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1.
Yakugaku Zasshi ; 140(11): 1313-1322, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132266

RESUMO

In total and formal syntheses of dictyodendrins A, B, C, D, E and F, the key step involved the direct construction of the pyrrolo[2,3-c]carbazole core by the gold-catalyzed annulation of a conjugated diyne with a pyrrole to form three bonds and two aromatic rings. The subsequent introduction of substituents at the C1 (Suzuki-Miyaura coupling), C2 (acylation), N3 (alkylation) and C5 positions (Ullmann coupling) provided divergent access to dictyodendrins. Some dictyodendrin analogues exhibited inhibitory activities toward CDK2/CycA2 and GSK3.


Assuntos
Carbazóis/síntese química , Pirróis/síntese química , Acilação , Alquilação , Catálise , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Di-Inos/química , Fenômenos de Química Orgânica , Pirróis/química
2.
Eur J Med Chem ; 191: 112181, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113125

RESUMO

Here, we formulated and investigated the structure-activity relationships of novel N-substituted carbazole sulfonamide derivatives with improved physicochemical properties. Most of these new compounds displayed good aqueous solubility. Certain molecules presented strong in vitro antiproliferative and in vivo antitumor activity. Relative to the control, 50 mg/kg compound 3v substantially reduced human HepG2 xenograft mouse tumor growth by 54.5% and its efficacy was comparable to that of CA-4P. Compound 3h demonstrated anticancer efficacy in both subcutaneous and orthotopic HepG2 xenograft mouse models. We also developed a novel synthetic method for 7-hydroxy-substituted carbazole sulfonamides. Compared with the control, 25 mg/kg compound 4c inhibited human HepG2 xenograft mouse tumor growth by 71.7% and was more potent than 50 mg/kg CA-4P with only 50% tumor shrinkage efficacy. Among the three water-soluble carbazole sulfonamide derivatives formulated in the present study, compound 4c displayed the most effective tumor growth inhibition in vivo and merit further investigation as potential antitumor agents for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Células Tumorais Cultivadas , Água/química
3.
Chem Pharm Bull (Tokyo) ; 68(2): 167-172, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009084

RESUMO

A heterogeneous metal catalyst enabled the intramolecular oxidative coupling of diarylamines to form carbazoles with molecular oxygen as the sole oxidant. Rh/C had efficient catalytic activity and allowed the catalyst loading to be reduced to 0.1 mol% while maintaining excellent yields of carbazoles. This reaction is operationally simple in an open-to-air setup, and provides a green and atom-economical process for an efficient synthetic approach to N-substituted carbazoles.


Assuntos
Carbazóis/síntese química , Carbazóis/química , Catálise , Técnicas de Química Sintética , Acoplamento Oxidativo , Oxigênio/química , Ródio/química
4.
Molecules ; 25(2)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936505

RESUMO

In this paper, we aimed to exploit and combine in the same molecule the carbazole and the 1,3,4-oxadiazole pharmacophores, to obtain novel carprofen derivatives, by using two synthesis pathways. For the first route, the following steps have been followed: (i) (RS)-2-(6-chloro-9H-carbazol-2-yl)propanonic acid (carprofen) treatment with methanol, yielding methyl (RS)-2-(6-chloro-9H-carbazol-2-yl)propanoate; (ii) the resulted methylic ester was converted to (RS)-2-(6-chloro-9H-carbazol-2-yl)propane hydrazide (carprofen hydrazide) by treatment with hydrazine hydrate; (iii) reaction of the hydrazide derivative with acyl chlorides led to N-[(2RS)-2-(6-chloro-9H-carbazol-2-yl)propanoil]-N'-R-substituted-benzoylhydrazine formation, which; (iv) in reaction with phosphorus oxychloride gave the (RS)-1-(6-chloro-9H-carbazol-2-yl)-1-(1,3,4-oxadiazol-2-yl)ethane derivatives. In the second synthesis pathway, new 1,3,4-oxadiazole ring compounds were obtained starting from carprofen which was reacted with isoniazid, in the presence of phosphorus oxychloride to form (RS)-1-(6-chloro-9H-carbazol-2-yl)-1-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]ethane. The synthesized compounds were characterized by IR, 1H-NMR and 13C-NMR, screened for their drug-like properties and evaluated for in vitro cytotoxicity and antimicrobial activity. The obtained compounds exhibited a good antimicrobial activity, some of the compounds being particularly active on E. coli, while others on C. albicans. The most significant result is represented by their exceptional anti-biofilm activity, particularly against the P. aeruginosa biofilm. The cytotoxicity assay revealed that at concentrations lower than 100 µg/mL, the tested compounds do not induce cytotoxicity and do not alter the mammalian cell cycle. The new synthesized compounds show good drug-like properties. The ADME-Tox profiles indicate a good oral absorption and average permeability through the blood brain barrier. However, further research is needed to reduce the predicted mutagenic potential and the hepatotoxicity.


