RESUMO
A group of functionalized fluorene derivatives that are structurally similar to the cellular prion protein ligand N,N'-(methylenedi-4,1-phenylene)bis [2-(1-pyrrolidinyl)acetamide] (GN8) have been synthesized. These compounds show remarkable native fluorescence due to the fluorene ring. The substituents introduced at positions 2 and 7 of the fluorene moiety are sufficiently flexible to accommodate the beta-conformational folding that develops in amyloidogenic proteins. Changes in the native fluorescence of these fluorene derivatives provide evidence of transformations in the amyloidogenic aggregation processes of insulin. The increase observed in the fluorescence intensity of the sensors in the presence of native insulin or amyloid aggregates suggest their potential use as fluorescence probes for detecting abnormal conformations; therefore, the compounds can be proposed for use as "turn-on" fluorescence sensors. Protein-sensor dissociation constants are in the 5-10 µM range and an intermolecular charge transfer process between the protein and the sensors can be successfully exploited for the sensitive detection of abnormal insulin conformations. The values obtained for the Stern-Volmer quenching constant for compound 4 as a consequence of the sensor-protein interaction are comparable to those obtained for the reference compound GN8. Fluorene derivatives showed good performance in scavenging reactive oxygen species (ROS), and they show antioxidant capacity according to the FRAP and DPPH assays.
Assuntos
Amiloide , Insulina , Amiloide/química , Proteínas Amiloidogênicas , Fluorometria , Fluorenos/químicaRESUMO
The 1,8-Diazaanthracene-2,9,10-triones, their 5,8-dihydro derivatives, and 1,8-diazaanthracene-2,7,9,10-tetraones, structurally related to the diazaquinomycin family of natural products, were synthesized in a regioselective fashion employing Diels-Alder strategies. These libraries were studied for their cytotoxicity in a variety of human cancer cell lines in order to establish structure-activity relationships. From the results obtained, we conclude that some representatives of the 1,8-diazaanthracene-2,9,10-trione framework show potent and selective cytotoxicity against solid tumors. Similar findings were made for the related 1-azaanthracene-2,9,10-trione derivatives, structurally similar to the marcanine natural products, which showed improved activity over their natural counterparts. An enantioselective protocol based on the use of a SAMP-related chiral auxiliary derived was developed for the case of chiral 5-substituted 1,8-diazaanthracene-2,9,10-triones, and showed that their cytotoxicity was not enantiospecific.
Assuntos
Antracenos , Produtos Biológicos , Humanos , Linhagem Celular , Relação Estrutura-AtividadeRESUMO
An efficient, secondary amine-catalyzed cascade annulation of 2-O/N-propargylarylaldehydes with 2,6-dialkylphenols was established to access biologically relevant functionalized 2H-chromenes and 1,2-dihydroquinolines tethered with a synthetically useful p-quinone methide scaffold in high yields under microwave irradiation and conventional heating conditions. The microwave-assisted strategy was convenient, clean, rapid, and high yielding in which the reactions were completed in just 15 min, and the yields obtained were up to 95%. This highly atom-economical domino process constructed two new C-C double bonds and a six-membered O/N-heterocyclic ring in a single synthetic operation. Its mechanism process was rationalized as involving sequential iminium ion formation, nucleophilic addition, and intramolecular annulation steps. Furthermore, the synthesized 2H-chromene derivatives were transformed into valuable indeno[2,1-c]chromenes, 5H-indeno[2,1-c]quinolines, and oxireno[2,3-c]chromene via a palladium-catalyzed double C-H bond activation process and epoxidation, respectively.
