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1.
J Org Chem ; 89(10): 6915-6928, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38687827

RESUMO

Owing to stereoelectronic effects, lactones often deviate in reactivity from their open-chain ester analogues as demonstrated by the CH acidity (in DMSO) of 3-isochromanone (pKa = 18.8) and 2-coumaranone (pKa = 13.5), which is higher than that of ethyl phenylacetate (pKa = 22.6). We have now characterized the reactivity of the lactone enolates derived from 3-isochromanone and 2-coumaranone by following the kinetics of their Michael reactions with p-quinone methides and arylidenemalonates (reference electrophiles) in DMSO at 20 °C. Evaluation of the experimentally determined second-order rate constants k2 by the Mayr-Patz equation, lg k2 = sN(N + E), furnished the nucleophilicity parameters N (and sN) of the lactone enolates. By localizing their position on the Mayr nucleophilicity scale, the scope of their electrophilic reaction partners becomes predictable, and we demonstrate a novel catalytic methodology for a series of carbon-carbon bond-forming reactions of lactone enolates with chalcones under phase transfer conditions in toluene.

2.
Int J Mol Sci ; 24(6)2023 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-36982854

RESUMO

The investigation of the reactivity of an α-amido sulfone derived from 2-formyl benzoate under organocatalytic conditions in the presence of acetylacetone allowed the synthesis of a new heterocyclic hybrid isoindolinone-pyrazole with high enantiomeric excess. Dibenzylamine was also used as a nucleophile to afford an isoindolinone with aminal substituent in 3-position in suitable selectivity. The use of Takemoto's bifunctional organocatalyst not only led to observed enantioselectivity but was also important in accomplishing the cyclization step in both cases. Notably, this catalytic system proved to be particularly effective in comparison to widely used phase transfer catalysts.


Assuntos
Pirazóis , Ciclização , Catálise
4.
J Org Chem ; 87(13): 8420-8428, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35699594

RESUMO

The asymmetric synthesis of novel 3-substituted isoindolinones is herein reported. A new cascade reaction was developed that consisted of the asymmetric nitro-Mannich reaction of suitable α-amido sulfones designed from 2-formyl benzoates, followed by the in situ cyclization of the adducts. Very high enantioselectivities, up to 98% ee, and very good yields were obtained in the presence of the readily available neutral bifunctional organocatalyst derived from trans-1,2-diaminocyclohexane, which is known as Takemoto's catalyst. The investigation of the reactivity of the obtained products allowed either the selective Boc-deprotection or reduction of the nitro group, leading to further functionalized 3-substituted isoindolinones without affecting the enantiomeric purity.


Assuntos
Sulfonas , Catálise , Ciclização , Estrutura Molecular , Estereoisomerismo
5.
Int J Mol Sci ; 23(22)2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36430855

RESUMO

The aim of this review is to give an updated perspective about the methods for chemical modifications of hyaluronic acid (HA) toward the development of new applications in medical devices and material engineering. After a brief introduction on chemical, structural and biological features of this important natural polysaccharide, the most important methods for chemical and physical modifications are disclosed, discussing both on the formation of new covalent bonds and the interaction with other natural polysaccharides. These strategies are of paramount importance in the production of new medical devices and materials with improved properties. In particular, the use of HA in the development of new materials by means of additive manufacturing techniques as electro fluid dynamics, i.e., electrospinning for micro to nanofibres, and three-dimensional bioprinting is also discussed.


Assuntos
Materiais Biocompatíveis , Bioimpressão , Materiais Biocompatíveis/química , Ácido Hialurônico/química , Engenharia Tecidual/métodos , Polissacarídeos/química
6.
Molecules ; 27(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36080411

RESUMO

Herein, we report the application of an efficient and practical K2CO3 promoted cascade reaction of 2-acetylbenzonitrile in the synthesis of novel 3-methylated analogs of Pazinaclone and PD172938, belonging to isoindolinones heterocyclic class bearing a tetrasubstituted stereocenter. Organocatalytic asymmetric synthesis of the key intermediate and its transformation into highly enantioenriched 3-methylated analog of (S)-PD172938 was also developed. These achievements can be of particular interest also for medicinal chemistry, since the methyl group is a very useful structural modification in the rational design of new and more effective bioactive compounds.


Assuntos
Isoindóis , Ftalimidas , Isoindóis/química , Naftiridinas , Compostos de Espiro , Estereoisomerismo
7.
Adv Synth Catal ; 363(7): 1955-1962, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33897314

RESUMO

We herein report the ammonium salt-catalyzed synthesis of chiral 3,3-disubstituted isoindolinones bearing a heteroatom functionality in the 3-position. A broad variety of differently substituted CF3S- and RS-derivatives were obtained with often high enantioselectivities when using Maruoka's bifunctional chiral ammonium salt catalyst. In addition, a first proof-of-concept for the racemic synthesis of the analogous F-containing products was obtained as well, giving access to one of the rare examples of a fairly stable α-F-α-amino acid derivative.