Assuntos
Antibacterianos/química , Anti-Infecciosos/química , Carbazóis/química , Oxidiazóis/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/patogenicidade , Carbazóis/síntese química , Carbazóis/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/patogenicidade , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Relação Estrutura-Atividade
5.
Chemistry ; 26(19): 4261-4268, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31793681

RESUMO

A series of carbazole-based boron dipyrromethenes (BODIPYs) 2 a-g bearing binaphthyl units have been synthesized by the Et2 AlCl-mediated reaction of the corresponding BODIPY difluorides 1 a-g with 1,1'-binaphthalene-2,2'-diol. Substituents such as halogen, nitrile, and amino groups were tolerated under the reaction conditions, and the reaction of the phenylethynyl-substituted 1 h gave (R,R)-3 h bearing two binaphthyl units. The chiroptical properties of these dyes with different substituents were investigated by UV/Vis, CD, fluorescence, and circularly polarized luminescence (CPL) spectroscopy. The CD spectra showed Cotton effects in the absorption region of the BODIPY moieties. In addition, they showed CPL both in solution and in the solid state. Interestingly, several dyes recorded higher glum values in the solid state, probably due to intermolecular interactions. Because (R,R)-3 h recorded relatively low glum values, the diastereomer (R,S)-3 h was prepared. The (R,S) diastereomer showed intense CPL, which suggests a synergetic effect of the two binaphthyl groups. Finally, chiral carbazole-based BODIPY dimers have been synthesized for the first time and their chiroptical properties were investigated. They showed redshifted fluorescence and CPL, which reached the near-IR (NIR) region in the solid state.


Assuntos
Compostos de Boro/síntese química , Carbazóis/síntese química , Corantes/química , Boro/química , Compostos de Boro/química , Carbazóis/química , Fluorescência , Luminescência , Estrutura Molecular , Análise Espectral
6.
Spectrochim Acta A Mol Biomol Spectrosc ; 227: 117692, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31703997

RESUMO

In this article, a fluorescent probe FCZ with fluorescein-carbazole as the basic skeleton was designed and synthesized. In contrast to the presences of other coexisting anions, active oxygen and organic thiols, the probe could be "turn-on", exhibiting specific fluorescence performance towards hypochlorite (ClO-). Comprehensive analyses by electrospray ionization mass spectrometry (ESI-MS), thin-layer chromatography (TLC), nuclear magnetic resonance (NMR), and density functional theory/time-dependent density functional theory (DFT/TDDFT) revealed that ClO- could react with the imine bond of the probe, forming fluorescein, resulting in a significant increase of fluorescence emission intensity. The probe has a detection limit for ClO- in water of 0.056 µmol/L. In addition, the probe was successfully applied to detect ClO- in water samples, as well as in the imaging of ClO- in RAW264.7 cells and zebrafish.


Assuntos
Carbazóis/química , Fluoresceína/química , Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Imageamento Tridimensional , Peixe-Zebra/metabolismo , Animais , Carbazóis/síntese química , Sobrevivência Celular , Fluoresceína/síntese química , Corantes Fluorescentes/síntese química , Larva/metabolismo , Camundongos , Modelos Moleculares , Células RAW 264.7 , Espectrometria de Fluorescência , Água/química
7.
Mol Divers ; 24(1): 211-223, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30927138

