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1.
Anal Chim Acta ; 1205: 339782, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35414388

RESUMO

Some inborn errors of metabolism and other diseases can result in increasing blood ammonium (hyperammonemia episodes), which can cause serious neurological complications in patients or even death. Early diagnosis, follow up and treatment are essential to minimize irreversible damages in brain. Currently, adequate analytical instrumentation for the necessary ammonium bedside determination is not available in all health centers but only in clinical laboratories of reference hospitals. We therefore have developed a low cost and portable potentiometric Point-of-Care microanalyzer (POC) to address this problem. It consists of a cyclic olefin copolymer-based microanalyzer, the size of a credit card and working in continuous flow, which integrates microfluidics, a gas-diffusion module and a potentiometric detection system. The analytical features achieved are a linear range from 30 to 1000 µmol L-1 NH4+, a detection limit of 18 µmol L-1 NH4+ and a required sample volume of 100 µL, which comply with the medical requirements. Plasma and blood samples are analyzed with no significant differences observed between ammonium concentrations obtained with both the proposed microanalyzer and the reference method. This demonstrates the value of the developed POC for bedside clinical applications.


Assuntos
Compostos de Amônio , Cicloparafinas , Humanos , Microfluídica , Sistemas Automatizados de Assistência Junto ao Leito , Potenciometria
2.
J Am Chem Soc ; 144(9): 3939-3948, 2022 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-35212219

RESUMO

Strained aminomethyl-cycloalkanes are a recurrent scaffold in medicinal chemistry due to their unique structural features that give rise to a range of biological properties. Here, we report a palladium-catalyzed enantioselective C(sp3)-H arylation of aminomethyl-cyclopropanes and -cyclobutanes with aryl boronic acids. A range of native tertiary alkylamine groups are able to direct C-H cleavage and forge carbon-aryl bonds on the strained cycloalkanes framework as single diastereomers and with excellent enantiomeric ratios. Central to the success of this strategy is the use of a simple N-acetyl amino acid ligand, which not only controls the enantioselectivity but also promotes γ-C-H activation of over other pathways. Computational analysis of the cyclopalladation step provides an understanding of how enantioselective C-H cleavage occurs and revealed distinct transition structures to our previous work on enantioselective desymmetrization of N-isobutyl tertiary alkylamines. This straightforward and operationally simple method simplifies the construction of functionalized aminomethyl-strained cycloalkanes, which we believe will find widespread use in academic and industrial settings relating to the synthesis of biologically active small molecules.


Assuntos
Ciclobutanos , Cicloparafinas , Catálise , Ciclobutanos/química , Ciclopropanos/química , Paládio/química , Estereoisomerismo
3.
Chemistry ; 28(19): e202200331, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35147261

RESUMO

Physico-chemical properties important to drug discovery (pKa , LogP, and aqueous solubility), as well as metabolic stability, were studied for a series of functionalized gem-difluorinated cycloalkanes and compared to those of non-fluorinated and acyclic counterparts to evaluate the impact of the fluorination. It was found that the influence of the CF2 moiety on the acidity/basicity of the corresponding carboxylic acids and amines was defined by inductive the effect of the fluorine atoms and was nearly the same for acyclic and cyclic aliphatic compounds. Lipophilicity and aqueous solubility followed more complex trends and were affected by the position of the fluorine atoms, ring size, and even the nature of the functional group present; also, significant differences were found for the acyclic and cyclic series. Also, gem-difluorination either did not affect or slightly improved the metabolic stability of the corresponding model derivatives. The presented results can be used as a guide for rational drug design employing fluorine and establish the first chapter in a catalog of the key in vitro properties of fluorinated cycloalkanes.