8.
J Org Chem ; 86(15): 10630-10639, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34255964

RESUMO

A highly stereoselective access to 3-sulfinyl-substituted isoindolinones has been achieved by a tandem organocatalytic addition/cyclization reaction of 2-carbobenzyloxy-N-tosylbenzylidenimine with thiols and succeeding diastereoselective oxidation with MCPBA. First, enantioenriched isoindolinone N,S-acetals have been obtained through a dynamic kinetic asymmetric transformation induced by a bifunctional chiral thiourea organocatalyst. In turn, the newly created carbon stereocenter enabled a high diastereocontrol in the subsequent sulfoxidation. Based on DFT calculations, a theoretical rationale for the stereoselectivity of the oxidation reaction is also provided.

9.
J Org Chem ; 86(21): 15128-15138, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34613731

RESUMO

Cascade reactions of ortho-carbonyl-substituted benzonitriles with ((chloromethyl)sulfonyl)benzenes as pronucleophiles led to new isoindolin-1-ones with a tetrasubstituted C-3 position or to (Z)-3-(sulfonyl-methylene)isoindolin-1-ones. The reactions start from readily available materials, are carried out under mild conditions, and do not require metal catalysis. Promoted only by the cheap and environmentally benign K2CO3 as the base, up to six elemental steps can be combined in a single pot. Hence, a sequential one-pot cascade/ß-elimination/alkylation furnished useful intermediates for the synthesis of aristolactam natural products. The observed selectivity and the mechanism were investigated by DFT studies.


Assuntos
Ciclização , Alquilação , Catálise
10.
Phytother Res ; 35(1): 486-493, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32785956

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder leading to cognitive deficits and cognitive decline. Since no cure or preventing therapy is currently available to counteract AD, natural-derived compounds are investigated to find new potential neuroprotective agents for its treatment. In the present study, we tested the neuroprotective effect of lavender and coriander essential oils (EOs) and their main active constituent linalool, against the neurotoxicity elicited by Aß1-42 oligomers, a key molecular factor in the neurodegeneration of AD. Importantly, our findings on neuronally differentiated PC12 cells exposed to Aß1-42 oligomers are in accordance with previous in vivo studies reporting the neuroprotective potential of lavender and coriander EOs and linalool. We found that lavender and coriander EOs at the concentration of 10 µg/mL as well as linalool at the same concentration were able to improve viability and to reduce nuclear morphological abnormalities in cells treated with Aß1-42 oligomers for 24 hours. Lavender and coriander EOs and linalool also showed to counteract the increase of intracellular reactive oxygen species production and the activation of the pro-apoptotic enzyme caspase-3 induced by Aß1-42 oligomers. Our findings provide further evidence that these EOs and their main constituent linalool could be natural agents of therapeutic interest against Aß1-42 -induced neurotoxicity.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Coriandrum/química , Lavandula/química , Fármacos Neuroprotetores/farmacologia , Óleos Voláteis/farmacologia , Fragmentos de Peptídeos/toxicidade , Monoterpenos Acíclicos/farmacologia , Doença de Alzheimer , Animais , Transtornos Cognitivos/induzido quimicamente , Disfunção Cognitiva , Células PC12 , Óleos de Plantas/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo
11.
Molecules ; 26(23)2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34885828

RESUMO

The properties of mixtures of two polysaccharides, arabinogalactan (AG) and hyaluronic acid (HA), were investigated in solution by the measurement of diffusion coefficients D of water protons by DOSY (Diffusion Ordered SpectroscopY), by the determination of viscosity and by the investigation of the affinity of a small molecule molecular probe versus AG/HA mixtures in the presence of bovine submaxillary mucin (BSM) by 1HNMR spectroscopy. Enhanced mucoadhesive properties, decreased mobility of water and decreased viscosity were observed at the increase of AG/HA ratio and of total concentration of AG. This unusual combination of properties can lead to more effective and long-lasting hydration of certain tissues (inflamed skin, dry eye corneal surface, etc.) and can be useful in the preparation of new formulations of cosmetics and of drug release systems, with the advantage of reducing the viscosity of the solutions.