RESUMO

Inhibition of butyrylcholinesterase (BChE) might be a useful therapeutic target for Alzheimer's disease (AD). A new series of 1,2,3,4-tetrahydro-9H-carbazole derivatives were designed synthesized and evaluated as BChE inhibitors. While all of the derivatives have shown for AChE IC50 values below the detectable limit (> 100 µM), they were selective potent BChE inhibitors. 1-(2-(6-fluoro-1,2,3,4-tetrahydro-9H-carbazole-9-yl)ethyl)piperidin-1-ium chloride (15 g) had the most potent anti-BChE activity (IC50 value = 0.11 µM), the highest BChE selectivity and mixed-type inhibition. Pharmacokinetic properties were accordant to Lipinski rule and compound 15g demonstrated neuroprotective and inhibition of ß-secretase (BACE1) activities. Furthermore, in vivo study of compound 15g in Morris water maze task has confirmed memory improvement in scopolamine-induced impairment. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD. A new series of 1,2,3,4-tetrahydro-9H-carbazole derivatives were designed synthesized and evaluated as BChE inhibitors. While all of the derivatives have shown for AChE IC50 values below the detectable limit, they were selective potent BChE inhibitors. Compound 15g had the most potent anti-BChE activity. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.


Assuntos
Butirilcolinesterase/química , Carbazóis/química , Carbazóis/farmacologia , Técnicas de Química Sintética , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Carbazóis/síntese química , Morte Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Cinética , Masculino , Estrutura Molecular , Neurônios , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Ratos
8.
Analyst ; 145(1): 233-239, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31746824

RESUMO

Three-component conjugated polymers of a strong donor-acceptor (D-A) type could be synthesized by Pd-catalyzed Suzuki coupling polymerization reaction of 1,2-bis(4-bromophenyl)-1,2-diphenylethene (M-1) with 9-octyl-3,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole (M-2) and 4,6-bis((E)-4-bromostyryl)-2,2-difluoro-5-phenyl-2H-1l3,3,2l4-dioxaborinine (M-3). Among them, P-1 and P-2 with high TPE ratios at 0.95 and 0.9 showed obvious aggregation-induced emission (AIE) behavior; in contrast P-3 with a low TPE ratio at 0.8 showed an aggregation-caused quenching (ACQ) phenomenon. In particular, the three resulting polymer dots (P-1 to P-3 Pdots) exhibited a 200 mV lower electrochemiluminescence (ECL) potential due to their strong D-A electronic structure. Most importantly, the ECL signals of Pdots could be enhanced as high as 3 times by increasing their AIE-active TPE moiety ratios from 0.8 (P-3) to 0.95 (P-1) via the band gap emission process. Herein, P-1 Pdots with the strongest ECL signal were successfully used as ECL biosensors for the detection of catechol, epinephrine and dopamine with detection limits of 1, 7 and 3 nM, respectively. This work provides a new strategy for developing highly sensitive ECL biosensors by the smart structure design of the AIE-active Pdots.


Assuntos
Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Substâncias Luminescentes/química , Medições Luminescentes/métodos , Polímeros/química , Pontos Quânticos/química , Compostos de Boro/síntese química , Compostos de Boro/química , Carbazóis/síntese química , Carbazóis/química , Catecóis/análise , Dopamina/análise , Técnicas Eletroquímicas/instrumentação , Eletrodos , Epinefrina/análise , Limite de Detecção , Polimerização , Polímeros/síntese química
9.
Int J Mol Sci ; 20(21)2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31683506

RESUMO

Benzofuran (BF), benzothiophene (BT), indole (IN), dibenzofuran (DBF), dibenzothiophene (DBT), and carbazole (CA) are typical heterocyclic aromatic compounds (NSO-HETs), which can coexist with polycyclic aromatic hydrocarbons (PAHs) in combustion and pyrolysis conditions. In this work, quantum chemical calculations were carried out to investigate the formation of DBF, DBT, and CA from the reactions of BF, BT, and IN with a cyclopentadienyl radical (CPDyl) by using the hybrid density functional theory (DFT) at the MPWB1K/6-311+G(3df,2p)//MPWB1K/6-31+G(d,p) level. The rate constants of crucial elementary steps were deduced over 600-1200 K, using canonical variational transition state theory with a small-curvature tunneling contribution (CVT/SCT). This paper showed that the production of DBF, DBT, and CA from the reactions of BF, BT, and IN with CPDyl involved six elementary steps: the addition reaction, ring closure, the first H shift, C-C cleavage, the second H shift, and elimination of CH3 or H. The cleavage of the C-C bond was regarded as the rate-determining step for each pathway due to the extremely high barrier. The 1-methyl substituted products were more easily formed than the 4-methyl substituted products. The main products were DBF and 1-methyl-DBF, DBT and 1-methyl-DBT, and CA and 1-methyl-CA for reactions of BF, BT, and IN with CPDyl, respectively. The ranking of DBF, DBT, and CA formation potential was as follows: DBT and methyl-DBT formation > DBF and methyl-DBF formation > CA, and methyl-CA formation. Comparison with the reaction of naphthalene with CPDyl indicated that the reactions of CPDyl attacking a benzene ring and a furan/thiophene/pyrrole ring could be inferred to be comparable under high temperature conditions.