Assuntos
Química Farmacêutica , Cicloparafinas , Flúor/química , Halogenação , Solubilidade
4.
Food Chem Toxicol ; 159: 112701, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34838897

RESUMO

Oral exposure to mineral oil may result in a narrow fraction of mineral oil saturated hydrocarbon (MOSH) being retained in tissues. Excess of MOSH hepatic retention may lead to the formation of lipogranuloma caused by predominantly multiring cycloalkanes (naphthenics) in a critical range of C25-C35. Although hepatic lipogranuloma is of low pathological concern, MOSH tissue deposition could be minimized by using an oil of similar quality but devoid of naphthenic structures to decrease hepatic retention. Synthetic Gas to liquid (GTL) oils offer an alternative to petroleum derived mineral oils, because they do not contain naphthenic structures. To demonstrate this point, SD rats were fed either GTL oil (99% iso-alkanes) or naphthenic mineral oil (84% cycloalkanes) at 200 mg/kg bw/day for 90 or 134 days with a recovery group. Liver, fat and mesenteric lymph nodes were analyzed for alkane sub-type levels using Online-HPLC-GC-FID and GCxGC-TOF-MS. Results indicate that at equal external dose, GTL hydrocarbons result in lower tissue levels and more rapid excretion than MOSH. GTL retained hepatic fractions were also qualitatively different than MOSH constituents. Because chemical composition differences, GTL oil show low absorption and tissue retention potential and thus an advantageous alternative to conventional mineral oil.


Assuntos
Fígado , Óleo Mineral , Óleos , Parafina , Animais , Cicloparafinas/química , Cicloparafinas/metabolismo , Feminino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Linfonodos/metabolismo , Óleo Mineral/química , Óleo Mineral/metabolismo , Óleo Mineral/farmacocinética , Óleos/química , Óleos/metabolismo , Óleos/farmacocinética , Parafina/química , Parafina/metabolismo , Parafina/farmacocinética , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
5.
Am J Health Syst Pharm ; 79(8): 665-675, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34971359

RESUMO

PURPOSE: This study evaluated the stability of diluted insulin aspart solutions (containing insulin aspart and preservatives) at their most commonly used concentration in intensive care units (1 unit/mL), in 2 container types: cyclic olefin copolymer (COC) vials and polypropylene (PP) syringes. METHODS: Insulin aspart solution (1 unit/mL, diluted in 0.9% sodium chloride injection) was stored for 365 days in COC vials with gray stoppers and PP syringes at refrigerated (5°C ± 3°C) and ambient temperatures (25°C ± 2°C at 60% ± 5% relative humidity and protected from light). Chemical testing was conducted monthly using a validated high-performance liquid chromatography method (quantification of insulin aspart, phenol, and metacresol). Physical stability was evaluated monthly via pH measurements, visible and subvisible particle counts, and osmolality measurements. Sterility testing was also performed to validate the sterile preparation process and the maintenance of sterility throughout the study. RESULTS: The limit of stability was set at 90% of the initial concentrations of insulin aspart, phenol, and metacresol. The physicochemical stability of 1-unit/mL insulin solutions stored refrigerated and protected from light, was unchanged in COC vials for the 365-day period and for 1 month in PP syringes. At ambient temperature, subvisible particulate contamination as well as the chemical stability of insulin and metacresol were acceptable for only 1 month's storage in PP syringes, while insulin chemical stability was maintained for only 3 months' storage in COC vials. CONCLUSION: According to our results, it is not recommended to administer 1-unit/mL pharmacy-diluted insulin solutions after 3 months' storage in COC vials at ambient temperature or after 1 month in PP syringes at ambient temperature. The findings support storage of 1-unit/mL insulin aspart solution in COC vials at refrigerated temperature as the best option over the long term. Sterility was maintained in every condition. Both sterility and physicochemical stability are essential to authorize the administration of a parenteral insulin solution.


Assuntos
Cicloparafinas , Seringas , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Humanos , Insulina Aspart , Polipropilenos/química
6.
Waste Manag ; 137: 275-282, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34814073

RESUMO

Poly-p-phenylene terephthamide (PPTA) is widely applied in bulletproof products and composite materials because of its high strength, high modulus, high temperature resistance and creep resistance. The PPTA molecule with highly symmetrical and regular structure is linear structure formed by the alternating connection of benzene ring and amide bond, and the amide bonds between the molecular chains form strong hydrogen bonds. Therefore, the dissolution and depolymerization of PPTA is very challenging. In this work, an efficient catalytic system was developed for the controllable degradation of waste PPTA, and the high-value added monomers terephthalic acid (TPA) and p-phenylenediamine (PPD) were recovered. The results show that the amide bonds of PPTA can be selectively cleaved by the strong Brönsted base catalysts in alcohols, especially in the NaOH/n-butanol system. Under the optimal degradation conditions (5 wt% NaOH in n-butanol, 180 °C, 6 h), the percentage degradation of PPTA is 100%, and the yields of TPA and PPD are 92.0% and 91.5%, respectively. In addition, it is found that the wettability of n-alcohols on PPTA monofilament and the addition of a small amount of water have important influences on the degradation of PPTA. The work elucidates the degradation mechanism of PPTA, and reveals the important factors affecting the depolymerization of PPTA.