Assuntos
Galactanos/farmacologia , Ácido Hialurônico/farmacologia , Sais/química , Sódio/química , Animais , Bovinos , Óxido de Deutério/química , Diclofenaco/química , Diclofenaco/farmacologia , Difusão , Galactanos/química , Ácido Hialurônico/química , Mucinas/química , Espectroscopia de Prótons por Ressonância Magnética , Soluções , Viscosidade , Água/química
12.
Molecules ; 25(10)2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32408552

RESUMO

In this work we report our endeavors toward the development of an asymmetric synthesis of a 3,3-disubstituted isoindolinone, dimethyl 2-(1-methyl-3-oxoisoindolin-1-yl)malonate, via asymmetric cascade reaction of 2-acetylbenzonitrile with dimethylmalonate and the determination of its absolute configuration (AC) by vibrational circular dichroism (VCD). Bifunctional ammonium salts, derived from trans-1,2-cyclohexanediamine in combination with inorganic bases under phase transfer conditions, were the most effective catalytic systems, leading to the target in high yields and moderate enantioselectivity. An efficient process of heterochiral crystallization allowed the increase of the enantiopurity up to 96% ee and in an acceptable overall yield. An important aim of the present work is the comparison of different VCD methodologies for AC determination of the target compound.


Assuntos
Ftalimidas/química , Ftalimidas/síntese química , Dicroísmo Circular , Modelos Moleculares
13.
Molecules ; 24(11)2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185639

RESUMO

Herein we describe a very useful application of the readily available trifunctional aromatic ketone methyl-2-(2-bromoacetyl)benzoate in reactions with primary amines. An unexpected in situ air oxidation that follows a cascade process allowed the access to a series of isoquinoline-1,3,4(2H)-triones, a class of heterocyclic compounds of great interest containing an oxygen-rich heterocyclic scaffold. A modification of the original protocol, utilizing a Staudinger reaction in the presence of trimethylphosphine, was necessary for the synthesis of Caspase inhibitor trione with free NH group.


Assuntos
Ar , Isoquinolinas/química , Metais/química , Conformação Molecular , Oxirredução
14.
Bioorg Med Chem ; 25(1): 327-337, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27856239

RESUMO

We recently identified indole derivatives (IIIe and IIIf) with anti-chikungunya virus (CHIKV) activities at lower micro molar concentrations and a selective index of inhibition higher than the lead compound Arbidol. Here we highlight new structural information for the optimization of the previously identified lead compounds that contain the indole chemical core. Based on the structural data, a series of indole derivatives was synthesized and tested for their antiviral activity against chikungunya virus in Vero cell culture by a CPE reduction assay. Systematic optimization of the lead compounds resulted in tert-butyl-5-hydroxy-1-methyl-2-(2-trifluoromethysulfynyl)methyl)-indole-3-carboxylate derivative IIc with a 10-fold improved anti-CHIKV inhibitory activity (EC50=6.5±1µM) as compared to Arbidol demonstrating a potent, selective and specific inhibition of CHIKV replication with only a moderate cell protective effect against other related alphaviruses. The reported computational insights, together with the accessible synthetic procedure, pave the road towards the design of novel synthetic derivatives with enhanced anti-viral activities.


Assuntos
Antivirais/farmacologia , Vírus Chikungunya/efeitos dos fármacos , Indóis/farmacologia , Sulfóxidos/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/síntese química , Vírus Chikungunya/fisiologia , Chlorocebus aethiops , Glicoproteínas/química , Indóis/síntese química , Simulação de Acoplamento Molecular , Células Vero , Proteínas do Envelope Viral/química
15.
Phys Chem Chem Phys ; 19(41): 28028-28036, 2017 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-29038811

RESUMO

Vibrational absorption and vibrational circular dichroism spectra (VA and VCD) have been recorded for two hybrid isoindolinone-phtalide stereoisomers dissolved in CDCl3. Density-functional calculations have been performed to determine their absolute configuration. A comparison of calculated and measured values has been made using several goodness-of-fit indicators, and also introducing a model-averaging technique, taking into account the variation of calculated spectra with the details of the computational method. The model-averaging technique, preliminarily tested on two VCD spectra already assigned to two diastereomers of tadalafil, gives higher credibility to the ab initio calculations, and should be useful for other molecules with high flexibility and/or more than one stereogenic center.

16.
Dermatology ; 233(2-3): 136-140, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28768255

RESUMO

Background /Aim: Acne fulminans is a rare form of acne vulgaris with acute clinical deterioration including systemic signs. Etiopathogenesis and management remain largely unknown. Our aim is to assess the efficacy of a combined therapeutic regimen of systemic isotretinoin and prednisolone following the recent concepts of acne pathogenesis and drug kinetics. METHODS: A prospective case series was recruited over 15 years. Isotretinoin 0.5 mg/kg bw/d (0.25-0-0.25) and prednisolone 30 mg/d (10-10-10) were administered concomitantly with prednisolone being tapered after that time. The overall efficacy was evaluated at month 1 and every month thereafter. Daily drug doses were split to reduce the risk for adverse effects. RESULTS: 26 patients (20 male, 77%) at a mean age of 19 years and a history of acne vulgaris of 3.2 years presented acutely necrotic and ulcerating skin papules (100%), fever (45%), arthralgia (38.5%), leukocytosis (88.5%) and elevated erythrocyte sedimentation rate (100%). After one month of treatment resolution of systemic signs was achieved in all patients and a >50% skin lesion improvement in 17 patients (65%). CONCLUSION: The concomitant administration of isotretinoin (0.5 mg/kg bw/d, 0.25-0-0.25) and prednisolone 30 mg/d (10-10-10) is able to resolve systemic signs and markedly improve skin lesions in 65% of the patients at one month.