Assuntos
Benzofuranos/química , Ciclopentanos/química , Gases/química , Indóis/química , Hidrocarbonetos Policíclicos Aromáticos/química , Tiofenos/química , Benzofuranos/síntese química , Carbazóis/síntese química , Carbazóis/química , Radicais Livres/química , Cinética , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Hidrocarbonetos Policíclicos Aromáticos/síntese química , Tiofenos/síntese química
10.
Eur J Med Chem ; 183: 111741, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31605873

RESUMO

Tumor-associated macrophages (TAMs) are one of the prominent components of the tumor microenvironment (TME). The polarization peculiarity of TAMs drives them to infiltrate and active with states between M1 (anti-tumor) and M2 (pro-tumor) phenotypes in cancers. Exploiting small molecular drugs through targeting TAMs to repolarize them into an antitumor phenotype is considered as a novel strategy for cancer treatments in recent years. For discovering novel compounds that target TAMs, a series of ureido tetrahydrocarbazole derivatives were designed, synthesized and evaluated both in vitro and in vivo. Among them, compound 23a was found to dose-dependently repolarize TAMs from M2 to M1 both in vitro and in vivo. And more importantly, the in vivo experiments also revealed that compound 23a was capable of remarkably inhibiting tumor growth of the LLC mouse model. Moreover, the synergy of compound 23a with anti-PD-1 antibody had more superior antineoplastic effects than the exclusive use of either in vivo.


Assuntos
Antineoplásicos/síntese química , Carbazóis/síntese química , Macrófagos/efeitos dos fármacos , Ureia/análogos & derivados , Ureia/síntese química , Animais , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Carbazóis/administração & dosagem , Carbazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas/métodos , Sinergismo Farmacológico , Feminino , Humanos , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Relação Estrutura-Atividade , Microambiente Tumoral , Ureia/administração & dosagem , Ureia/farmacologia
11.
Bioorg Med Chem ; 27(22): 115123, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31623971

RESUMO

Although a diverse range of chemical entities offering striking therapeutic potential against urease enzyme has been reported, the key challenges (toxicity and safety) associated with these inhibitors create a large unmet medical need to unveil new, potent and safe inhibitors of urease enzyme. In this pursuit, the present study demonstrates the successful synthesis of carbazole-chalcone hybrids (4a-n) in good yields. The evaluation of the preliminary in vitro biological results showed that selected members of the investigated library of hybrid compounds possess excellent urease inhibitory efficacy. In particular, compounds 4c and 4k were the most potent inhibitors with lowest IC50 values of 8.93 ±â€¯0.21 and 6.88 ±â€¯0.42 µM, respectively. Molecular docking analysis of the most potent inhibitor 4k suggests that the compound is fitted neatly at the active site interface and mediates interaction with both nickel atoms present in the active site. Several other obvious interactions including metal-carbonyl contact, hydrogen bonding and hydrophobic interactions were also observed, playing a crucial part in the stabilization of 4k in the active site of urease.


Assuntos
Carbazóis/química , Carbazóis/síntese química , Chalconas/química , Chalconas/síntese química , Urease/antagonistas & inibidores , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
12.
Molecules ; 24(20)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652581

RESUMO

Herein we report a significant, valuable extension of a recently implemented pyrrole benzannulation methodology that, employing versatile nitrodienes from our lab as useful C4 building blocks, led to indole derivatives characterized by unusual patterns of substitution. The 6-nitro-7-arylindoles resulting from suitably derivatized, non-symmetric dienes are of foreseeable synthetic interest in search for new polyheterocyclic systems. As an example, pyrrolocarbazoles with a rarely reported ring fusion were synthesized with the classical Cadogan protocol. Furthermore, the proven easy reducibility of the nitro group to amine will surely open the way to further interesting elaborations.


