53-Derived Peptides Binding to Mdm2/Mdm4

Vaas¹,

Zimmermann²,

Klett³

et al. 2023

DDDT

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Therapeutic peptides are a significant class of drugs in the treatment of a wide range of diseases. To enhance their properties, such as stability or binding affinity, they are usually chemically modified. This includes, among other techniques, cyclization of the peptide chain by bridging, modifications to the backbone, and incorporation of unnatural amino acids. One approach previously established, is the use of halogenated aromatic amino acids. In principle, they are thereby enabled to form halogen bonds (XB). In this study, we focus on the -R-CF 2 X moiety (R = O, NHCO; X = Cl, Br) as an uncommon halogen bond donor. These groups enable more spatial variability in protein-protein interactions. The chosen approach via Fmoc-protected building blocks allows for the incorporation of these modified amino acids in peptides using solid-phase peptide synthesis. Results and Discussion: Using a competitive fluorescence polarization assay to monitor binding to Mdm4, we demonstrate that a p53-derived peptide with Lys24Nle(εNHCOCF 2 X) exhibits an improved inhibition constant K i compared to the unmodified peptide. Decreasing K i values observed with the increasing XB capacity of the halogen atoms (F ≪ Cl < Br) indicates the formation of a halogen bond. By reducing the side chain length of Nle(εNHCOCF 2 X) to Abu(γNHCOCF 2 X) as control experiments and through quantum mechanical calculations, we suggest that the observed affinity enhancement is related to halogen bond-induced intramolecular stabilization of the α-helical binding mode of the peptide or a direct interaction with His54 in human Mdm4.

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Intersecting Xenobiology and Neometabolism To Bring Novel Chemistries to Life

Nieto-Domínguez

Nikel

2020

ChemBioChem

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The diversity of life relies on a handful of chemical elements (carbon, oxygen, hydrogen, nitrogen, sulfur and phosphorus) as part of essential building blocks; some other atoms are needed to a lesser extent, but most of the remaining elements are excluded from biology. This circumstance limits the scope of biochemical reactions in extant metabolism – yet it offers a phenomenal playground for synthetic biology. Xenobiology aims to bring novel bricks to life that could be exploited for (xeno)metabolite synthesis. In particular, the assembly of novel pathways engineered to handle nonbiological elements (neometabolism) will broaden chemical space beyond the reach of natural evolution. In this review, xeno‐elements that could be blended into nature's biosynthetic portfolio are discussed together with their physicochemical properties and tools and strategies to incorporate them into biochemistry. We argue that current bioproduction methods can be revolutionized by bridging xenobiology and neometabolism for the synthesis of new‐to‐nature molecules, such as organohalides.

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Synthesis of Halogenated α‐Amino Acids

Cited by 4 publications

References 96 publications

Natural and Synthetic Halogenated Amino Acids—Structural and Bioactive Features in Antimicrobial Peptides and Peptidomimetics

Natural and Synthetic Halogenated Amino Acids—Structural and Bioactive Features in Antimicrobial Peptides and Peptidomimetics

Synthesis of Amino Acids Bearing Halodifluoromethyl Moieties and Their Application to p53-Derived Peptides Binding to Mdm2/Mdm4

Intersecting Xenobiology and Neometabolism To Bring Novel Chemistries to Life

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