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1.
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
2.
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
3.
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
/farmacologia , Antineoplásicos/farmacologia , Carbazóis/farmacologia , MAP Quinase Quinase 1/antagonistas & inibidores , Piperazina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , /síntese 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
4.
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
5.
Analyst ; 144(16): 4972-4977, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31322159

RESUMO

Sulfur dioxide (SO2) plays a vital role in physiological and pathological processes. Excessive inhalation of SO2 is associated with several diseases. However, the potential physiological mechanisms of SO2 in living systems are still unclear due to the lack of an effective technique for imaging SO2 in real time in living mice. Herein, a ratiometric fluorescent probe CSP has been constructed for monitoring SO2. The novel probe CSP displayed fast sensing of SO2, excellent selectivity and photostability. More importantly, CSP was effectively employed for the detection of mitochondrial SO2 not only at the cellular level but also in zebrafish and living mice.


Assuntos
Corantes Fluorescentes/química , Mitocôndrias/metabolismo , Dióxido de Enxofre/análise , Animais , Benzotiazóis/síntese química , Benzotiazóis/química , Carbazóis/síntese química , Carbazóis/química , Fluorescência , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Camundongos Endogâmicos BALB C , Microscopia de Fluorescência/métodos , Imagem Óptica/métodos , Peixe-Zebra
6.
Molecules ; 24(15)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344865

RESUMO

In this study, a new series of N-alkyl-3,6-dibromocarbazole and N-alkyl-5-bromoindole derivatives have been synthesized and evaluated in vitro as anti-cancer and anti-migration agents. Cytotoxic and anti-migratory effects of these compounds were evaluated in MCF-7 and MDA-MB-231 breast cancer cell lines and an insight on the structure-activity relationship was developed. Preliminary investigations of their anti-cancer activity demonstrated that several compounds have moderate antiproliferative effects on cancer cell lines with GI50 values in the range of 4.7-32.2 µM. Moreover, carbazole derivatives 10, 14, 15, 23, and 24 inhibit migration activity of metastatic cell line MDA-MB-231 in the range of 18-20%. The effect of compounds 10, 14, and 15 in extension of invadopodia and filopodia was evaluated by fluorescence microscopy and results demonstrated a reduction in actin-based cell extensions by compounds 10 and 15.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Indóis/química , Indóis/farmacologia , Antineoplásicos/síntese química , Carbazóis/síntese química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Estrutura Molecular , Relação Estrutura-Atividade
7.
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 , Ligações de Hidrogênio , Limite de Detecção , Metilaminas/análise , Metilaminas/química , Ácido Nítrico/análise , Ácido Nítrico/química , Reprodutibilidade dos Testes , Espectrometria de Fluorescência/métodos
8.
Eur J Med Chem ; 178: 802-817, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31252285

RESUMO

We report in this work the discovery of novel allosteric MEK inhibitors by pharmacophore modeling and virtual screening. Two out of 13 virtual hit compounds were identified as MEK kinase inhibitors using a MEK1 binding assay. Structural derivations on the hit compound M100 (IC50 = 27.2 ±â€¯4.5 µM in RAF-MEK cascading assay) by substituent transformation and bioisosterism replacement have led to the synthesis of a small library of carbazoles. The enzymatic studies revealed the preliminary structure-activity relationships and the derivative 22k (IC50 = 12.8 ±â€¯0.5 µM) showed the most potent inhibitory effect against Raf-MEK cascading. Compound 7 was discovered as toxic as M100 to tumor cells whereas safer to HEK293 cells (IC50 > 100 µM) than M100 (IC50 = 8.9 ±â€¯2.0 µM). It suggests that carbazole is a good scaffold for the design of novel MEK inhibitors for therapeutic uses. More importantly, the developed pharmacophore model can serve as a reliable criterion in novel MEK inhibitor discovery.


Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Descoberta de Drogas , MAP Quinase Quinase Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Regulação Alostérica/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , MAP Quinase Quinase Quinases/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
9.
Chem Commun (Camb) ; 55(44): 6151-6164, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31093637

RESUMO

Chiral tetrahydrocarbazoles (THCs) are prevalent in numerous natural indole alkaloids as well as synthetic pharmaceuticals, and exhibit a broad spectrum of bioactivities. As such, the development of efficient synthetic methodologies for the synthesis of chiral THCs is of substantial interest. The advent of asymmetric catalysis provides a powerful platform to assemble chiral THC motifs and great efforts have been devoted to this field over the past decades. In this feature article, we summarise recent advances in catalytic asymmetric synthesis of THCs, with particular emphases on reaction types and reaction mechanism.


