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1.
Eur J Med Chem ; 192: 112160, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32146375

RESUMO

A series of tripeptidic proteasome inhibitors with furylketone as C-terminus were designed and synthesized. Biochemical evaluations against ß1, ß2 and ß5 subunits revealed that they acted selectively on ß5 subunit with IC50s against chymotrypsin-like (CT-L) activity in micromolar range. LC-MS/MS analysis of the ligand-20S proteasome mixture showed that the most potent compound 11m (IC50 = 0.18 µM) made no covalent modification on 20S proteasome. However, it was identified acting in a slowly reversible manner in wash-out assay and the reversibility was much lower than that of MG132, suggesting the possibility of these tripeptidic furylketones forming reversible covalent bonds with 20S proteasome. Several compounds were selected for anti-proliferative assay towards multiple cancer cell lines, and compound 11m displayed comparable potency to positive control (MG132) in all cell lines tested. Furthermore, the pharmacokinetic (PK) data in rats indicated 11m behaved similarly (Cmax, 2007 µg/L; AUC0-t, 680 µg/L·h; Vss, 0.66 L/kg) to the clinical used agent carfilzomib. All these data suggest 11m is a good lead compound to be developed to novel anti-tumor agent.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Furanos/farmacologia , Cetonas/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/química , Células HCT116 , Humanos , Cetonas/síntese química , Cetonas/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
2.
J Vis Exp ; (156)2020 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-32116307

RESUMO

Heteroarylation introduces heteroaryl fragments to organic molecules. Despite the numerous available reactions reported for arylation via transition metal catalysis, the literature on direct heteroarylation is scarce. The presence of heteroatoms such as nitrogen, sulfur and oxygen often make heteroarylation a challenging research field due to catalyst poisoning, product decomposition and the rest. This protocol details a highly efficient direct α-C(sp3) heteroarylation of ketones under microwave irradiation. Key factors for successful heteroarylation include the use of XPhos Palladacycle Gen. 4 Catalyst, excess base to suppress side reactions and the high temperature and pressure achieved in a sealed reaction vial under microwave irradiation. The heteroarylation compounds prepared by this method were fully characterized by proton nuclear magnetic resonance spectroscopy (1H NMR), carbon nuclear magnetic resonance spectroscopy (13C NMR) and high-resolution mass spectrometry (HRMS). This methodology has several advantages over literature precedents including broad substrate scope, rapid reaction time, greener procedure and operational simplicity by eliminating the preparation of intermediates such as silyl enol ether. Possible applications for this protocol include, but are not limited to, diversity-oriented synthesis for the discovery of biologically active small molecules, domino synthesis for the preparation of natural products and ligand development for new transition metal catalytic systems.


Assuntos
Cetonas/síntese química , Metais/química , Micro-Ondas , Elementos de Transição/química , Compostos Inorgânicos de Carbono/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Catálise , Cromatografia , Cetonas/química , Paládio/química , Espectroscopia de Prótons por Ressonância Magnética , Compostos de Silício/química , Temperatura
3.
Org Biomol Chem ; 18(10): 1881-1885, 2020 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-32100807

RESUMO

A convenient two-step method is reported for the ligation of alkoxyamine- or hydrazine-bearing cargo to proline N-termini. Using this approach, bifunctional proline N-terminal bioconjugates are constructed and proline N-terminal proteins are immobilized.


Assuntos
Aminas/química , Hidrazinas/química , Prolina/química , Proteínas/síntese química , Hidrazonas/síntese química , Cetonas/síntese química , Oxirredução , Oximas/síntese química , Pyrococcus furiosus/química , Vírus do Mosaico do Tabaco/química
4.
J Med Chem ; 63(4): 1660-1670, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31990537

RESUMO

Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12. Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.


