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1.
Chirality ; 34(1): 86-103, 2022 01.
Article in English | MEDLINE | ID: mdl-34713503

ABSTRACT

Amino acids (AAs) play an important role in the modern health industry as key synthetic precursors for pharmaceuticals, biomaterials, biosensors, and drug delivery systems. Currently, over 30% of small-molecule drugs contain residues of tailor-made AAs or derived from them amino-alcohols and di-amines. In this review article, we profile 12 AA-derived new pharmaceuticals approved by the FDA in 2020. These newly introduced drugs include Tazverik (epithelioid sarcoma), Gemtesa (overactive bladder), Zeposia (multiple sclerosis), Byfavo (induction and maintenance of procedural sedation), Cu 64 dotatate, and Gallium 68 PSMA-11 (both PET imaging), Rimegepant (acute migraine), Zepzelca (lung cancer), Remdesivir (COVID-19), Amisulpride (nausea and vomiting), Setmelanotide (obesity), and Lonafarnib (progeria syndrome). For each compound, we describe the spectrum of biological activity, medicinal chemistry discovery, and synthetic preparation.


Subject(s)
Amino Acids/pharmacology , Drug Approval , Pharmaceutical Preparations/chemistry , Amino Acids/chemistry , Molecular Structure , United States , United States Food and Drug Administration
2.
Chirality ; 33(10): 685-702, 2021 10.
Article in English | MEDLINE | ID: mdl-34402557

ABSTRACT

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.


Subject(s)
Amino Acids , Nickel , Kinetics , Ligands , Stereoisomerism
3.
Eur J Med Chem ; 220: 113448, 2021 Aug 05.
Article in English | MEDLINE | ID: mdl-33906050

ABSTRACT

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.


Subject(s)
Amino Acids/pharmacology , Drug Design , Small Molecule Libraries/pharmacology , Amino Acids/chemistry , Chemistry, Pharmaceutical , Humans , Molecular Structure , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry
4.
Chirality ; 32(12): 1354-1360, 2020 12.
Article in English | MEDLINE | ID: mdl-33217049

ABSTRACT

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.


Subject(s)
Glycine/chemistry , Nickel/chemistry , Schiff Bases/chemistry , Alkylation , Chemistry Techniques, Synthetic , Coordination Complexes/chemistry , Molecular Structure , Stereoisomerism
5.
Eur J Med Chem ; 208: 112736, 2020 Dec 15.
Article in English | MEDLINE | ID: mdl-32966895

ABSTRACT

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.


Subject(s)
Amino Acids, Cyclic/chemistry , Pharmaceutical Preparations/chemistry , Amino Acids, Cyclic/chemical synthesis , Amino Acids, Cyclic/pharmacology , Animals , Cell Line , Chemistry, Pharmaceutical , Drug Design , Humans , Pharmaceutical Preparations/chemical synthesis
6.
Amino Acids ; 52(9): 1227-1261, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32880009

ABSTRACT

Amino acids (AAs) are among a handful of paramount classes of compounds innately involved in the origin and evolution of all known life-forms. Along with basic scientific explorations, the major goal of medicinal chemistry research in the area of tailor-made AAs is the development of more selective and potent pharmaceuticals. The growing acceptance of peptides and peptidomimetics as drugs clearly indicates that AA-based molecules become the most successful structural motif in the modern drug design. In fact, among 24 small-molecule drugs approved by FDA in 2019, 13 of them contain a residue of AA or di-amines or amino-alcohols, which are commonly considered to be derived from the parent AAs. In the present review article, we profile 13 new tailor-made AA-derived pharmaceuticals introduced to the market in 2019. Where it is possible, we will discuss the development form drug-candidates, total synthesis, with emphasis on the core-AA, therapeutic area, and the mode of biological activity.


Subject(s)
Amino Acids/chemistry , Drug Approval , Peptide Fragments/chemistry , Peptide Fragments/therapeutic use , Peptidomimetics , Pharmaceutical Preparations/chemistry , Animals , Chemistry, Pharmaceutical , Humans , United States , United States Food and Drug Administration
7.
Molecules ; 25(12)2020 Jun 12.
Article in English | MEDLINE | ID: mdl-32545684

ABSTRACT

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.


Subject(s)
Amino Acids/chemical synthesis , Chemistry, Pharmaceutical/trends , Schiff Bases/chemistry , Amino Acids/chemistry , Chemistry, Pharmaceutical/methods , Coordination Complexes/chemistry , Drug Design , Glycine/chemistry , Ligands , Nickel/chemistry , Stereoisomerism
8.
Chemistry ; 26(50): 11349-11390, 2020 Sep 04.
Article in English | MEDLINE | ID: mdl-32359086

ABSTRACT

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.