Assuntos
Álcoois , Cicloparafinas , Amidas , Catálise
7.
Commun Biol ; 4(1): 1337, 2021 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-34824357

RESUMO

Membrane proteins are essential for cellular growth, signalling and homeostasis, making up a large proportion of therapeutic targets. However, the necessity for a solubilising agent to extract them from the membrane creates challenges in their structural and functional study. Although amphipols have been very effective for single-particle electron cryo-microscopy (cryoEM) and mass spectrometry, they rely on initial detergent extraction before exchange into the amphipol environment. Therefore, circumventing this pre-requirement would be a big advantage. Here we use an alternative type of amphipol: a cycloalkane-modified amphiphile polymer (CyclAPol) to extract Escherichia coli AcrB directly from the membrane and demonstrate that the protein can be isolated in a one-step purification with the resultant cryoEM structure achieving 3.2 Å resolution. Together this work shows that cycloalkane amphipols provide a powerful approach for the study of membrane proteins, allowing native extraction and high-resolution structure determination by cryoEM.


Assuntos
Microscopia Crioeletrônica/métodos , Cicloparafinas/química , Proteínas de Escherichia coli/isolamento & purificação , Escherichia coli/fisiologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/isolamento & purificação , Polímeros/química , Microscopia Crioeletrônica/instrumentação
8.
Zhongguo Zhong Yao Za Zhi ; 46(20): 5284-5290, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34738431

RESUMO

This study aimed to investigate the enhancing effect of muscone on the transdermal penetration of traditional Chinese medicine ingredients and explore its possible mechanism of action. The Franz diffusion cells were employed to investigate the effect of muscone on the transdermal permeation of a series of model drugs with a wide range of log P values. The solubilities at saturation and the stratum corneum(SC)/vehicle partition coefficients of model drugs were measured to evaluate the effect of muscone on drug thermodynamic activities and partition of drugs into SC. Attenuated total reflectance-Fourier transform infrared spectroscopy(ATR-FTIR) was employed to explore the effect of muscone on the molecular structure of SC. The results showed that muscone significantly promoted the transdermal penetration of hydrophilic and lipophilic drugs, and the enhancement ratio(ER) increased with the decrease in the log P. Muscone could interact with the SC lipids to increase the disorder and fluidity of lipid bilayer packing, which improved skin permeability and promoted transdermal absorption of drugs. This study provides a scientific basis for the application of muscone in traditional Chinese medicine topical preparations.


Assuntos
Medicina Tradicional Chinesa , Absorção Cutânea , Administração Cutânea , Animais , Cicloparafinas , Permeabilidade , Ratos , Ratos Sprague-Dawley , Pele/metabolismo
9.
Int J Mol Sci ; 22(21)2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34769287

RESUMO

A recent strong trend toward green and sustainable chemistry has promoted the intensive use of renewable carbon sources for the production of polymers, biofuels, chemicals, monomers and other valuable products. The Diels-Alder reaction is of great importance in the chemistry of renewable resources and provides an atom-economic pathway for fine chemical synthesis and for the production of materials. The biobased furans furfural and 5-(hydroxymethyl)furfural, which can be easily obtained from the carbohydrate part of plant biomass, were recognized as "platform chemicals" that will help to replace the existing oil-based refining to biorefining. Diels-Alder cycloaddition of furanic dienes with various dienophiles represents the ideal example of a "green" process characterized by a 100% atom economy and a reasonable E-factor. In this review, we first summarize the literature data on the regio- and diastereoselectivity of intermolecular Diels-Alder reactions of furfural derivatives with alkenes with the aim of establishing the current progress in the efficient production of practically important low-molecular-weight products. The information provided here will be useful and relevant to scientists in many fields, including medical and pharmaceutical research, polymer development and materials science.