RESUMO
Inhibition of cyclooxygenase-2 (COX-2) has been extensively studied as an approach to reduce proinflammatory markers in acute brain diseases, but the anti-neuroinflammatory role of cyclooxygenase-1 (COX-1) inhibition has been rather neglected. We report that m-terphenylamine derivatives are selective COX-1 inhibitors, able to block microglia inflammatory response and elicit a neuroprotective effect. These compounds were synthesized via a three-component reaction of chalcones, ß-ketoesters, and primary amines, followed by hydrolysis/decarboxylation of the ester group. Together with their synthetic intermediates and some urea derivatives, they were studied as inhibitors of COX-1 and COX-2. The m-terphenylamine derivatives, which were selective COX-1 inhibitors, were also analyzed for their ability to block microglia inflammatory and oxidative response. Compound 3b presented an interesting anti-inflammatory and neuroprotective profile by reducing nitrite release, ROS overproduction, and cell death in organotypic hippocampal cultures subjected to LPS. We thus show that COX-1 inhibition is a promising approach to provide enhanced neuroprotection against acute inflammatory processes, which are crucial in the development of a plethora of acute neurodegenerative injuries.
Assuntos
Microglia , Fármacos Neuroprotetores , Ciclo-Oxigenase 2/metabolismo , Neuroproteção , Inibidores de Ciclo-Oxigenase/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/metabolismo , Lipopolissacarídeos/farmacologiaRESUMO
Catalytic asymmetric Povarov protocols have undergone an explosive growth, especially in the last ten years, since the first example was published in 1996. The use of chiral Lewis and Brønsted acids and dual strategies based on their combination with catalysts acting by hydrogen bond formation, as well as covalent aminocatalysis, are reviewed. More recent variations such as the nitroso Povarov reaction and interrupted Povarov reactions as a route to chiral scaffolds other than tetrahydroquinolines are also discussed.
RESUMO
In spite of advances in vaccination, control of the COVID-19 pandemic will require the use of pharmacological treatments against SARS-CoV2. Their development needs to consider the existence of two phases in the disease, namely the viral infection and the inflammatory stages. The main targets for antiviral therapeutic intervention are: (a) viral proteins, including the spike (S) protein characteristic of the viral cover and the viral proteases in charge of processing the polyprotein arising from viral genome translation; (b) host proteins, such as those involved in the processes related to viral entry into the host cell and the release of the viral genome inside the cell, the elongation factor eEF1A and importins. The use of antivirals targeted at host proteins is less developed but it has the potential advantage of not being affected by mutations in the genome of the virus and therefore being active against all its variants. Regarding drugs that address the hyperinflammatory phase of the disease triggered by the so-called cytokine storm, the following strategies are particularly relevant: (a) drugs targeting JAK kinases; (b) sphingosine kinase 2 inhibitors; (c) antibodies against interleukin 6 or its receptor; (d) use of the traditional anti-inflammatory corticosteroids.
Assuntos
Antivirais/química , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , COVID-19/patologia , Química Farmacêutica , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/ultraestruturaRESUMO
Ball milling of aromatic, heteroaromatic, vinylic, and aliphatic esters with ethanol and calcium nitride afforded the corresponding primary amides in a transformation that was compatible with a variety of functional groups and maintained the integrity of a stereocenter α to carbonyl. This methodology was applied to α-amino esters and N-BOC dipeptide esters and also to the synthesis of rufinamide, an antiepileptic drug.
Assuntos
Amidas , Ésteres , DipeptídeosRESUMO
Tetrahydroquinoline is one of the most important simple nitrogen heterocycles, being widespread in nature and present in a broad variety of pharmacologically active compounds. This Review summarizes the progress achieved in the chemistry of tetrahydroquinolines, with emphasis on their synthesis, during the period from mid-2010 to early 2018.
Assuntos
Quinolinas/química , Quinolinas/farmacologia , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Humanos , Terapia de Alvo MolecularRESUMO
The aza-vinylogous Povarov reaction between aromatic amines, α-ketoaldehydes or α-formylesters and α,ß-unsaturated dimethylhydrazones was carried out in a sequential three-component fashion under mechanochemical conditions. Following extensive optimization work, the reaction was performed on a vibratory ball mill operating at 20 Hz and using zirconium oxide balls and milling jar, and afforded 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro- 1,5-naphthyridines functionalized at C-2, C-4 and also at C-6, in the latter case. This protocol generally afforded the target compounds in good to excellent yields and diastereoselectivities. A comparison of representative examples with the results obtained under conventional conditions revealed that the mechanochemical protocol affords faster Povarov reactions in comparable yields using a solvent-less environment.