Subject(s)
Amino Acids , Pharmaceutical Preparations , Chemistry, Pharmaceutical , Humans , Hydrocarbons, Fluorinated
9.
Eur J Med Chem ; 186: 111826, 2020 Jan 15.
Article in English | MEDLINE | ID: mdl-31740056

ABSTRACT

Fluorine-containing amino acids are becoming increasingly prominent in new drugs due to two general trends in the modern pharmaceutical industry. Firstly, the growing acceptance of peptides and modified peptides as drugs; and secondly, fluorine editing has become a prevalent protocol in drug-candidate optimization. Accordingly, fluorine-containing amino acids represent one of the more promising and rapidly developing areas of research in organic, bio-organic and medicinal chemistry. The goal of this Review article is to highlight the current state-of-the-art in this area by profiling 42 selected compounds that combine fluorine and amino acid structural elements. The compounds under discussion represent pharmaceutical drugs currently on the market, or in clinical trials as well as examples of drug-candidates that although withdrawn from development had a significant impact on the progress of medicinal chemistry and/or provided a deeper understanding of the nature and mechanism of biological action. For each compound, we present features of biological activity, a brief history of the design principles and the development of the synthetic approach, focusing on the source of tailor-made amino acid structures and fluorination methods. General aspects of the medicinal chemistry of fluorine-containing amino acids and synthetic methodology are briefly discussed.


Subject(s)
Amino Acids/chemical synthesis , Drug Design , Fluorine/chemistry , Amino Acids/chemistry , Drug Industry
10.
Molecules ; 24(9)2019 May 12.
Article in English | MEDLINE | ID: mdl-31083636

ABSTRACT

This work discloses a new procedure for the resolution of commercially available racemic rimantadine hydrochloride to enantiomerically pure (S)-rimantadine using (R)-phenoxypropionic acid as a recyclable resolving reagent. Good chemical yields, operational ease, and low-cost structure underscore the preparative value of this method for the production of enantiomerically pure rimantadine for medicinal or synthetic studies.


Subject(s)
Rimantadine/chemistry , Amines/chemistry , Molecular Structure , Stereoisomerism
11.
Org Biomol Chem ; 16(27): 4968-4972, 2018 07 11.
Article in English | MEDLINE | ID: mdl-29947401

ABSTRACT

We report a discovery of a new rimantadine [1-(1-adamantyl)ethanamine]-derived chiral ligand and its application for the preparation of α-amino acids using the second-order asymmetric transformation approach. The operational ease of experimental procedures coupled with excellent chemical yields and stereochemical outcome suggests some potential synthetic generality of this approach.

12.
ACS Omega ; 3(8): 9729-9737, 2018 Aug 31.
Article in English | MEDLINE | ID: mdl-31459102

ABSTRACT

In this work, we disclose an advanced general process for the synthesis of tailor-made α-amino acids (α-AAs) via tandem alkylation-second-order asymmetric transformation. The first step is the alkylation of the chiral Ni(II) complex of glycine Schiff base, which is conducted under mild phase-transfer conditions allowing the structural construction of target α-AAs. The second step is based on the methodologically rare second-order asymmetric transformation, resulting in nearly complete precipitation of the corresponding (SC,RN,RC)-configured diastereomer, which can be collected by a simple filtration. The operational convenience and potential scalability of all experimental procedures, coupled with excellent stereochemical outcome, render this method of high synthetic value for the preparation of various tailor-made α-AAs.

13.
Chem Pharm Bull (Tokyo) ; 65(9): 854-861, 2017.
Article in English | MEDLINE | ID: mdl-28867713

ABSTRACT

Teneraic acid (piperidine-2,6-dicarboxylic acid) is a naturally occurring imino acid that comprises three stereoisomers due to its two asymmetric centers at C2 and C6. The configuration of natural teneraic acid is reported to correspond to trans-(2S,6S). However, a few studies are focused on the stereospecific synthesis of trans-(2S,6S)-teneraic acid. The present study investigates a convenient synthetic method that includes regiospecific anodic oxidation and stereospecific cobalt-catalyzed carbonylation to obtain trans-(2S,6S)-teneraic acid. Methyl (S)-N-benzoyl-α-methoxypipecolate, the key intermediate that displays a structure that corresponds to an intermediate (N-α-hydroxyalkyl amide) of intramolecular amidocarbonylation, was obtained via an anodic oxidation of methyl (S)-N-benzoylpipecolate. Subsequently, cobalt-catalyzed carbonylation converted the methyl (S)-N-benzoyl-α-methoxypipecolate to trans-(2S,6S)-N-benzoyl-teneraic acid dimethyl ester in good optical purity (>95% enantiomeric excess (ee)) and modest yield (63%). Finally, de-protection occurred via acidic hydrolysis to obtain trans-(2S,6S)-teneraic acid. The stereochemistry of synthesized teneraic acid was confirmed as corresponding to trans-(2S,6S) by comparing its physical properties with those of a cis-meso-isomer and those of a trans-(2S,6S)-isomer that were reported in previous studies.