Assuntos
Carbazóis/química , Indóis/química , Pirróis/química , Carbazóis/síntese química , Indóis/síntese química , Estrutura Molecular , Pirróis/síntese química
13.
Future Med Chem ; 11(19): 2491-2504, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31633398

RESUMO

Aim: The p53 cancer mutation Y220C creates a conformationally unstable protein with a unique elongated surface crevice that can be targeted by molecular chaperones. We report the structure-guided optimization of the carbazole-based stabilizer PK083. Materials & methods: Biophysical, cellular and x-ray crystallographic techniques have been employed to elucidate the mode of action of the carbazole scaffolds. Results: Targeting an unoccupied subsite of the surface crevice with heterocycle-substituted PK083 analogs resulted in a 70-fold affinity increase to single-digit micromolar levels, increased thermal stability and decreased rate of aggregation of the mutant protein. PK9318, one of the most potent binders, restored p53 signaling in the liver cancer cell line HUH-7 with homozygous Y220C mutation. Conclusion: The p53-Y220C mutant is an excellent paradigm for the development of mutant p53 rescue drugs via protein stabilization. Similar rescue strategies may be applicable to other cavity-creating p53 cancer mutations.


Assuntos
Carbazóis/farmacologia , Chaperonas Moleculares/metabolismo , Ativação Transcricional/genética , Proteína Supressora de Tumor p53/genética , Carbazóis/síntese química , Carbazóis/química , Humanos , Chaperonas Moleculares/síntese química , Chaperonas Moleculares/química , Estrutura Molecular , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/metabolismo
14.
Org Biomol Chem ; 17(36): 8330-8342, 2019 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-31497833

RESUMO

Carbazoles are privileged nitrogen heterocycles that are present in a wide range of natural products, pharmaceuticals, and functional materials. Due to their wide application, various synthetic strategies are available in the literature using substituted amines or indoles as a substrate. Thus, this review comprehensively highlights the (2015-2019) article that focuses on the synthesis of carbazoles derived from an indole-template through transition-metal catalyzed C-H functionalization, metal-free cyclization, three-component reaction, and electrophilic iodocyclizations. The synthetic strategies described in this review provided diversely substituted carbazoles and few of them have profound pharmacological activity.


Assuntos
Carbazóis/síntese química , Indóis/química , Carbazóis/química , Estrutura Molecular
15.
J Med Chem ; 62(17): 8235-8248, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31419132

RESUMO

Development of neuroinflammation agents targeting the translocator protein (TSPO) has been hindered by a common single nucleotide polymorphism (A147T) at which TSPO ligands commonly lose affinity. To this end, carbazole acetamide scaffolds were synthesized and structure activity relationships elaborated to explore the requirements for high-affinity binding to both TSPO wild type (WT) and the polymorphic TSPO A147T. This study reports high binding affinity and nondiscriminating TSPO ligands.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Carbazóis/farmacologia , Receptores de GABA/metabolismo , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Carbazóis/síntese química , Carbazóis/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Receptores de GABA/genética , Relação Estrutura-Atividade
16.
J Enzyme Inhib Med Chem ; 34(1): 1544-1561, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31448648

RESUMO

In this paper, a series of novel 1H-dibenzo[a,c]carbazole derivatives of dehydroabietic acid bearing different N-(piperazin-1-yl)alkyl side chains were designed, synthesised and evaluated for their in vitro anticancer activities against three human hepatocarcinoma cell lines (SMMC-7721, HepG2 and Hep3B). Among them, compound 10g exhibited the most potent activity against three cancer cell lines with IC50 values of 1.39 ± 0.13, 0.51 ± 0.09 and 0.73 ± 0.08 µM, respectively. In the kinase inhibition assay, compound 10g could significantly inhibit MEK1 kinase activity with IC50 of 0.11 ± 0.02 µM, which was confirmed by western blot analysis and molecular docking study. In addition, compound 10g could elevate the intracellular ROS levels, decrease mitochondrial membrane potential, destroy the cell membrane integrity, and finally lead to the oncosis and apoptosis of HepG2 cells. Therefore, compound 10g could be a potent MEK inhibitor and a promising anticancer agent worthy of further investigations.


