RESUMO
An efficient multicomponent reaction of newly designed ß-trifluoromethyl ß-diazo esters, acetonitrile, and carboxylic acids via an interrupted esterification process under copper-catalyzed conditions has been developed, which affords various unsymmetrical ß-trifluoromethyl N,N-diacyl-ß-amino esters in good to excellent yields. The reaction features mild conditions, a wide scope of ß-amino esters and carboxylic acids, and also applicability to large-scale synthesis, thus providing an efficient way for the synthesis of ß-trifluoromethyl ß-diacylamino esters. Furthermore, this reaction represents the first example of a Mumm rearrangement of ß-trifluoromethyl ß-diazo esters.
RESUMO
Many researchers around the world are working on the development of novel anticancer drugs with different mechanisms of action. In this case, coumarin is a highly promising pharmacophore for the development of novel anticancer drugs. Besides, the hybridization of this moiety with other anticancer pharmacophores has emerged as a potent breakthrough in the treatment of cancer to decrease its side effects and increase its efficiency. This review aims to provide a comprehensive overview of the recent development of coumarin derivatives and their application as novel anticancer drugs. Herein, we highlight and describe the largest number of research works reported in this field from 2015 to August 2023, along with their mechanisms of action and structure-activity relationship studies, making this review different from the other review articles published on this topic to date.
RESUMO
A new SN2' reaction type of Morita-Baylis-Hillman (MBH) ester with sulfonyl anion, generated in situ via detrifluoroacetylation as a nucleophile is developed. Experimental results and DFT calculations disclose that the reaction proceeds via C-C bond cleavage to generate a PhSO2CF2 anion, C-S bond cleavage to generate a sulfonyl anion with the release of CF2 carbene, and an SN2' reaction with the MBH ester. The reaction features operational simplicity, wide substrate scope, high yields, and excellent stereoselectivity, which represents a new reaction mode of fluorinated gem-diols and also provides an efficient way to obtain ß,γ-unsaturated sulfones.
RESUMO
Sclareolide was developed as an efficient C-nucleophilic reagent for an asymmetric Mannich addition reaction with a series of N-tert-butylsulfinyl aldimines. The Mannich reaction was carried out under mild conditions, affording the corresponding aminoalkyl sclareolide derivatives with up to 98% yield and 98:2:0:0 diastereoselectivity. Furthermore, the reaction could be performed on a gram scale without any reduction in yield and diastereoselectivity. Additionally, deprotection of the obtained Mannich addition products to give the target sclareolide derivatives bearing a free N-H group was demonstrated. In addition, target compounds 4-6 were subjected to an antifungal assay in vitro, which showed considerable antifungal activity against forest pathogenic fungi.
Assuntos
Antifúngicos , Diterpenos , Antifúngicos/farmacologia , FungosRESUMO
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.
Assuntos
Antifibrinolíticos , Flúor , Flúor/química , Aminoácidos/química , Halogenação , Preparações FarmacêuticasRESUMO
Novel type of Pd(II) complexes have been synthesized under operationally simple and convenient conditions and applied in the dynamic thermodynamic resolution of racemic N,C-unprotected α-amino acids. After rapid hydrolysis, these Pd(II) complexes produced the corresponding α-amino acids in satisfactory yields and enantioselectivities, accompanied by the recyclable proline-derived ligand. In addition, the method can be readily applied for S/R interconversion to obtain unnatural (R)-α-amino acids from readily available (S)-α-amino acids. Furthermore, biological assays showed that Pd(II) complexes (S,S)-3i and (S,S)-3m exhibited significant antibacterial activities similar to vancomycin, which may represent promising lead structures for further development of antibacterial agents.
Assuntos
Aminoácidos , Prolina , Prolina/química , Ligantes , Estereoisomerismo , Aminoácidos/química , Antibacterianos/farmacologia , TermodinâmicaRESUMO
An operationally simple and convenient resolution method via Cu(II) complexes was reported, efficiently providing valuable enantiopure N,C-unprotected α-amino acids. This protocol features synthetically attractive yields and a stereochemical outcome, using a recyclable Schiff base ligand and inexpensive easily accessible metal copper salts. These novel Cu(II) complexes can be obtained in an enantiopure state by means of column chromatography or recrystallization. Furthermore, all the Cu(II) complexes were evaluated for their antibacterial activities. Among them, complexes (S,2S)-3a, (S,2S)-3g, and (S,2S)-3o showed significant antibacterial activities against Staphylococcus aureus Mu50. Further biological evaluation indicated that they were effective against most of Gram-positive bacteria. It is the first study on the biological activities of transition metal complexes with this type of proline-derived Schiff base ligand.
Assuntos
Complexos de Coordenação , Bases de Schiff , Aminoácidos/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Cobre/farmacologia , Ligantes , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Prolina/farmacologia , Sais , Bases de Schiff/química , Bases de Schiff/farmacologiaRESUMO
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.
RESUMO
γ-Aminobutyric acid (GABA) represents one of the most prolific structural units widely used in the design of modern pharmaceuticals. For example, ß-substituted GABA derivatives are found in numerous neurological drugs, such as baclofen, phenibut, tolibut, pregabalin, phenylpiracetam, brivaracetam, and rolipram, to mention just a few. In this review, we critically discuss the literature data reported on the preparation of substituted GABA derivatives using the Michael addition reaction as a key synthetic transformation. Special attention is paid to asymmetric methods featuring synthetically useful stereochemical outcomes and operational simplicity.