Subject(s)
Cobalt/chemistry , Dicarboxylic Acids/chemistry , Piperidines/chemistry , Aldehydes/chemistry , Amides/chemistry , Catalysis , Circular Dichroism , Dicarboxylic Acids/chemical synthesis , Oxidation-Reduction , Stereoisomerism
14.
Org Biomol Chem ; 15(33): 6978-6983, 2017 Aug 23.
Article in English | MEDLINE | ID: mdl-28792052

ABSTRACT

α-Deuterated-α-amino acids represent a very special class of stable isotopically labeled compounds, used in advanced biomedical research. Herein, we disclose a generalized approach for the preparation of α-2H-α-amino acids in enantiomerically pure form and with up to 99% deuteration. The reaction chemistry involved in this process is based on the dynamic kinetic resolution of racemates or (S)-(R) interconversion via the formation of intermediate Ni(ii) complexes derived from unprotected amino acids and recyclable tridentate ligands. Operationally convenient conditions, excellent chemical yields, diastereoselectivity and the degree of the deuteration bode well for the wide application of this methodology for the preparation of tailor-made α-2H-α-amino acids.


Subject(s)
Amino Acids/chemistry , Amino Acids/chemical synthesis , Deuterium/chemistry , Chemistry Techniques, Synthetic , Isotope Labeling
15.
Curr Pharm Des ; 23(30): 4493-4554, 2017.
Article in English | MEDLINE | ID: mdl-28530544

ABSTRACT

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.

17.
Amino Acids ; 48(4): 973-986, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26661034

ABSTRACT

Asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid (vinyl-ACCA) is in extremely high demand due to the pharmaceutical importance of this tailor-made, sterically constrained α-amino acid. Here we report the development of an advanced procedure for preparation of the target amino acid via two-step SN2 and SN2' alkylation of novel axially chiral nucleophilic glycine equivalent. Excellent yields and diastereoselectivity coupled with reliable and easy scalability render this method of immediate use for practical synthesis of (1R,2S)-vinyl-ACCA.


Subject(s)
Antiviral Agents/chemical synthesis , Coordination Complexes/chemical synthesis , Cyclopropanes/chemical synthesis , Glycine/chemistry , Nickel/chemistry , Schiff Bases/chemistry , Vinyl Compounds/chemical synthesis , Alkylation , Catalysis , Cations, Divalent , Cyclization , Molecular Structure , Stereoisomerism
18.
Angew Chem Int Ed Engl ; 53(45): 12214-7, 2014 Nov 03.
Article in English | MEDLINE | ID: mdl-25244328

ABSTRACT

Reported herein is the first purely chemical method for the dynamic kinetic resolution (DKR) of unprotected racemic α-amino acids (α-AAs), a method which can rival the economic efficiency of the enzymatic reactions. The DKR reaction principle can be readily applied for S/R interconversions of α-AAs, the methodological versatility of which is unmatched by biocatalytic approaches. The presented process features a virtually complete stereochemical outcome, fully recyclable source of chirality, and operationally simple and convenient reaction conditions, thus allowing its ready scalability. A quite unique and novel mode of the thermodynamic control over the stereochemical outcome, including an exciting interplay between axial, helical, and central elements of chirality is proposed.


Subject(s)
Amino Acids/chemistry , Catalysis , Kinetics , Stereoisomerism
19.
Nucleosides Nucleotides Nucleic Acids ; 28(5): 713-23, 2009 May.
Article in English | MEDLINE | ID: mdl-20183611

ABSTRACT

A series of novel 2'-C-methylribonucleosides, involving 5-iodo and 5-alkynyl uridine analogues as well as related bicyclic furano- and pyrrolo[2,3-d]pyrimidinone compounds, has been synthesized and evaluated for their inhibitory effect on replication of the hepatitis C virus (HCV). The new nucleoside analogues did not show meaningful anti-HCV activity.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Pyrimidines/chemistry , Pyrimidines/pharmacology , Ribonucleosides/chemistry , Ribonucleosides/pharmacology , Antiviral Agents/chemical synthesis , Cell Line , Hepatitis C/drug therapy , Humans , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacology , Ribonucleosides/chemical synthesis
20.
Nucleic Acids Symp Ser (Oxf) ; (52): 605-6, 2008.
Article in English | MEDLINE | ID: mdl-18776525

ABSTRACT

A series of novel derivatives of 2'-C-beta-methylcytidine, involving nucleosides modified in the "upper part" of the pyrimidine base (N(4)- and/or 5-position), has been synthesized and evaluated for their inhibitory effect on in vitro replication of the hepatitis C virus and the yellow fever virus (both Flaviviridae).


Subject(s)
Antiviral Agents/chemical synthesis , Cytidine/analogs & derivatives , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cytidine/chemical synthesis , Cytidine/chemistry , Cytidine/pharmacology , Hepacivirus/drug effects , Yellow fever virus/drug effects
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