Assuntos
Cicloparafinas/síntese química , Furanos/síntese química , Reação de Cicloadição , Cicloparafinas/química , Furanos/química , Química Verde , Estereoisomerismo
11.
Molecules ; 26(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34500600

RESUMO

Carbon-carbon bond forming reactions, such as aldol reaction and condensation, belong to extremely desired transformations as manifested by >25,000 entries in SciFinder. Their stereoselective variant requires the use of an appropriate catalyst with a strictly defined structure. Hence, chiral 2-azabicycloalkane-based catalysts were designed, synthesized and tested in a stereoselective aldol reaction between cyclic/acyclic ketone and p-nitrobenzaldehyde both in organic and aqueous media. Among catalysts containing a chiral bicyclic backbone, amide based on 2-azabicyclo[3.2.1]octane and pyrrolidine units showed the best catalytic activity and afforded aldol product in excellent chemical yields (up to 95%) and good diastereo- and enantioselectivity (dr 22:78, ee up to 63%).


Assuntos
Aminoácidos/química , Cicloparafinas/química , Poliaminas/química , Amidas/química , Carbono/química , Catálise , Cetonas/química , Pirrolidinas/química , Estereoisomerismo
12.
J Org Chem ; 86(19): 13503-13513, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34435497

RESUMO

We present herein for the first time the use of the [Cu(Xantphos)(neoc)]BF4 as a photocatalyst for the selective C-H allylic oxygenation of cycloalkenes into the corresponding allylic hydroperoxides or alcohols in the presence of molecular oxygen. The proposed methodology affords the products at good yields and has also been applied successfully to several bioactive terpenoids, such as geraniol, linalool, ß-citronellol, and phytol. A mechanistic study involving also kinetic isotope effects (KIEs) supports the proposed singlet oxygen-mediated reaction. On the basis of the high chemoselectivity and yields and the fast and clean reaction processes observed, the present catalytic system, [Cu(Xantphos)(neoc)]BF4, has also been applied to the synthesis, at a laboratory scale, of the cis-Rose oxide, a well-known perfumery ingredient used in rose and geranium perfumes.


Assuntos
Cicloparafinas , Catálise , Fosfinas , Terpenos , Xantenos
13.
Biosensors (Basel) ; 11(8)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34436094

RESUMO

This review summarizes and compares the available surface treatment and bonding techniques (e.g., corona triggered surface activation, oxygen plasma surface activation, chemical gluing, and mixed techniques) and quality/bond-strength testing methods (e.g., pulling test, shear test, peel test, leakage test) for bonding PDMS (polydimethylsiloxane) with other materials, such as PDMS, glass, silicon, PET (polyethylene terephthalate), PI (polyimide), PMMA (poly(methyl methacrylate)), PVC (polyvinyl chloride), PC (polycarbonate), COC (cyclic olefin copolymer), PS (polystyrene) and PEN (polyethylene naphthalate). The optimized process parameters for the best achievable bond strengths are collected for each substrate, and the advantages and disadvantages of each method are discussed in detail.


Assuntos
Técnicas Analíticas Microfluídicas , Cicloparafinas , Dimetilpolisiloxanos , Microfluídica , Cimento de Policarboxilato , Polímeros , Polimetil Metacrilato , Silício , Propriedades de Superfície , Temperatura
14.
Mar Drugs ; 19(6)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205074