Assuntos
Baclofeno , Ácido gama-Aminobutírico , Pregabalina , Estereoisomerismo , Ácido gama-Aminobutírico/químicaRESUMO
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
Over the recent years there has been a noticeable upsurge of interest in aza-analogs of tryptophan which are isosteric to the latter and found numerous applications in medicinal, bioorganic chemistry, and peptide research. In the present review article, five aza-tryptophan derivatives are profiled, including aza-substitution in the positions 2, on the five-membered ring, as well as in positions 4, 5, 6, and 7 on the six-membered ring. A detailed and comprehensive literature overview of the synthetic methods for the preparation of these aza-tryptophans is presented and general facets of the biological properties and most promising applications are discussed.
Assuntos
Aminoácidos , Triptofano , Química Farmacêutica , Indústria Farmacêutica , PeptídeosRESUMO
Incorporation of fluorine into organic molecules is a well-established strategy in the design of advanced materials, agrochemicals, and pharmaceuticals. Among numerous modern synthetic approaches, functionalization of unsaturated bonds with simultaneous addition of trifluoromethyl group along with other substituents is currently one of the most attractive methods undergoing wide-ranging development. In this review article, we discuss the most significant contributions made in this area during the last decade (2012-2021). The reactions reviewed in this work include chloro-, bromo-, iodo-, fluoro- and cyano-trifluoromethylation of alkenes and alkynes.
RESUMO
A new reactivity mode of tert-butanesulfinamide has been developed, which proceeds through C-S and O-S bond cleavage of N-propargyl tert-butanesulfinylamide allowing rapid assembly of poly functionalized isothiazoles. This intramolecular cyclization reaction could be conducted under mild and convenient conditions and tolerates several fluoroalkyl and substituted phenyl groups with good chemical yields. This reaction not only represents a new reactivity of tert-butanesulfinamide but also provides an easy strategy for the synthesis of isothiazoles.
RESUMO
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
We wish to draw attention to an important issue concerning scientific practice with regard to enhancing the quality of publications in Molecules (as well as for other journals) [...].
RESUMO
The purpose of this review is to highlight the necessity of conducting tests to gauge the magnitude of the self-disproportionation of enantiomers (SDE) phenomenon to ensure the veracity of reported enantiomeric excess (ee) values for scalemic samples obtained from enantioselective reactions, natural products isolation, etc. The SDE always occurs to some degree whenever any scalemic sample is subjected to physicochemical processes concomitant with the fractionation of the sample, thus leading to erroneous reporting of the true ee of the sample if due care is not taken to either preclude the effects of the SDE by measurement of the ee prior to the application of physicochemical processes, suppressing the SDE, or evaluating all obtained fractions of the sample. Or even avoiding fractionation altogether if possible. There is a clear necessity to conduct tests to assess the magnitude of the SDE for the processes applied to samples and the updated and improved recommendations described herein cover chromatography and processes involving gas-phase transformations such as evaporation or sublimation.
RESUMO
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
Over the last 100-120 years, due to the ever-increasing importance of fluorine-containing compounds in modern technology and daily life, the explosive development of the fluorochemical industry led to an enormous increase of emission of fluoride ions into the biosphere. This made it more and more important to understand the biological activities, metabolism, degradation, and possible environmental hazards of such substances. This comprehensive and critical review focuses on the effects of fluoride ions and organofluorine compounds (mainly pharmaceuticals and agrochemicals) on human health and the environment. To give a better overview, various connected topics are also discussed: reasons and trends of the advance of fluorine-containing pharmaceuticals and agrochemicals, metabolism of fluorinated drugs, withdrawn fluorinated drugs, natural sources of organic and inorganic fluorine compounds in the environment (including the biosphere), sources of fluoride intake, and finally biomarkers of fluoride exposure.
Assuntos
Poluentes Ambientais/química , Flúor/química , Poluição Ambiental , Hidrocarbonetos Fluorados/químicaRESUMO
The use of chiral Ni (II)-complexes of glycine Schiff bases has recently emerged as a leading methodology for asymmetric synthesis of structurally diverse Tailor-Made Amino Acids™, playing a key role in the design of modern pharmaceuticals. Here, we report first example of enantioselective preparation of (S)-3-methyleneglutamic acid and its N-Fmoc derivative via a new type of Michael addition-elimination reaction between chiral nucleophilic glycine equivalent and enol tosylates. This reaction was found to proceed with excellent yield (91%) and diastereoselectivity (>99/1 de) allowing straightforward asymmetric synthesis of (S)-3-methyleneglutamic acid derivatives and analogues. The observed results bode well for general application of this Ni (II) complex approach for preparation and biological studies of this previously unknown type of Tailor-Made Amino Acids™.
RESUMO
In the present work, arylethynes were studied as new C-nucleophiles in the asymmetric Mannich addition reactions with (S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine. The reactions were conducted under operationally convenient conditions affording the corresponding Mannich adducts with up to 87% yield and 70:30 diastereoselectivity. The isomeric products can be separated using regular column chromatography to afford diastereomerically pure compounds. The purified Mannich addition products were deprotected to give the target enantiomerically pure trifluoromethylpropargylamines. A mechanistic rationale for the observed stereochemical outcome is discussed.