Assuntos
HDL-Colesterol/metabolismo , Inibidores Enzimáticos/farmacologia , Cetonas/farmacologia , Lipase/antagonistas & inibidores , Oxidiazóis/farmacologia , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Cetonas/síntese química , Cetonas/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Relação Estrutura-Atividade
5.
Luminescence ; 35(4): 572-579, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31908148

RESUMO

Two new difluoroboron ß-carbonyl cyclic ketonate complexes C2B and DC2B were investigated using several spectroscopic methods. Relative to the absorption spectra, the fluorescence spectra were more affected by the polarity of the solvent. Also, compound C2B showed a more pronounced Stokes' shift after solvent polarity increased. Transient absorption measurements then demonstrated the relaxation behaviour of the excited state compound molecule. The kinetic results showed that the excited state C2B in tetrahydrofuran (THF) can return from the intramolecular charge-transfer (ICT) state and the initial excited state to the ground state. The kinetic relaxation pathway after THF was replaced by dimethyl sulfoxide became single. When the carbazole unit was introduced, DC2B also exhibited an ICT state but there was no significant difference in the excited state relaxation path after solvent polarity was changed. The results indicated that C2B is more susceptible to solvent polarity regulation. The global fit results revealed that an increase in the solvent polarity prolonged the lifetime of the ICT state of compound C2B and had the opposite effect on compound DC2B. These results provide guidance for understanding the relationship between solvent polarity and the designing and synthesizing advanced compound materials.


Assuntos
Compostos de Boro/química , Carbazóis/química , Furanos/química , Cetonas/química , Compostos de Boro/síntese química , Cetonas/síntese química , Fenômenos Ópticos , Solventes/química , Espectrometria de Fluorescência
6.
Org Lett ; 22(1): 1-5, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31621338

RESUMO

Suzuki-Miyaura cross-couplings of amides offer an approach to the synthesis of ketones that avoids the use of basic or pyrophoric nucleophiles. However, these reactions require glovebox manipulations, thus limiting their practicality. We report a benchtop protocol for Suzuki-Miyaura cross-couplings of aliphatic amides that utilizes a paraffin capsule containing a Ni(0) precatalyst and NHC ligand. This methodology is broad in scope, is scalable, and provides a user-friendly approach to convert aliphatic amides to alkyl-aryl ketones.


Assuntos
Amidas/química , Cetonas/síntese química , Níquel/química , Catálise , Cetonas/química , Estrutura Molecular
7.
Nat Prod Res ; 34(15): 2173-2178, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30822134

RESUMO

A stereoselective total synthesis of 16-membered C2-symmetric macrodiolide Pyrenophorol, Tetrahydropyrenophorol and 4,4-diacetylpyrenophorol have been accomplished. The synthesis started from commercially available L-Aspartic acid and the key reactions involved are regioselective epoxide opening, CBS reduction, Pinnick oxidation and Mitsunobu dilactonization.


Assuntos
Produtos Biológicos/síntese química , Compostos Heterocíclicos/síntese química , Cetonas/síntese química , Ácido Aspártico/química , Produtos Biológicos/química , Compostos de Epóxi/química , Oxirredução , Estereoisomerismo
8.
Int J Mol Sci ; 20(24)2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31835639

RESUMO

Carbohydrates and their conjugates are the most abundant natural products, with diverse and highly important biological roles. Synthetic glycoconjugates are versatile tools used to probe biological systems and interfere with them. In an endeavor to provide an efficient route to glycomimetics comprising structurally diverse carbohydrate units, we describe herein a robust, stereoselective, multicomponent approach. Isopropylidene-protected carbohydrate-derived aldehydes and ketones were utilized in the Passerini reaction, giving different glycosylated structures in high yields and diastereoselectivities up to 90:10 diastereomeric ratio (d.r). Access to highly valuable building blocks based on α-hydroxy C-glycosyl acids or more complex systems was elaborated by simple post-condensation methodologies.


Assuntos
Aldeídos/síntese química , Alcenos/química , Cetonas/síntese química , Aldeídos/química , Mimetismo Biológico , Glicoconjugados/química , Glicosilação , Cetonas/química , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Estereoisomerismo
9.
Org Lett ; 21(24): 9940-9944, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31750667

RESUMO

A general protocol for the hydroacylation of styrenes from aliphatic carboxylic acids is reported. These reactions proceed via ß-scission of a phosphoranyl radical that is accessed by photoredox catalysis, followed by addition of the resulting acyl radical to the styrenyl olefin. We show that phosphine tunability is critical for efficient intermolecular coupling due to competitive quenching of the photocatalyst by the olefin. Primary, secondary, and structurally rigid tertiary carboxylic acids all generate valuable unsymmetrical dialkyl ketones.