Assuntos
Acne Vulgar/complicações , Acne Vulgar/tratamento farmacológico , Isotretinoína/uso terapêutico , Prednisolona/uso terapêutico , Acne Vulgar/patologia , Adolescente , Adulto , Artralgia/etiologia , Quimioterapia Combinada , Feminino , Febre/etiologia , Humanos , Isotretinoína/administração & dosagem , Leucocitose/etiologia , Masculino , Necrose/etiologia , Prednisolona/administração & dosagem , Estudos Prospectivos , Pele/patologia , Úlcera Cutânea/etiologia , Adulto Jovem
17.
Bioorg Med Chem Lett ; 26(21): 5284-5289, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27720293

RESUMO

A focused N-substituted 3-(2-piperazin-1-yl-2-oxoethyl)-2-(pyridin-2-yl)iso-indolin-1-ones small library was synthesized for modulation of GABA-A receptor function and compared to Zopiclone for the ability to increase GABA-activated chloride currents. All compounds were tested for their effects on GABA-activated chloride currents in rat cerebellar granule cells by use of the whole-cell patch clamp technique. Electrophysiological studies on cultured cerebellar granule cells revealed 3-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2-(5-nitropyridin-2-yl)iso-indolin-1-one (Id) as a partial agonist displaying 34% increase of the 10µM GABA evoked peak chloride currents, antagonized by flumazenil. Moreover, a second group of compounds, with bulky functional groups at N-4 position of piperazine, have shown inverse agonist effects. The simple synthetic procedure and the possibility of modulating the efficacy of this class of ligands through additional structural modifications pave the way for further development of new molecules as a novel class of compounds able to interfere with benzodiazepine receptors.


Assuntos
Cerebelo/efeitos dos fármacos , Canais de Cloreto/efeitos dos fármacos , Grânulos Citoplasmáticos/efeitos dos fármacos , Isoindóis/farmacologia , Ácido gama-Aminobutírico/farmacologia , Animais , Células Cultivadas , Cerebelo/citologia , Isoindóis/química , Técnicas de Patch-Clamp , Ratos
18.
Molecules ; 20(5): 8484-98, 2015 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-25985353

RESUMO

Readily available chiral ammonium salts derived from cinchona alkaloids have proven to be effective phase transfer catalysts in the asymmetric Michael reaction of 3-substituted isoindolinones. This protocol provides a convenient method for the construction of valuable asymmetric 3,3-disubstituted isoindolinones in high yields and  moderate to good enantioselectivity. Diastereoselectivity was also investigated in the construction of contiguous tertiary and quaternary stereocenters. The use of acrolein as Michael acceptor led to an interesting tricyclic derivative, a pyrroloisoindolinone analogue, via a tandem conjugated addition/cyclization reaction.


Assuntos
Isoindóis/química , Ftalimidas/química , Ftalimidas/síntese química , Acroleína/química , Compostos de Amônio/química , Carbono/química , Catálise , Alcaloides de Cinchona/química , Ciclização , Estrutura Molecular , Estereoisomerismo
19.
Beilstein J Org Chem ; 11: 2591-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26734105

RESUMO

New bifunctional chiral ammonium salts were investigated in an asymmetric cascade synthesis of a key building block for a variety of biologically relevant isoindolinones. With this chiral compound in hand, the development of further transformations allowed for the synthesis of diverse derivatives of high pharmaceutical value, such as the Belliotti (S)-PD172938 and arylated analogues with hypnotic sedative activity, obtained in good overall total yield (50%) and high enantiomeric purity (95% ee). The synthetic routes developed herein are particularly convenient in comparison with the current methods available in literature and are particularly promising for large scale applications.

20.
Mol Divers ; 18(2): 323-33, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24415224

RESUMO

By means of C-H acids activation on Pt-cathode, an electrochemically initiated strategy aimed to developing a diversity-oriented synthesis based on the isoindolinone nucleus has been established. Conveniently, the achievement of a small library of new heterocycle-fused isoindolinone compounds with potential interest for drug design was carried out by using tandem reactions and one-pot sequential processes.


Assuntos
Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Indóis/química , Técnicas de Química Sintética , Eletroquímica , Estereoisomerismo
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