RESUMO

This review focuses on the rare group of carbon-bridged steroids (CBS) and triterpenoids found in various natural sources such as green, yellow-green, and red algae, marine sponges, soft corals, ascidians, starfish, and other marine invertebrates. In addition, this group of rare lipids is found in amoebas, fungi, fungal endophytes, and plants. For convenience, the presented CBS and triterpenoids are divided into four groups, which include: (a) CBS and triterpenoids containing a cyclopropane group; (b) CBS and triterpenoids with cyclopropane ring in the side chain; (c) CBS and triterpenoids containing a cyclobutane group; (d) CBS and triterpenoids containing cyclopentane, cyclohexane or cycloheptane moieties. For the comparative characterization of the antitumor profile, we have added several semi- and synthetic CBS and triterpenoids, with various additional rings, to identify possible promising sources for pharmacologists and the pharmaceutical industry. About 300 CBS and triterpenoids are presented in this review, which demonstrate a wide range of biological activities, but the most pronounced antitumor profile. The review summarizes biological activities both determined experimentally and estimated using the well-known PASS software. According to the data obtained, two-thirds of CBS and triterpenoids show moderate activity levels with a confidence level of 70 to 90%; however, one third of these lipids demonstrate strong antitumor activity with a confidence level exceeding 90%. Several CBS and triterpenoids, from different lipid groups, demonstrate selective action on different types of tumor cells such as renal cancer, sarcoma, pancreatic cancer, prostate cancer, lymphocytic leukemia, myeloid leukemia, liver cancer, and genitourinary cancer with varying degrees of confidence. In addition, the review presents graphical images of the antitumor profile of both individual CBS and triterpenoids groups and individual compounds.


Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Carcinogênese/efeitos dos fármacos , Esteroides/farmacologia , Triterpenos/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Organismos Aquáticos/química , Produtos Biológicos/química , Carbono/química , Proliferação de Células/efeitos dos fármacos , Clorófitas/química , Cicloparafinas/química , Cicloparafinas/farmacologia , Fungos/química , Humanos , Invertebrados/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Rodófitas/química , Esteroides/química , Triterpenos/química
15.
Bioorg Chem ; 114: 105099, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34174635

RESUMO

A series of the title curcuminoids with structural variance in the heteroatom of the cycloalkanone and the p-substituents of the phenyl rings were tested for their activities against Leishmania major and Toxoplasma gondii parasites. The majority of them showed high activities against both parasite forms with EC50 values in the sub-micromolar concentration range. Bis(p-pentafluorothio)-substituted 3,5-di[(E)-benzylidene]piperidin-4-one 1b was not just noticeable antiparasitic, but also exhibited a considerable selectivity for L. major promastigotes over normal Vero cells. While derivatives differing only in the p-phenyl substituents being CF3 or SF5 showed similar antiparasitic activities, the cyclic ketone hub was more decisive both for the anti-parasitic activities and the selectivities for the parasites vs. normal cells. QSAR calculations confirmed the observed structure-activity relations and suggested structural variations for a further improvement of the antiparasitic activity. Docking studies based on DFT calculations revealed L. major pteridine reductase 1 as a likely molecular target protein of the title compounds.


Assuntos
Antiparasitários/farmacologia , Cicloparafinas/farmacologia , Diarileptanoides/farmacologia , Leishmania major/efeitos dos fármacos , Toxoplasma/efeitos dos fármacos , Antiparasitários/síntese química , Antiparasitários/química , Cicloparafinas/química , Diarileptanoides/síntese química , Diarileptanoides/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
16.
Chem Commun (Camb) ; 57(45): 5546-5549, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-33969835

RESUMO

An efficient asymmetric hydrogenation of cyclic tetrasubstituted-olefinic dehydroamino acid derivatives has been achieved with a Rh-ArcPhos catalyst, affording a series of α-acylamino-ß-alkyl tetrahydropyranones with two contiguous chiral centers in up to 96% ee and 1000 TON.


Assuntos
Aminoácidos/síntese química , Cicloparafinas/síntese química , Catálise , Complexos de Coordenação/química , Temperatura Alta , Hidrogênio/química , Hidrogenação , Cinética , Ligantes , Estrutura Molecular , Pressão , Ródio/química , Estereoisomerismo
17.
Bioorg Chem ; 112: 104859, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33836453

RESUMO

A novel series of enantiopure naphthalimide-cycloalkanediamine conjugates were designed, synthetized and evaluated for in vitro cytotoxicity against human colon adenocarcinoma (LoVo), human lung adenocarcinoma (A549), human cervical carcinoma (Hela) and human promyelocytic leukemia cell lines (HL-60). The cytotoxicity of the compounds was highly dependent on size and relative stereochemistry of the cycloalkyl ring as well as length of the spacer. By contrast, any kind of enantioselection was observed for each pair of enantiomers. Flow cytometric analysis indicated that compounds 22 and 23 could effectively induce G2/M arrest in the four previous cell lines despite a mild apoptotic effect.