Assuntos
Ácidos Carboxílicos/química , Cetonas/síntese química , Processos Fotoquímicos , Estirenos/química , Acilação , Catálise , Cetonas/química , Estrutura Molecular
10.
Molecules ; 24(20)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652542

RESUMO

Chagas disease and Leishmaniasis are neglected endemic protozoan diseases recognized as public health problems by the World Health Organization. These diseases affect millions of people around the world however, efficient and low-cost treatments are not available. Different steroid molecules with antimicrobial and antiparasitic activity were isolated from diverse organisms (ticks, plants, fungi). These molecules have complex structures that make de novo synthesis extremely difficult. In this work, we designed new and simpler compounds with antiparasitic potential inspired in natural steroids and synthesized a series of nineteen steroidal arylideneketones and thiazolidenehydrazines. We explored their biological activity against Leishmania infantum, Leishmania amazonensis, and Trypanosoma cruzi in vitro and in vivo. We also assayed their genotoxicity and acute toxicity in vitro and in mice. The best compound, a steroidal thiosemicarbazone compound 8 (ID_1260) was active in vitro (IC50 200 nM) and in vivo (60% infection reduction at 50 mg/kg) in Leishmania and T. cruzi. It also has low toxicity in vitro and in vivo (LD50 >2000 mg/kg) and no genotoxic effects, being a promising compound for anti-trypanosomatid drug development.


Assuntos
Doença de Chagas/tratamento farmacológico , Leishmaniose/tratamento farmacológico , Esteroides/uso terapêutico , Tiossemicarbazonas/uso terapêutico , Tripanossomicidas/química , Tripanossomicidas/uso terapêutico , Animais , Desenvolvimento de Medicamentos , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Hidrazinas/farmacologia , Cetonas/síntese química , Cetonas/química , Cetonas/farmacologia , Leishmania infantum/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Testes de Sensibilidade Parasitária , Esteroides/síntese química , Esteroides/química , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Tiossemicarbazonas/toxicidade , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos
11.
Org Lett ; 21(20): 8261-8265, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31599599

RESUMO

The homologation of Weinreb amides into difluoromethylketones with a formal nucleophilic CHF2 transfer agent is reported. Activating TMSCHF2 with potassium tert-amylate enables a convenient access to the difluorinated homologation reagent, which adds to the acylating partners. The high chemoselectivity showcased in the presence of variously multifunctionalized Weinreb amides, jointly with uniformly high yields, enables the strategy of general applicability without requiring any stabilization element for the putative carbanion.


Assuntos
Amidas/química , Hidrocarbonetos Fluorados/química , Cetonas/síntese química , Metano/análogos & derivados , Cetonas/química , Metano/química , Estrutura Molecular , Estereoisomerismo
12.
Pharmacol Res Perspect ; 7(5): e00524, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31523435

RESUMO

5-lipoxygenase (5-LO) catalyzes the biosynthesis of leukotrienes, potent lipid mediators involved in inflammatory diseases, and both 5-LO and the leukotrienes are validated therapeutic targets. Caffeic acid phenethyl ester (CAPE) is an effective inhibitor of 5-LO and leukotriene biosynthesis but is susceptible to hydrolysis by esterases. In this study a number of CAPE analogues were synthesized with modifications to the caffeoyl moiety and the replacement of the ester linkage with a ketone. Several new molecules showed better inhibition of leukotriene biosynthesis than CAPE in isolated human neutrophils and in whole blood with IC50 values in the nanomolar (290-520 nmol/L) and low micromolar (1.0-2.3 µmol/L) ranges, respectively. Sinapic acid and 2,5-dihydroxy derivatives were more stable than CAPE in whole blood, and ketone analogues were degraded more slowly in HepaRG hepatocyte cultures than esters. All compounds underwent modification consistent with glucuronidation in HepaRG cultures as determined using LC-MS/MS analysis, though the modified sinapoyl ketone (10) retained 50% of its inhibitory activity after up to one hour of incubation. This study has identified at least one CAPE analogue, compound 10, that shows favorable properties that warrant further in vivo investigation as an antiinflammatory compound.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Hidroxibenzoatos/síntese química , Cetonas/síntese química , Inibidores de Lipoxigenase/síntese química , Análise Química do Sangue , Ácidos Cafeicos/química , Linhagem Celular , Estabilidade de Medicamentos , Ésteres/química , Células HEK293 , Humanos , Hidroxibenzoatos/química , Hidroxibenzoatos/farmacologia , Concentração Inibidora 50 , Cetonas/química , Cetonas/farmacologia , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Simulação de Acoplamento Molecular , Neutrófilos/química , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química
13.
J Am Chem Soc ; 141(38): 15433-15440, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31502449

