Tailor-made Amino Acids Research Articles

New Approved Drugs Appearing in the Pharmaceutical Market in 2022 Featuring Fragments of Tailor-Made Amino Acids and Fluorine.

The strategic fluorination of oxidatively vulnerable sites in bioactive compounds is a relatively recent, widely used approach allowing us to modulate the stability, bio-absorption, and overall efficiency of pharmaceutical drugs. On the other hand, natural and tailor-made amino acids are traditionally used as basic scaffolds for the development of bioactive molecules. The main goal of this review article is to emphasize these general trends featured in recently approved pharmaceutical drugs.

The Latest FDA-Approved Pharmaceuticals Containing Fragments of Tailor-Made Amino Acids and Fluorine.

Nowadays, the selective introduction of fluorine into bioactive compounds is a mature strategy in the design of drugs allowing to increase efficiency, biological half-life and bio-absorption. On the other hand, amino acids (AAs) represent one of the most ubiquitious classes of naturally occurring organic compounds, which are found in over 40% of newly marked small-molecule pharmaceutical drugs and medical formulations. The primary goal of this work is to underscore two major trends in the design of modern pharmaceuticals. The first is dealing with the unique structural characteristics provided by the structure of amino acids featuring an abundance of functionality and the presence of a stereogenic center, all of which bodes well for the successful development of targeted bioactivity. The second is related to fine-tuning the desired activity and pharmacokinetics by selective introduction of fluorine. Historically, both trends were developed separately as innovative and prolific approaches in modern drug design. However, in recent decades, these approaches are clearly converging leading to an ever-increasing number of newly approved pharmaceuticals containing both structural features of amino acids and fluorine.

Cp*Co(III)-Catalyzed Enantioselective Hydroarylation of Unactivated Terminal Alkenes via C-H Activation.

Enantioselective hydroarylation of unactivated terminal akenes constitutes a prominent challenge in organic chemistry. Herein, we reported a Cp*Co(III)-catalyzed asymmetric hydroarylation of unactivated aliphatic terminal alkenes assisted by a new type of tailor-made amino acid ligands. Critical to the chiral induction was the engaging of a novel noncovalent interaction (NCI), which has seldomly been disclosed in the C-H activation area, arising from the molecular recognition among the organocobalt(III) intermediate, the coordinated alkene, and the well-designed chiral ligand. A broad range of C2-alkylated indoles were obtained in high yields and excellent enantioselectivities. DFT calculations revealed the reaction mechanism and elucidated the origins of chiral induction in the stereodetermining alkene insertion step.

Comparative study of different chiral ligands for dynamic kinetic resolution of amino acids.

Dynamic kinetic resolution (DKR) of unprotected amino acids (AAs), via intermediate formation of Ni(II) complexes, is currently a leading methodology for preparation of natural and tailor-made AAs in enantiomerically pure form. In this work, we conduct a comparative case study of synthetic performance of four different ligands in DKR of six AAs representing aryl-, benzyl-, alkyl-, and long alkyl-type derivatives. The results of this study allow for rational selection of ligand/AA type to develop a practical procedure for preparation of target enantiomerically pure AAs.

Tailor-made amino acids in the design of small-molecule blockbuster drugs.

The role of amino acids (AAs) in modern health industry is well-appreciated. Residues of individual AAs, or their chemical modifications, such as diamines and amino alcohols, are frequently found in the structures of modern pharmaceuticals. The goal of this review article, is to emphasize that, currently, tailor-made AAs serve as key structural features in many most successful pharmaceuticals, so-called blockbuster drugs. In the present article, we profile 14 small-molecule drugs, underscoring the breadth of structural variety of AAs applications in numerous therapeutic areas. For each compound, we provide spectrum of biological activity, medicinal chemistry discovery, and synthetic approaches.

Ni(II) Schiff-Base Complexes as Chiral Electroauxiliaries and Methodological Platform for Stereoselective Electrochemical Functionalization of Amino Acids.

The concept of chiral electroauxiliary based on the redox active chiral platform to perform transformations of a redox inactive substrate is suggested and discussed in the context of the targeted stereoselective electrochemical functionalization of amino acids. Tailor-made amino acids are essential structural features of modern medicinal chemistry and drug design; the development of efficient synthetic approaches to these compounds is of topical interest. The modified substrate (an amino acid) is included as a structural motif in the redox active complex (with a possibility to be released after modification) that integrates "a bifunctional linker" (the structural motif capable to "catch" a substrate) and a chiral moiety responsible for asymmetry induction. The amino acid, being included as a part of such ensemble, becomes stable towards redox destruction and its targeted electrochemical modification saving the amino acid skeleton is possible, thus developing new modes of reactivity for well-known compounds.