Assuntos
Compostos Aza/química , Fenômenos Mecânicos , Naftiridinas/química , Quinolinas/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
A step- and atom-economical protocol allowing the synthesis of 1,4-diazepanes and also tetrahydro- and decahydro-1,5-benzodiazepines is described. The method proceeds from very simple starting materials such as 1,2-diamines and alkyl 3-oxohex-5-enoates and can be performed under solvent-free conditions in many instances. The key event of this process was the generation in situ of an aza-Nazarov reagent and its subsequent intramolecular aza-Michael cyclization. An intermolecular version of the reaction was also established and applied to the synthesis of the first example of the pyrrolo[1,2-a][1,5]diazonine framework.
RESUMO
A Ce(IV)-catalyzed three-component reaction between chalcones, anilines and ß-ketoesters followed by a microwave-assisted thermal cyclization afforded 1,3-diaryl-1,2-dihydroacridin-9(10H)-ones. Their microwave irradiation in nitrobenzene, acting both as solvent and oxidant, afforded fully unsaturated 1,3-diarylacridin-9(10H)-ones, which combine acridin-9-(10H)one and m-terphenyl moieties. Overall, the route generates three C-C and one C-N bond and has the advantage of requiring a single chromatographic separation.
Assuntos
Acridinas/química , Substâncias Intercalantes/química , Compostos de Terfenil/química , Compostos de Anilina/química , Catálise , Chalconas/química , Ciclização , Ésteres/química , Estrutura MolecularRESUMO
An efficient green protocol for the synthesis of complex hybrid heterocycles containing [1,6]-naphthyridine and coumarin/pyrazole moieties was established, involving an intramolecular [4 + 2] hetero Diels-Alder reaction as the key step. The biologically significant 12,13-dihydro-6H-benzo[h]chromeno[3,4-b][1,6]naphthyridin-6-ones and 6,10-dihydro-5H-benzo[h]pyrazolo[3,4-b][1,6]naphthyridines were synthesized starting from 2-(N-propargylamino)-arylaldehydes and 3-aminocoumarins or 3-methyl-1-aryl-1H-pyrazol-5-amines in the presence of an Amberlyst-15 catalyst in PEG-200 in good yields. The easy access to diverse complex molecules in a single operation from readily available starting materials, a commercially available, transition metal-free and recyclable catalyst, the use of a green solvent, a very high atom economy and the release of water as the only side product are the highlights of this protocol.
RESUMO
A small library of spirooxindole-pyrrolidine hybrids have been synthesized for the first time in an ionic liquid, [bmim]Br in good to excellent yields employing a new class of non-stabilized azomethine ylides derived from isatin and tyrosine, a combination that has been rarely employed for the in situ generation of azomethine ylides using [3+2] cycloaddition strategy. Following the synthesis and characterization of the spirooxindole-pyrrolidine heterocyclic hybrids, they were tested for their anticancer activity as against the changes in the concentrations and time periods with different in vitro cell cultures containing cancer and non-cancer cells, where the results revealed for a potential therapeutic activity. Further analysis for the mechanism of cell death by the cancer cells indicated for the caspase-dependent apoptotic pathway, specifically mediated by caspase-3. Based on these results, it can be demonstrated that the synthesized spirooxindole-pyrrolidine hybrids may serve as one of the better therapeutic agents used for the treatment of malignant tumors.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Indóis/química , Pirrolidinas/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reação de Cicloadição , Humanos , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
A series of 4-iminonaringenin derivatives 2-6 have been prepared in good overall yields from a condensation reaction between naringenin and primary amines. The structures of all products were confirmed by ultraviolet, infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques. These derivatives were analyzed by high-performance liquid chromatography using polysaccharide-based chiral stationary phases, namely, Chiralpak IB and Chiralcel OD, using various mobile phases. 2-Propanol showed a high enantioselectivity for naringin and its derivatives using achiral column containing immobilized polysaccharides (Chiralpak IB).