Assuntos
Abietanos/farmacologia , Antineoplásicos/farmacologia , Carbazóis/farmacologia , MAP Quinase Quinase 1/antagonistas & inibidores , Piperazina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Abietanos/síntese química , Abietanos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , MAP Quinase Quinase 1/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Piperazina/síntese química , Piperazina/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 182: 111571, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425908

RESUMO

Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with 18F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Carbazóis/farmacologia , Crizotinibe/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe/síntese química , Crizotinibe/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Radioisótopos de Flúor , Humanos , Camundongos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Cintilografia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Distribuição Tecidual
18.
Sci Rep ; 9(1): 9982, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292477

RESUMO

Development of an efficient and scalable synthesis of 6-formylindolo[3,2-b]carbazole (FICZ), a naturally-occurring aryl hydrocarbon receptor (AhR) ligand, allowed its biological and physical properties to be studied. FICZ was shown to be the most potent among a series of 6-substituted indolo[3,2-b]carbazoles for activation of AhR in cells. Photostability studies of FICZ revealed a non-enzymatic mechanism for its conversion to a biologically active quinone. These results further support the hypothesis that FICZ is a light-dependent hormone that links sun exposure to regulation of biological pathways in peripheral tissues.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carbazóis/síntese química , Receptores de Hidrocarboneto Arílico/metabolismo , Carbazóis/química , Carbazóis/farmacologia , Linhagem Celular , Estabilidade de Medicamentos , Humanos , Ligantes , Estrutura Molecular , Processos Fotoquímicos
19.
Angew Chem Int Ed Engl ; 58(38): 13349-13353, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31350791

RESUMO

Carquinostatin A (CQS), a potent neuroprotective substance, is a unique carbazole alkaloid with both an ortho-quinone function and an isoprenoid moiety. We identified the entire gene cluster responsible for CQS biosynthesis in Streptomyces exfoliatus through heterologous production of CQS and gene deletion. Biochemical characterization of seven CQS biosynthetic gene products (CqsB1-7) established the total biosynthetic pathway of CQS. Reconstitution of CqsB1 and CqsB2 showed that the synthesis of the carbazole skeleton involves CqsB1-catalyzed decarboxylative condensation of an α-hydroxyl-ß-keto acid intermediate with 3-hydroxybutyryl-ACP followed by CqsB2-catalyzed oxidative cyclization. Based on crystal structures and mutagenesis-based biochemical assays, a detailed mechanism for the unique deprotonation-initiated cyclization catalyzed by CqsB2 is proposed. Finally, analysis of the substrate specificity of the biosynthetic enzymes led to the production of novel carbazoles.


Assuntos
Alcaloides/química , Carbazóis/síntese química , Streptomyces/química , Ciclização , Humanos
20.
Talanta ; 204: 592-601, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31357339

RESUMO

Development of conjugated polymers with fluorescence sensing characteristics has received close attention from researchers in fields of environmental protection, biosensing and toxins detection on food. In this paper, novel polyaniline derivatives of poly(9-methyl-9H-carbazol-3-amine) and poly(9,9-dihexyl-9H-fluoren-2-amine) are prepared by facile chemical polymerization. Then they are characterized with NMR (Nuclear Magnetic Resonance), GPC (Gel Permeation Chromatography), XRD (X-Ray Diffraction), FT-IR (Fourier Transform Infrared spectroscopy), FL (Fluorescence spectrometry) and UV-vis (Ultraviolet-visible spectroscopy) characterizations and further applied to the fluorescence detection of different acids and amines. Moreover, the obtained poly(9-methyl-9H-carbazol-3-amine) displays excellent fluorescence properties in the detection for both acids and amines. Besides, this poly(9-methyl-9H-carbazol-3-amine) can not only be used for fluorescence detection in solution, but also can be prepared into solid state and applied in the gas phase fluorescence detection. This work has greatly expanded the scope of application to these polyaniline derivatives materials, opening a new path for the researches on multi-functional chemosensor.


Assuntos
Compostos de Anilina/química , Carbazóis/química , Fluorenos/química , Corantes Fluorescentes/química , Compostos de Anilina/síntese química , Carbazóis/síntese química , Etilenodiaminas/análise , Etilenodiaminas/química , Fluorenos/síntese química , Fluorescência , Corantes Fluorescentes/síntese química , Ácido Clorídrico/análise , Ácido Clorídrico/química , Ligação de Hidrogênio , Limite de Detecção , Metilaminas/análise , Metilaminas/química , Ácido Nítrico/análise , Ácido Nítrico/química , Reprodutibilidade dos Testes , Espectrometria de Fluorescência/métodos
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