Electrochemical Approaches for Preparation of Tailor-Made Amino Acids

Electrochemical Approaches for Preparation of Tailor-Made Amino Acids

Peptide-functionalized delivery vehicles for enhanced cancer therapy.

Functional peptides that are made up of diverse endogenous amino acids with a specific sequence and length have shown various functionalities including specific biological recognition and cell penetrating ability for biomedical applications. Therefore, incorporation of peptide with a certain tailor-made amino acid sequence to the delivery systems has endowed the resulting delivery vehicles with specific functions, which provided a robust strategy for enhancing the therapeutic efficiency for malignant diseases. To make a timely review on this hot subject of research, we summarized the recent progress on peptide-functionalized delivery vehicles for enhanced cancer therapy with an emphasis on the chemistry adopted for the conjugation of peptide compared to most of the published reviews with a focus on the property and performance of the peptide-functionalized delivery systems. The primary synthetic strategies used for peptide conjugation were first summarized. An exhibition of four different types of peptide-functionalized delivery vehicles were next presented following a classification standard of the functions of each peptide category including tumor-targeting peptide, cell-penetrating peptide, subcellular organelle-targeting peptide and tumor-penetrating peptide. A concluding remark on the future direction of this rapidly developing research field was made finally. The important principles on the design of peptide, screening of the conjugation strategy, and optimization of peptide property that were drawn from the detailed comparison of the representative literature in this review will provide useful guidelines for the future development of advanced peptide-functionalized delivery platforms with enhanced therapeutic efficiency for cancer therapy.

Asymmetric synthesis of (S)-α-(octyl)glycine via alkylation of Ni(II) complex of chiral glycine Schiff base.

Over last decade, the use of Ni(II) complexes, derived from of glycine Schiff bases with chiral tridentate ligands, has emerge as a leading methodology for preparation of structurally diverse Tailor-Made Amino Acids, the key structural units in modern medicinal chemistry, and drug design. Here, we report asymmetric synthesis of derivatives of (S)-α-(octyl)glycine ((S)-2-aminodecanoic acid) and its N-Fmoc derivative via alkylation of chiral nucleophilic glycine equivalent with n-octyl bromide. Under the optimized conditions, the alkylation proceeds with excellent yield (98.1%) and diastereoselectivity (98.8% de). The observed stereochemical outcome and convenient reaction conditions bode well for application of this method for large-scale asymmetric synthesis of (S)-2-aminodecanoic acid and its derivatives.

Frontispiece: Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Tailor-made amino acids and fluorinated motifs are two important features in modern pharmaceuticals. A variety of compounds containing both of this structural elements is presented with regard to their total synthesis, medicinal application and biological properties in the Review by S. White, K. Izawa, N. A. Meanwell, V. A. Soloshonok et al. on page 11349 ff.

Cyclic tailor-made amino acids in the design of modern pharmaceuticals.

Tailor-made AAs are indispensable components of modern medicinal chemistry and are becoming increasingly prominent in new drugs. In fact, about 30% of small-molecule pharmaceuticals contain residues of tailor-made AAs or structurally related diamines and amino-alcohols. Cyclic tailor-made AAs present a particular value to rational structural design by virtue of their local conformational constraints and are widely used in lead optimization programs. The present review article highlights 34 compounds, all of which are derived from cyclic AAs, representing recently-approved, small-molecule pharmaceuticals as well as promising drug candidates currently in various phases of clinical study. For each compound, the discussion includes the discovery, therapeutic profile and optimized synthesis, with a focus on the preparation of cyclic tailor-made AA as the principal structural feature. The present review article is intended to serve as a reference source for organic, medicinal and process chemists along with other professionals working in the fields of drug design and pharmaceutical discovery.

Tailor-Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals.

Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor-made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man-made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.

Asymmetric Synthesis of Tailor-Made Amino Acids Using Chiral Ni(II) Complexes of Schiff Bases. An Update of the Recent Literature

Tailor-made amino acids are indispensable structural components of modern medicinal chemistry and drug design. Consequently, stereo-controlled preparation of amino acids is the area of high research activity. Over last decade, application of Ni(II) complexes of Schiff bases derived from glycine and chiral tridentate ligands has emerged as a leading methodology for the synthesis of various structural types of amino acids. This review article summarizes examples of asymmetric synthesis of tailor-made α-amino acids via the corresponding Ni(II) complexes, reported in the literature over the last four years. A general overview of this methodology is provided, with the emphasis given to practicality, scalability, cost-structure and recyclability of the chiral tridentate ligands.