RESUMO
A series of spirooxindolopyrrolidine fused N-styrylpiperidone heterocyclic hybrids has been synthesized in excellent yield via a domino multicomponent protocol that involves one-pot three component 1,3-dipolar cycloaddition and concomitant enamine reactions performed in an inexpensive ionic liquid, namely 1-butyl-3-methylimidazolium bromide ([bmim]Br). Compounds thus synthesized were evaluated for their cytotoxicity against U-937 tumor cells. Interestingly; compounds 5i and 5m exhibited a better cytotoxicity than the anticancer drug bleomycin. In addition; the effect of the synthesized compounds on the nuclear morphology of U937 FaDu cells revealed that treatment with compounds 5aâ»m led to their apoptotic cell death.
Assuntos
Antineoplásicos/síntese química , Indóis/síntese química , Piperidonas/síntese química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirrolidinas/síntese química , Compostos de Espiro/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Bleomicina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Reação de Cicloadição , Desenho de Fármacos , Humanos , Imidazóis/química , Indóis/farmacologia , Concentração Inibidora 50 , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Simulação de Acoplamento Molecular , Piperidonas/farmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Proteínas Proto-Oncogênicas c-met/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirrolidinas/farmacologia , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
The combination of a three-component, solvent-free pyrrole synthesis performed under mechanochemical conditions with a TMSOTf-catalyzed oxonium-mediated cyclization gave general access to pyrrolo[2,1-a]isoquinoline derivatives under very mild conditions. The structural diversity generated by this method was extended by the preparation of six additional unusual polyheterocyclic frameworks.
RESUMO
The microwave-promoted three-component reaction between o-nitrochalcones, primary amines and ß-dicarbonyl compounds in the presence of Ce(IV) ammonium nitrate constitutes the first example of a multicomponent carbazole synthesis. This reaction furnishes highly substituted and functionalized carbazole derivatives via a double annulation process that generates two C-C and two C-N bonds, with water as the only side product. Mechanistically, this transformation has some unusual features that include an intramolecular coupled hydrogenation-dehydrogenation process, the functionalization of a C-H group by direct attack onto a nitrogen function and a CAN-catalyzed reduction via hydride transfer from ethanol. The mechanisms of these reactions were studied with the aid of computational techniques.
RESUMO
The pseudo-five-component reaction between ß-dicarbonyl compounds (2 molecules), diamines and α-iodoketones (2 molecules), prepared in situ from aryl ketones, was performed efficiently under mechanochemical conditions involving high-speed vibration milling with a single zirconium oxide ball. This reaction afforded symmetrical frameworks containing two pyrrole or fused pyrrole units joined by a spacer, which are of interest in the exploration of chemical space for drug discovery purposes. The method was also extended to the synthesis of one compound containing three identical pyrrole fragments via a pseudo-seven-component reaction. Access to compounds having a double bond in their spacer chain was achieved by a different approach involving the homodimerization of 1-allyl- or 1-homoallylpyrroles by application of cross-metathesis chemistry.
RESUMO
An efficient and selective procedure for the synthesis of epiminodibenzo[b,f][1,5]diazocines involving a AB2 three-component reaction is developed. Two equivalents of suitably substituted 2-aminoarylaldehydes reacted with arylamines in the presence of Yb(OTf)3 to afford the desired products in high yields. The reaction is highly atom-economic and waste-free, in addition to allowing the generation of two heterocyclic rings and four C-N bonds in a single operation. Significantly, this approach is complementary to the existing literature procedures, affording arylamine-derived products that could not be accessed previously. A plausible mechanism is proposed involving an imine formation-intermolecular annulation-intramolecular iminium ion cyclization sequence.
RESUMO
A highly efficient synthesis of 5,6-dihydrodibenzo[b,h][1,6]naphthyridines was achieved by reaction between 2-(N-propargylamino)benzaldehydes and arylamines in the presence of CuBr2. The in situ generated electron-deficient heterodienes bearing a tethered alkyne partner underwent an intramolecular inverse electron-demand hetero-Diels-Alder reaction followed by air oxidation to furnish the products in high yields. This reaction tolerated a large number of substituents to afford diverse products under mild conditions. This strategy was also successfully extended to the synthesis of 12,13-dihydro-6H-benzo[h]chromeno[3,4-b][1,6]naphthyridin-6-ones starting from 3-amino-2H-chromen-2-one, again in high yields.