Assuntos
Carbazóis/síntese química , Alquilação , Carbazóis/química , Catálise , Reação de Cicloadição , Indóis/química , Ácidos de Lewis/química , Estrutura Molecular , Estereoisomerismo
10.
Molecules ; 24(6)2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909464

RESUMO

KOH/DMSO-promoted C-N bond formation via nucleophilic aromatic substitution (SNAr) between chloroarenes or fluoroarenes with indoles and carbazole under transition metal-free conditions affording the corresponding N-arylated indoles and carbazoles has been developed.


Assuntos
Carbazóis/química , Indóis/química , Carbazóis/síntese química , Carbono/química , Indóis/síntese química , Estrutura Molecular , Nitrogênio/química
11.
Appl Microbiol Biotechnol ; 103(9): 3627-3636, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30888461

RESUMO

Rebeccamycin is an antibiotic and antitumor substance isolated from the filamentous bacterium Lentzea aerocolonigenes. After its discovery, investigations of rebeccamycin focused on elucidating its structure, biological activity, and biosynthetic pathway. For potential medical application, a sufficient drug supply has to be ensured, meaning that the production process of rebeccamycin plays a major role. In addition to the natural production of rebeccamycin in L. aerocolonigenes, where the complex cell morphology is an important factor for a sufficient production, rebeccamycin can also be heterologously produced or chemically synthesized. Each of these production processes has its own challenges, and first approaches to production often lead to low final product concentrations, which is why process optimizations are performed. This review provides an overview of the production of rebeccamycin and the different approaches used for rebeccamycin formation including process optimizations.


Assuntos
Antibióticos Antineoplásicos/biossíntese , Bactérias/metabolismo , Carbazóis/metabolismo , Microbiologia Industrial , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/química , Bactérias/genética , Carbazóis/síntese química , Carbazóis/química
12.
Bioorg Chem ; 85: 475-486, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30776558

RESUMO

A series of spirochromenocarbazole tethered 1,2,3-triazoles were synthesized via click chemistry based one-pot, five component reaction between N-propargyl isatins, malononitrile, 4-hydroxycarbazole, aralkyl halides and sodium azide using cellulose supported CuI nanoparticles (Cell-CuI NPs) as the heterogeneous catalyst. Antiproliferative activity of all the synthesized compounds was investigated against panel of cancer cell lines such as MCF-7, MDA-MB-231, HeLa, PANC-1, A-549, and THP-1. Many of the synthesized compounds exhibited good anti-proliferative activity against breast (MCF-7 and MDA-MB-231) and cervical (HeLa) cancer cells with IC50 values less than 10 µM. In case of MCF-7 cells, among the nine compounds that showed good anti-proliferative activity, compounds 6f and 6j were found to be highly potent (IC50 = 2.13 µM and 4.80 µM, respectively). In case of MDA-MB-231, three compounds (6k, 6j and 6s) showed antiproliferative activity amongst which 6k was the most potent one (IC50 = 3.78 µM). On the other hand, in cervical cancer HeLa cells, compounds 6b, 6g, 6s and 6u showed excellent antiproliferative activity (IC50 = 4.05, 3.54, 3.83, 3.35 µM, respectively). All the compounds were found to be nontoxic to the human umbilical vein endothelial cells (HUVECs). AO and EtBr staining and fluorescence microscopy studies of the active compounds (IC50 < 5 µM) suggested that these compounds induce cell death by apoptosis.