Fluorine-containing drugs approved by the FDA in 2019

Eleven new fluorine-containing FDA-approved drugs have been profiled and details of their discovery and preparation are discussed. Therapeutic areas include schizophrenia, migraine, multiple sclerosis, insomnia, rheumatoid arthritis, anti-tuberculosis, breast cancer, lymphoma kinase inhibitor, serotonin receptor antagonist. New pharmaceuticals feature four examples of aromatic fluorine, three aromatic CF3 group, three aliphatic CF3 and one compound with aromatic CF3O group. Furthermore, among the new compounds, six are chiral and seven are derived from tailor-made amino acids.

Asymmetric synthesis, biological activity and molecular docking studies of some unsaturated α-amino acids, derivatives of glycine, allylglycine and propargylglycine

New enantiomerically enriched unsaturated tailor-made amino acids have been obtained. As a starting amino acid synthon for the asymmetric synthesis of tailor-made unsaturated amino acids, Ni(II) square-planar complexes of Schiff’s bases of propargylglycine, allylglycine and glycine with chiral auxiliary (S)-2-N-(N’-benzylprolyl)-aminobenzophenone ((S)-BPB) were used. The Cα-alkylation of propargylglycine, allylglycine and glycine moieties resulted in the asymmetric synthesis of novel (S)-α-propargylglycine, (S)-α-allylglycine and glycine derivatives containing an aromatic group in the side chain (de 80–95,5%). After purification and cleavage of the metal complexes, the amino acids were isolated in high enantiomeric purity (ee >99%). Of the obtained seven tailor-made amino acids four showed inhibitory activity to collagenase G. The amino acid with an acetylene bond in the side chain (IC50 = 1.29 ± 0.02 mM) had the best result. Molecular docking showed that the amino acids with activity to collagenase G contained hydrogen and π-π bonds with the enzyme.

Large-Scale Synthesis of the Glycine Schiff Base Ni(II) Complex Derived from (S)- and (R)-N-(2-Benzoyl-4-chlorophenyl)-1-[(3,4-dichlorophenyl)methyl]-2-pyrrolidinecarboxamide

Non-natural, tailor-made amino acids are of crucial importance to the synthesis of bioactive peptides and new chemical entities. Innovative methodology is always needed for the preparation of enant...

Development of Hamari Ligands for Practical Asymmetric Synthesis of Tailor-Made Amino Acids.

Enantiomerically pure tailor-made amino acids are in extremely high demand in nearly every sector of the health-related industries. In particular, the rapidly growing number of amino-acid-based pharmaceuticals calls for the development of advanced synthetic approaches featuring practicality and commercial viability. Here we provide a brief summary of the development of axially chiral tridentate Hamari ligands and their application for general asymmetric synthesis of various structural types of amino acids. The methodological diversity includes: dynamic kinetic resolution and (S)-/(R)-interconversion of unprotected amino acids and homologation of nucleophilic glycine equivalents via alkyl halide alkylation reactions as well as multiple-step transformations allowing preparation of polyfunctional and cyclic derivatives. The practicality of these methods is critically discussed.

Effect of substituents on the configurational stability of the stereogenic nitrogen in metal(II) complexes of α-amino acid Schiff bases.

Herein, we report a general method for quantitative measurement of the configurational stability of the stereogenic nitrogen coordinated to M (II) in the corresponding square planar complexes. This stereochemical approach is quite sensitive to steric and electronic effects of the substituents and shown to work well for Ni(II), Pd(II), and Cu(II) complexes. Structural simplicity of the compounds used, coupled with high sensitivity and reliability of experimental procedures, bodes well for application of this approach in evaluation of chemical stability and stereochemical properties of newly designed chiral ligands for general asymmetric synthesis of tailor-made amino acids.

The Second-generation of Highly Potent Hepatitis C Virus (HCV) NS3/4A Protease Inhibitors: Evolutionary Design Based on Tailor-made Amino Acids, Synthesis and Major Features of Bio-activity.

Hepatitis C is a current pandemic liver disease caused by the hepatitis C virus (HCV) with high morbidity and mortality. Recently, the direct-acting antiviral agents (DAAs) targeting HCV NS3/4A, NS5A and NS5B have become the most effective therapies against HCV infection in the clinical treatment. Among them, the second-generation of NS3/4A inhibitors have emerged as the mainstay of the DAA therapies, which are derived from the peptide substrate of NS3/4A protease and modified with various tailor-made amino acids in order to achieve high sustained virologic response (SVR) against HCV. This review summarizes sixteen examples of the second-generation of HCV NS3/4A inhibitors, mainly focusing on the clinical application, structure development, structure-activity relationship (SAR) and their synthesis.

ChemInform Abstract: Tailor‐Made α‐Amino Acids in the Pharmaceutical Industry: Synthetic Approaches to (1R,2S)‐1‐Amino‐2‐vinylcyclopropane‐1‐carboxylic Acid (Vinyl‐ACCA)

AbstractReview: [68 refs.