RESUMO
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.
Assuntos
Aminoácidos/farmacologia , Aprovação de Drogas , Preparações Farmacêuticas/química , Aminoácidos/química , Estrutura Molecular , Estados Unidos , United States Food and Drug AdministrationRESUMO
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.
Assuntos
Aminoácidos , Níquel , Cinética , Ligantes , EstereoisomerismoRESUMO
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.
Assuntos
Aminoácidos , Preparações Farmacêuticas , Química Farmacêutica , Humanos , Hidrocarbonetos FluoradosRESUMO
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.
Assuntos
Aminoácidos/química , Aprovação de Drogas , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/uso terapêutico , Peptidomiméticos , Preparações Farmacêuticas/química , Animais , Química Farmacêutica , Humanos , Estados Unidos , United States Food and Drug AdministrationRESUMO
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.
Assuntos
Glicina/química , Níquel/química , Bases de Schiff/química , Alquilação , Técnicas de Química Sintética , Complexos de Coordenação/química , Estrutura Molecular , EstereoisomerismoRESUMO
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.
Assuntos
Aminoácidos/síntese química , Química Farmacêutica/tendências , Bases de Schiff/química , Aminoácidos/química , Química Farmacêutica/métodos , Complexos de Coordenação/química , Desenho de Fármacos , Glicina/química , Ligantes , Níquel/química , EstereoisomerismoRESUMO
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.
Assuntos
Rimantadina/química , Aminas/química , Estrutura Molecular , EstereoisomerismoRESUMO
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.
RESUMO
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.
Assuntos
Aminoácidos/química , Aminoácidos/síntese química , Deutério/química , Técnicas de Química Sintética , Marcação por IsótopoRESUMO
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.
Assuntos
Cobalto/química , Ácidos Dicarboxílicos/química , Piperidinas/química , Aldeídos/química , Amidas/química , Catálise , Dicroísmo Circular , Ácidos Dicarboxílicos/síntese química , Oxirredução , EstereoisomerismoRESUMO
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.
Assuntos
Antivirais/síntese química , Complexos de Coordenação/síntese química , Ciclopropanos/síntese química , Glicina/química , Níquel/química , Bases de Schiff/química , Compostos de Vinila/síntese química , Alquilação , Catálise , Cátions Bivalentes , Ciclização , Estrutura Molecular , EstereoisomerismoRESUMO
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/Râ 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.
Assuntos
Aminoácidos/química , Catálise , Cinética , EstereoisomerismoRESUMO
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.
Assuntos
Aminoácidos/farmacologia , Desenho de Fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Aminoácidos/química , Química Farmacêutica , Humanos , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/químicaRESUMO
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.
Assuntos
Aminoácidos/síntese química , Desenho de Fármacos , Flúor/química , Aminoácidos/química , Indústria FarmacêuticaRESUMO
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.
Assuntos
Aminoácidos Cíclicos/química , Preparações Farmacêuticas/química , Aminoácidos Cíclicos/síntese química , Aminoácidos Cíclicos/farmacologia , Animais , Linhagem Celular , Química Farmacêutica , Desenho de Fármacos , Humanos , Preparações Farmacêuticas/síntese químicaRESUMO
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.
RESUMO
A synthetic method for 2',3'-dideoxyinosine (ddI) from inosine was established via radical deoxygenation of N1,5'-O-diprotected-2',3'-bis-S-methyl dithiocarbonate of inosine derivatives. The radical deoxygenation proceeded smoothly to give the desired dideoxy compounds in good yields using 1-ethylpiperidinium hypophosphite and triethylborane. Benzyl or p-methoxybenzyl protection of inosine at the N1, 5'-O-positions were effective for the ddI synthesis.
Assuntos
Didanosina/síntese química , Didanosina/química , Radicais Livres/química , Métodos , Oxirredução , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/químicaRESUMO
A series of novel analogs of acyclovir, substituted with an alkyl (methyl, ethyl, n-butyl) or phenyl group at the positions 1', 4', and/or 5', has been obtained in a direct one-pot coupling reaction of guanosine and the respective 1,3-dioxolanes. The new acyclonucleosides were essentially inactive in antiviral (HSV, VV, VSV, HBV) evaluation in vitro.
Assuntos
Aciclovir/análogos & derivados , Antivirais/síntese química , Aciclovir/síntese química , Aciclovir/química , Aciclovir/farmacologia , Animais , Antivirais/química , Antivirais/farmacologia , Células Cultivadas , Desenho de Fármacos , Vírus da Hepatite B/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Vaccinia virus/efeitos dos fármacos , Vírus da Estomatite Vesicular Indiana/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
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.