RESUMO

In recent years, a wide array of methods for achieving nickel-catalyzed substitution reactions of alkyl electrophiles by organometallic nucleophiles, including enantioconvergent processes, have been described; however, experiment-focused mechanistic studies of such couplings have been comparatively scarce. The most detailed mechanistic investigations to date have examined catalysts that bear tridentate ligands and, with one exception, processes that are not enantioselective; studies of catalysts based on bidentate ligands could be anticipated to be more challenging, due to difficulty in isolating proposed intermediates as a result of instability arising from coordinative unsaturation. In this investigation, we explore the mechanism of enantioconvergent Kumada reactions of racemic α-bromoketones catalyzed by a nickel complex that bears a bidentate chiral bis(oxazoline) ligand. Utilizing an array of mechanistic tools (including isolation and reactivity studies of three of the four proposed nickel-containing intermediates, as well as interrogation via EPR spectroscopy, UV-vis spectroscopy, radical probes, and DFT calculations), we provide support for a pathway in which carbon-carbon bond formation proceeds via a radical-chain process wherein a nickel(I) complex serves as the chain-carrying radical and an organonickel(II) complex is the predominant resting state of the catalyst. Computations indicate that the coupling of this organonickel(II) complex with an organic radical is the stereochemistry-determining step of the reaction.


Assuntos
Complexos de Coordenação/química , Cetonas/química , Níquel/química , Oxazóis/química , Catálise , Cetonas/síntese química , Estrutura Molecular , Estereoisomerismo
14.
Eur J Med Chem ; 182: 111669, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494473

RESUMO

A series of 2,8-diazaspiro[4.5]decan-1-one derivatives were designed, synthesized and screened for their inhibition activities against chitin synthase (CHS) and antimicrobial activities in vitro. The biological assays revealed that compounds 4a, 4e, 4h, 4j, 4o, 4q and 4r exhibited moderated to excellent potency against CHS with IC50 values ranging from 0.12 to 0.29 mM. Compounds 4e, 4j with IC50 value of 0.13 mM, 0.12 mM respectively, showed excellent inhibition potency among these compounds, which were similar to that of polyoxin B whose IC50 value was 0.08 mM. Meanwhile, the screening of the antifungal activity showed that compounds 4j and 4r had the same potency of inhibiting the growth of A. fumigatus with MIC value of 0.08 mmol/L. Compound 4d displayed excellent activity against C. albicans (ATCC 90023) with MIC value of 0.04 mmol/L, which was superior to fluconazole (0.104 mmol/L) and polyoxin B (0.129 mmol/L). The result of antibacterial assay showed that these compounds had little potency against those selected bacteria strains including three Gram-positive bacteria and three Gram-negative bacteria. Furthermore, the combination use of 4c-fluconazole, 4i-fluconazole, 4j-fluconazole, and 4o-fluconazole against C. albicans,A. fumigatus and A. flavus showed additive or synergistic effects. These results indicated that the designed compounds serve as potential chitin synthase inhibitors and have selectively antifungal activities.


Assuntos
Antifúngicos/farmacologia , Aspergillus flavus/efeitos dos fármacos , Aspergillus fumigatus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Quitina Sintase/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Quitina Sintase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Cetonas/síntese química , Cetonas/química , Cetonas/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
15.
Parasit Vectors ; 12(1): 382, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362759