Assuntos
Antineoplásicos/farmacologia , Cicloparafinas/farmacologia , Diaminas/farmacologia , Desenho de Fármacos , Naftalimidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cicloparafinas/química , Diaminas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Naftalimidas/química , Relação Estrutura-Atividade
18.
Bioresour Technol ; 323: 124634, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33422792

RESUMO

The efficient depolymerization and hydrodeoxygenation of enzymatic hydrolysis lignin are achieved in cyclohexane solvents over a gamma-alumina supported nickel molybdenum alloy catalyst in a single step. Under initial 3 MPa hydrogen at 320 °C, the highest overall cycloalkane yield of 104.4 mg/g enzymatic hydrolysis lignin with 44.4 wt% selectivity of ethyl-cyclohexane was obtained. The reaction atmosphere and temperature have significant effects on enzymatic hydrolysis lignin conversion, product type and distribution. The conversion of enzymatic hydrolysis lignin was also investigated over different nickel and molybdenum-based catalysts, and the gamma-alumina supported nickel molybdenum alloy catalyst exhibited the highest activity among those catalysts. To reveal the reaction pathways of alkylphenol hydrodeoxygenation, 4-ethylphenol was tested as a model compound. Complete conversion of 4-ethylphenol into cycloalkanes was achieved. A two-step mechanism of 4-ethylphenol dihydroxylation - hydrogenation is proposed, in which the benzene ring saturation is deemed as the rate-determining step.


Assuntos
Cicloparafinas , Lignina , Ligas , Óxido de Alumínio , Catálise , Hidrólise , Molibdênio , Níquel
19.
Chem Rev ; 121(12): 6850-6914, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-33400520

RESUMO

Reactions that occur under physiological conditions find diverse uses in the chemical and biological sciences. However, the limitations that biological systems place on chemical reactions restrict the number of such bioorthogonal reactions. A profound understanding of the mechanistic principles and structure-reactivity trends of these transformations is therefore critical to access new and improved versions of bioorthogonal chemistry. The present article reviews the mechanisms and substituent effects of some of the principal metal-free bioorthogonal reactions based on inverse-electron demand Diels-Alder reactions, 1,3-dipolar cycloadditions, and the Staudinger reaction. Mechanisms of modified versions that link these reactions to a dissociative step are further discussed. The presented summary is anticipated to aid the advancement of bioorthogonal chemistry.


Assuntos
Reação de Cicloadição , Modelos Químicos , Cicloparafinas/química , Termodinâmica
20.
Bioorg Chem ; 108: 104649, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33517001

RESUMO

Five new examples of 9,10-chloro(bromo)-7-amine-spiro[chromeno[4,3-b]quinoline-6,1'-cycloalkanes] - in which cycloalkanes = cyclopentane, cyclohexane, and cycloheptane - were synthesized at yields of 42-56%, using a sequential one-pot two-step cyclocondensation reaction of three different scaffolds of 2-aminobenzonitriles and the respective spiro[chroman-2,1'-cycloalkan]-4-ones, and using AlCl3 as the catalyst in a solvent-free method. Subsequently, the five new spirochromeno-quinolines and nine quinolines previously published by us (14 modified tacrine scaffolds) were subjected to AChE and BChE inhibitory activity evaluation. The molecule containing a spirocyclopentane derivative had the highest AChE and BChE inhibitory activity (IC50 = 3.60 and 4.40 µM, respectively), and in general, the non-halogenated compounds were better inhibitors of AChE and BChE than the halogenated molecules. However, the inhibitory potency of compounds 3a-n was weaker than that of tacrine. By molecular docking simulations, it was found that the size of the spirocarbocyclic moieties is inversely proportional to the inhibitory activity of the cholinesterases, probably because an increase in the size of the spirocyclic component sterically hindered the interaction of tacrine derivatives with the active site of tested cholinesterases. The findings obtained here may help in the design and development of new anticholinesterase drugs.


Assuntos
Inibidores da Colinesterase/farmacologia , Colinesterases/metabolismo , Cicloparafinas/farmacologia , Quinolinas/farmacologia , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cicloparafinas/síntese química , Cicloparafinas/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
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