Assuntos
Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Carbazóis/farmacologia , Compostos de Espiro/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Benzopiranos/síntese química , Carbazóis/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Química Click , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais da Veia Umbilical Humana , Humanos , Estrutura Molecular , Compostos de Espiro/síntese química , Relação Estrutura-Atividade
13.
Molecules ; 24(2)2019 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-30669461

RESUMO

A novel deep-blue fluorescent emitter was designed and synthesized. The external quantum efficiency (ηEQE) of the blue-emitting, doped, organic light-emitting diode (OLED) was as high as 4.34%. The device also exhibited an excellent color purity with Commission Internationale de l'Eclairage (CIE) coordinates of x = 0.15 and y = 0.05. In addition, the triplet energy had a value of 2.7 eV, which is rare for an emitter with deep-blue emission, which makes it a preferred choice for high-performance white OLEDs. By optimizing the device architectures, the color of hybrid-white OLEDs could be tunable from warm white to cool white using the aforementioned material as a bifunctional material. That is, the ηEQE of the hybrid warm-white OLED is 20.1% with a CIE x and y of 0.46 and 0.48 and the ηEQE of the hybrid cool-white OLED is 9% with a CIE x and y of 0.34 and 0.33.


Assuntos
Carbazóis/síntese química , Corantes Fluorescentes/síntese química , Pirazinas/síntese química , Cor , Técnicas Eletroquímicas , Fluorescência , Estrutura Molecular , Transição de Fase , Processos Fotoquímicos , Relação Estrutura-Atividade , Termodinâmica
14.
Bioorg Med Chem ; 27(5): 777-784, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30692023

RESUMO

A simple and one-pot approach for the synthesis of highly functionalized novel (E)-2-benzylideno-(Z)-carbazolylideno cyanoacetamide derivatives from different 2-(2',3',4',9'-tetrahydro-carbazol-1'-ylidene)-propanedinitriles and aryl/heteroaryl carbaldehydes via vinylogous aldol reaction. The structures of the molecules were designated by FT-IR, 1H NMR, 13C NMR studies, elemental and X-ray crystallographic analysis. The synthesized pure products have been screened for in vitro antibiofilm inhibitory activity towards antibiotic-resistant pathogenic organisms. All the synthesized compounds showed biofilm inhibition. Promisingly, the moieties 3a, 3d and 3h showed higher antibiofilm activity at biofilm inhibitory concentration (BIC) (200 µg/mL) against bacterial pathogens. Among the three moieties, 3a showed high prospective against E. coli biofilm with minimal and maximal BIC percentage of 32% (10 µg/mL) and 89% (100 µg/mL) and chosen lowest BIC for further evaluation. Also, the 3a generate ROS two fold at 1 h treatment in E. coli biofilm. The 3a exhibited no toxic effect on cell viability upto 75 µg/mL in HEK293 cell lines. The results of the present study reveal that among (E)-2-benzylideno-(Z)-carbazolylideno cyanoacetamides, (E)-2-benzylideno-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-(Z)-α-carbamino-α-cyano-1-ylidene (3a) could be exploited as an excellent antibiofilm agent against carbapenem-resistant E. coli bacteria strains.


Assuntos
Acetamidas/farmacologia , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Carbazóis/farmacologia , Acetamidas/síntese química , Acetamidas/toxicidade , Antibacterianos/síntese química , Antibacterianos/toxicidade , Bacillus megaterium/efeitos dos fármacos , Bacillus subtilis/efeitos dos fármacos , Carbazóis/síntese química , Carbazóis/toxicidade , Bactérias Gram-Negativas/efeitos dos fármacos , Células HEK293 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
15.
Anticancer Agents Med Chem ; 19(2): 256-264, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30173652

RESUMO

BACKGROUND: Autotaxin-LPA signaling has been implicated in cancer progression, and targeted for the discovery of cancer therapeutic agents. OBJECTIVE: Potential ATX inhibitors were synthesized to develop novel leading compounds and effective anticancer agents. METHODS: The present work designs and synthesizes a series of 2,7-subsitituted carbazole derivatives with different terminal groups R [R = -Cl (I), -COOH (II), -B(OH)2 (III), or -PO(OH)2 (I-IV)]. The inhibition of these compounds on the enzymatic activity of ATX was measured using FS-3 and Bis-pNpp as substrates, and the cytotoxicity of these compounds was evaluated using SW620, SW480, PANC-1, and SKOV-3 human carcinoma cells. Furthermore, the binding of leading compound with ATX was analyzed by molecular docking. RESULTS: Compound III was shown to be a promising antitumor candidate by demonstrating both good inhibition of ATX enzymatic activity and high cytotoxicity against human cancer cell lines. Molecular docking study shows that compound III is located in a pocket, which mainly comprises amino acids 209 to 316 in domain 2 of ATX, and binds with these residues of ATX through van der Waals, conventional hydrogen bonds, and hydrophobic interactions. CONCLUSION: Compound III with the terminal group R = -B(OH)2 has the most potent inhibitory effect with the greatest cytotoxicity to cancer cells. Moreover, the docking model provides a structural basis for the future optimization of promising antitumor compounds.


Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
16.
ACS Chem Neurosci ; 10(1): 396-411, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30301349

RESUMO

We have developed a series of carbazole-derived compounds based on our hybrid D2/D3 agonist template to design multifunctional compounds for the symptomatic and disease-modifying treatment of Parkinson's disease (PD). The lead molecules (-)-11b (D-636), (-)-15a (D-653), and (-)-15c (D-656) exhibited high affinity for both D2 and D3 receptors and in GTPγS functional assay, the compounds showed potent agonist activity at both D2 and D3 receptors (EC50 (GTPγS); D2 = 48.7 nM, D3 = 0.96 nM for 11b, D2 = 0.87 nM, D3 = 0.23 nM for 15a and D2 = 2.29 nM, D3 = 0.22 nM for 15c). In an animal model of PD, the test compounds exhibited potent in vivo activity in reversing hypolocomotion in reserpinized rats with a long duration of action compared to the reference drug ropinirole. In a cellular antioxidant assay, compounds (-)-11b, (-)-15a, and (-)-15c exhibited potent activity in reducing oxidative stress induced by neurotoxin 6-hydroxydopamine (6-OHDA). Also, in a cell-based PD neuroprotection model, these lead compounds significantly increased cell survival from toxicity of 6-OHDA, thereby producing a neuroprotective effect. Additionally, compounds (-)-11b and (-)-15a inhibited aggregation and reduced toxicity of recombinant alpha synuclein protein in a cell based in vitro assay. These observations suggest that the lead carbazole-based dopamine agonists may be promising multifunctional molecules for a viable symptomatic and disease-modifying therapy of PD and should be further investigated.


Assuntos
Carbazóis/síntese química , Agonistas de Dopamina/síntese química , Desenho de Drogas , Doença de Parkinson/metabolismo , Animais , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/uso terapêutico , Feminino , Masculino , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Oxidopamina/toxicidade , Células PC12 , Doença de Parkinson/tratamento farmacológico , Ratos , Ratos Sprague-Dawley
17.
Eur J Med Chem ; 162: 203-211, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30447433

RESUMO

Several 6-substituted tetrahydrocarbazole derivatives were designed, synthesized and evaluated for the antibacterial activities against Staphylococcus aureus Newman strain. Subsequently, 2,4-diaminopyrimidine scaffold was merged with the tetrahydrocarbazole unit to generate a series of novel hybrid derivatives and the antibacterial activities were also investigated. Among these novel hybrids, compound 12c showed the most potent activity with a MIC of 0.39-0.78 µg/mL against S. aureus Newman and Escherichia coli AB1157 strain. In addition, compound 12c exhibited low MIC values against a panel of multidrug-resistant strains of S. aureus.


Assuntos
Antibacterianos/farmacologia , Carbazóis/farmacologia , Pirimidinas/química , Antibacterianos/síntese química , Antibacterianos/química , Carbazóis/síntese química , Carbazóis/química , Desenho de Drogas , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
18.
Bioorg Chem ; 83: 235-241, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30384179

RESUMO

In this work a total of 12 carbazoles and hydrazone-bridged thiazole-pyrrole derivatives have been identified as new competitive inhibitors of tyrosinase. Carbazole derivative with 2-benzoimidazole substitution showed most potent inhibition in the series. Other carbazole derivatives containing benzothiazole and benzoxazole substitutions showed comparable levels of tyrosinase inhibition. The hydrazone derivatives also showed potent tyrosinase inhibitory activity with comparable Ki values except one with fluoride at its terminal position. Kinetic studies showed competitive inhibition of tyrosinase by all compounds that increased the substrate Km without changing the Vmax value. Moreover, experimental evidence suggests that the target compounds specifically bind to the binuclear copper center of the tyrosinase active site in an apparent mono-dentate fashion. Carbazoles and hydrazones are new and emerging classes of compounds as tyrosinase inhibitors that may provide new structural avenues to discovery of drugs targeting the treatment of hyperpigmentation and related dermatological disorders.