RESUMO

BACKGROUND: The Asian tiger mosquito, Aedes albopictus, an increasingly relevant arboviral vector, has spread worldwide. However, currently available tools are limited in terms of effective monitoring of vector populations and accurate determination of the extent of viral transmission, especially before and during outbreaks. Therefore, it is essential to develop novel monitoring and surveillance tools, particularly those that target adult mosquitoes and enhance the trapping efficiency for Ae. albopictus. METHODS: A variety of human body odorants associated with different types of mosquito olfactory receptors were selected, and their attractiveness to Ae. albopictus was tested by a four-arm olfactometer. The optimal compatibility and proportion of the odorants, Mix-5, was observed via orthogonal design analyses. The attractiveness of Mix-5 to Ae. albopictus in the laboratory was assessed using Mosq-ovitraps and Electric Mosquito Killers. In the field, the effectiveness of generic BG-Lure, Mix-5 and a control treatment was compared with a baited Biogents Sentinel trap (BGS-trap) using a Latin square design. RESULTS: In the olfactometer experiments, the attractiveness of the selected candidate compounds at varying dilutions was poor when the individual compounds were used alone. The optimal combination, Mix-5, was generated based on orthogonal design analyses. In the laboratory, the average numbers of female Ae. albopictus mosquitoes attracted by the synthetic odorant blend Mix-5 were 27.00 and 27.50, compared with 12.00 and 14.83 for the control, when using Mosq-ovitraps and Electric Mosquito Killers, respectively. In the field, the average number of Ae. albopictus female mosquitoes trapped by Mix-5 was 9.67 females/trap, whereas the average numbers for BG-Lure and the control were 7.78 and 4.47, respectively. The lure also played an important role in attracting Culex quinquefasciatus mosquitoes, and the average numbers of Cx. quinquefasciatus female mosquitoes attracted by Mix-5, BG-Lure and the control were 18.78, 25.11 and 12.22, respectively. CONCLUSIONS: A human odor-based bait blend was developed and exhibited enhanced effectiveness at attracting Ae. albopictus This blend can be used to monitor and trap dengue vector mosquitoes in Chinese cities.


Assuntos
Aedes/efeitos dos fármacos , Aedes/fisiologia , Comportamento Animal/efeitos dos fármacos , Odorantes/análise , Feromônios Humano/farmacologia , Feromônios/farmacologia , Animais , Feminino , Humanos , Cetonas/síntese química , Cetonas/farmacologia , Controle de Mosquitos , Mosquitos Vetores , Feromônios/síntese química , Feromônios Humano/síntese química , Receptores Odorantes/efeitos dos fármacos
16.
Phys Chem Chem Phys ; 21(35): 19480-19487, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31461090

RESUMO

The deoxygenation reaction of m-benzenediol (resorcinol), an important lignin model compound, was studied in a hot microreactor. We revealed three decomposition channels by detecting elusive and reactive intermediates and product isomers selectively and found that resorcinol, similarly to catechol (o-benzenediol) and hydroquinone (p-benzenediol), (i) gets decarbonylated to yield hydroxycyclopentadiene. Additionally, (ii) decarboxylation (CO2 loss) yields C5H6 species in a retro-Diels-Alder reaction from a lactone species. Only acyclic products are detected at lower reactor temperatures and the most stable C5H6 isomer, cyclopentadiene (c-C5H6), is only observed at higher temperatures. Finally, (iii) two reactive ketene species, ethenone and buta-1,3-dienal, were observed in a third reaction channel. Both decarboxylation and ketene formation channels are unique among benzenediols for the meta-isomer, resorcinol. We have explored the resorcinol potential energy surface to rationalize the observed reactions. These findings may help to understand the source of ketenes in catalytic lignin depolymerization and give new insight into isomer-specific deoxygenation processes.


Assuntos
Dióxido de Carbono/síntese química , Etilenos/síntese química , Cetonas/síntese química , Resorcinóis/química , Reação de Cicloadição , Isomerismo , Oxigênio/química , Temperatura
17.
Angew Chem Int Ed Engl ; 58(40): 14234-14239, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31353794

RESUMO

A catalytic enantioselective method for the synthesis of 1,4-keto-alkenylboronate esters by a rhodium-catalyzed conjugate addition pathway is disclosed. A variety of novel, bench-stable alkenyl gem-diboronate esters are synthesized. These easily accessible reagents react smoothly with a collection of cyclic α,ß-unsaturated ketones, generating a new C-C bond and stereocenter. Products are isolated in up to 99 % yield with greater than 20:1 E/Z and greater than 99:1 e.r. Mechanistic studies show the site-selectivity of transmetalation and reactivity is ligand dependent. The utility of the approach is highlighted by gram-scale synthesis of enantioenriched cyclic 1,4-diketones, and stereoselective transformations of the products by hydrogenation, allylation, and isomerization.


Assuntos
Ácidos Borônicos/síntese química , Ésteres/síntese química , Cetonas/síntese química , Ródio/química , Ácidos Borônicos/química , Catálise , Ésteres/química , Cetonas/química , Estrutura Molecular , Estereoisomerismo
18.
Chemistry ; 25(58): 13354-13362, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31338861

RESUMO

New L-shaped fluorophores possessing five conjugated rings have been synthesized through a four-step procedure involving diketopyrrolopyrrole synthesis and its double N-alkylation, followed by trimethylsilyl bromide-mediated rearrangement to thieno[2,3-f]isoindole-5,8-dione and an intramolecular Friedel-Crafts reaction. In comparison with the parent isoindolediones and π-expanded diketopyrrolopyrroles, these new dyes show red-shifted absorption and emission (up to ≈630 nm). Their structural rigidity is responsible for both the observed small Stokes shifts and large fluorescence quantum yields. Tissue imaging studies revealed that these new dyes show advantageous features including minimal autofluorescence interference and pronounced solvent-sensitive emission. Interestingly, there is a fundamental difference between a dye possessing an amino group and its analog bearing an N-alkyl substituent. The former dye under two-photon excitation at 900 nm gives bright images whereas its N-alkylated counterpart does not. A new type of membrane localization has been discovered by an N-alkylated isoindoledione possessing a benzofuryl substituent. In spite of the fact that the fluorescence quantum yield of this dye in a range of solvents is rather low, it does stain cell membranes exclusively. This new mode of cellular staining opens the door towards further development of membrane staining dyes.


Assuntos
Corantes Fluorescentes/química , Isoindóis/química , Células A549 , Animais , Humanos , Cetonas/síntese química , Camundongos Endogâmicos BALB C , Imagem Óptica , Pirróis/síntese química , Compostos de Trimetilsilil/química
19.
Angew Chem Int Ed Engl ; 58(35): 12081-12085, 2019 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-31287943

RESUMO

Synthesis of the C-C bonds of ketones relies upon one high-availability reagent (carboxylic acids) and one low-availability reagent (organometallic reagents or alkyl iodides). We demonstrate here a ketone synthesis that couples two different carboxylic acid esters, N-hydroxyphthalimide esters and S-2-pyridyl thioesters, to form aryl alkyl and dialkyl ketones in high yields. The keys to this approach are the use of a nickel catalyst with an electron-poor bipyridine or terpyridine ligand, a THF/DMA mixed solvent system, and ZnCl2 to enhance the reactivity of the NHP ester. The resulting reaction can be used to form ketones that have previously been difficult to access, such as hindered tertiary/tertiary ketones with strained rings and ketones with α-heteroatoms. The conditions can be employed in the coupling of complex fragments, including a 20-mer peptide fragment analog of Exendin(9-39) on solid support.


Assuntos
Ésteres/química , Cetonas/química , Níquel/química , Sequência de Aminoácidos , Ácidos Carboxílicos/química , Catálise , Iodetos/química , Cetonas/síntese química , Peptídeos/química , Ftalimidas/química , Técnicas de Síntese em Fase Sólida
20.
J Med Chem ; 62(15): 7089-7110, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31294975

RESUMO

CDC25 phosphatases play a critical role in the regulation of the cell cycle and thus represent attractive cancer therapeutic targets. We previously discovered the 4-(2-carboxybenzoyl)phthalic acid (NSC28620) as a new CDC25 inhibitor endowed with promising anticancer activity in breast, prostate, and leukemia cells. Herein, we report a structure-based optimization of NSC28620, leading to the identification of a series of novel naphthylphenylketone and naphthylphenylamine derivatives as CDC25B inhibitors. Compounds 7j, 7i, 6e, 7f, and 3 showed higher inhibitory activity than the initial lead, with Ki values in the low micromolar range. Kinetic analysis, intrinsic fluorescence studies, and induced fit docking simulations provided a mechanistic understanding of the activity of these derivatives. All compounds were tested in the highly aggressive human melanoma cell lines A2058 and A375. Compound 4a potently inhibited cell proliferation and colony formation, causing an increase of the G2/M phase and a reduction of the G0/G1 phase of the cell cycle in both cell lines.


Assuntos
Compostos de Anilina/síntese química , Antineoplásicos/síntese química , Desenho de Fármacos , Descoberta de Drogas/métodos , Cetonas/síntese química , Fosfatases cdc25/antagonistas & inibidores , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Humanos , Cetonas/farmacologia , Cetonas/uso terapêutico , Melanoma/tratamento farmacológico , Estrutura Terciária de Proteína , Resultado do Tratamento
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