Assuntos
Carbazóis/metabolismo , Cobre/metabolismo , Inibidores Enzimáticos/metabolismo , Hidrazonas/metabolismo , Monofenol Mono-Oxigenase/química , Agaricales/enzimologia , Carbazóis/síntese química , Carbazóis/química , Domínio Catalítico , Cobre/química , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Hidrazonas/síntese química , Hidrazonas/química , Cinética
19.
Bioorg Chem ; 83: 336-347, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30399465

RESUMO

Due to recently discovered non-classical acetylcholinesterase (AChE) function, dual binding-site AChE inhibitors have acquired a paramount attention of drug designing researchers. The unique structural arrangements of AChE peripheral anionic site (PAS) and catalytic site (CAS) joined by a narrow gorge, prompted us to design the inhibitors that can interact with dual binding sites of AChE. Eighteen homo- and heterodimers of desloratadine and carbazole (already available tricyclic building blocks) were synthesized and tested for their inhibition potential against electric eel acetylcholinesterase (eeAChE) and equine serum butyrylcholinesterase (eqBChE). We identified a six-carbon tether heterodimer of desloratadine and indanedione based tricyclic dihydropyrimidine (4c) as potent and selective inhibitor of eeAChE with IC50 value of 0.09 ±â€¯0.003 µM and 1.04 ±â€¯0.08 µM (for eqBChE) with selectivity index of 11.1. Binding pose analysis of potent inhibitors suggest that tricyclic ring is well accommodated into the AChE active site through hydrophobic interactions with Trp84 and Trp279. The indanone ring of most active heterodimer 4b is stabilized into the bottom of the gorge and forms hydrogen bonding interactions with the important catalytic triad residue Ser200.


Assuntos
Carbazóis/química , Inibidores da Colinesterase/química , Loratadina/análogos & derivados , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Carbazóis/síntese química , Carbazóis/metabolismo , Domínio Catalítico , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Desenho de Drogas , Electrophorus , Ligações de Hidrogênio , Loratadina/síntese química , Loratadina/química , Loratadina/metabolismo , Ligação Proteica , Eletricidade Estática , Torpedo
20.
Molecules ; 23(12)2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30513661

RESUMO

The carbazole ligand 3 was synthesized, characterized and its binding interactions with human telomeric (22HT) G-quadruplex DNA in Na⁺ and K⁺-containing buffer were investigated by ultraviolet-visible (UV-Vis) spectrophotometry, fluorescence, circular dichroism (CD) spectroscopy, and DNA melting. The results showed that the studied carbazole ligand interacted and stabilized the intramolecular G-quadruplexes formed by the telomeric sequence in the presence of sodium and potassium ions. In the UV-Vis titration experiments a two-step complex formation between ligand and G-quadruplex was observed. Very low fluorescence intensity of the carbazole derivative in Tris HCl buffer in the presence of the NaCl or KCl increased significantly after addition of the 22HT G4 DNA. Binding stoichiometry of the ligand/G-quadruplex was investigated with absorbance-based Job plots. Carbazole ligand binds 22HT with about 2:1 stoichiometry in the presence of sodium and potassium ions. The binding mode appeared to be end-stacking with comparable binding constants of ~105 M-1 as determined from UV-Vis and fluorescence titrations data. The carbazole ligand is able to induce formation of G4 structure of 22HT in the absence of salt, which was proved by CD spectroscopy and melting studies. The derivative of carbazole 3 shows significantly higher cytotoxicity against breast cancer cells then for non-tumorigenic breast epithelial cells. The cytotoxic activity of ligand seems to be not associated with telomerase inhibition.


Assuntos
Carbazóis/química , Quadruplex G , Telômero/metabolismo , Carbazóis/síntese química , Carbazóis/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dicroísmo Circular , Humanos , Cinética , Ligantes , Desnaturação de Ácido Nucleico , Solventes , Espectrometria de Fluorescência , Telomerase/metabolismo
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