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1.
J Enzyme Inhib Med Chem ; 34(1): 1298-1306, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31307242

RESUMO

10H-1,9-diazaphenothiazine was obtained in the sulphurisation reaction of diphenylamine with elemental sulphur and transformed into new 10-substituted derivatives, containing alkyl and dialkylaminoalkyl groups at the thiazine nitrogen atom. The 1,9-diazaphenothiazine ring system was identified with advanced 1H and 13C NMR techniques (COSY, NOESY, HSQC and HMBC) and confirmed by X-ray diffraction analysis of the methyl derivative. The compounds exhibited significant anticancer activities against the human glioblastoma SNB-19, melanoma C-32 and breast cancer MDA-MB-231 cell lines. The most active 1,9-diazaphenothiazines were the derivatives with the propynyl and N, N-diethylaminoethyl groups being more potent than cisplatin. For those two compounds, the expression of H3, TP53, CDKN1A, BCL-2 and BAX genes was detected by the RT-QPCR method. The proteome profiling study showed the most probable compound action on SNB-19 cells through the intrinsic mitochondrial pathway of apoptosis. The 1,9-diazaphenotiazine system seems to be more potent than known isomeric ones (1,6-diaza-, 1,8-diaza-, 2,7-diaza- and 3,6-diazaphenothiazine).


Assuntos
Antineoplásicos/farmacologia , Fenotiazinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
2.
Artigo em Inglês | MEDLINE | ID: mdl-30857466

RESUMO

The current research article involves one pot synthesis of novel substituted 1-nitro-10H-phenothiazines via Smiles rearrangement. These substituted phenothiazines undergo oxidation to yield 10H-phenothiazine-5,5-dioxides (sulfones) while on treatment with ß-D-ribofuranose-1-acetate-2,3,5-tribenzoate yield ribofuranosides. These compounds were screened for their antimicrobial vitalities (in vitro) against selected strains of bacteria and fungi. The characterization of synthesized compounds was done by elemental and spectral studies.


Assuntos
Anti-Infecciosos/síntese química , Nitrocompostos/síntese química , Nucleosídeos/química , Fenotiazinas/síntese química , Sulfonas/química , Anti-Infecciosos/farmacologia , Proteínas de Bactérias/química , Benzoatos/química , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Nitrocompostos/farmacologia , Oxirredução , Fenotiazinas/farmacologia , Relação Estrutura-Atividade , Sulfonas/farmacologia
3.
Molecules ; 24(2)2019 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-30642021

RESUMO

New 10-substituted derivatives of 3,6-diazaphenothiazine, containing the triple bond linker terminated with tertiary cyclic and acyclic amine groups, were synthesized and screened for their anticancer action. The compounds exhibited varied anticancer activities against human glioblastoma SNB-19, melanoma C-32, and breast cancer MDA-MB231 cell lines, depending on the nature of the substituents. The most active 3,6-diazaphenothiazine, 4, was the derivative with the N,N-diethylamino-2-butynyl substituent against glioblastoma SNB-19, and was ten times more potent than cisplatin. For this compound, the expression of H3, TP53, CDKN1A, BCL-2, and BAX genes was detected by the RT-qPCR method. The gene expression ratio BAX/BCL-2 indicated the induction of mitochondrial apoptosis in cancer cell lines. The transformation of the propynyl substituent into amino-2-butynyl can be a method applicable to the search for more anticancer-active azaphenothiazines.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Fenotiazinas/síntese química , Fenotiazinas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Fenotiazinas/química
4.
Analyst ; 144(5): 1696-1703, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30657480

RESUMO

In this paper, we introduced a new strategy for converting aggregation-induced emission (AIE) to fluorescence emission in solution into the rational design of new fluorescent probes. Two fluorescent probes based on this strategy, namely, PDAM-Lyso and PDAM-Me, have been synthesized and tested both in vitro and in vivo. The fluorophores of the two probes are both phenothiazine molecules, which link to the diaminomaleonitrile (DAMN) moiety through imine bonds. In the presence of imine bonds, the probes emit red fluorescence in an aqueous solution caused by the AIE effect. As the imine bonds are selectively cut-off by HClO, the DAMN moiety gets removed, inducing blue fluorescence of the reaction product. In this way, the selectivity of the DAMN-based probes toward HClO against metal ions and other reactive oxygen species (ROS) was successfully improved. The imaging of endogenous and exogenous HClO with these two probes reveals that lysosome-targeting probes are of great advantage in the detection of natively generated HClO. Furthermore, the imaging of endogenous HClO in zebrafish suggests that PDAM-Lyso is capable of monitoring the generation of HClO in vivo, illustrating that this strategy is of great significance in designing new probes.


Assuntos
Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Nitrilos/química , Fenotiazinas/química , Animais , Fenômenos Químicos , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Ácido Hipocloroso/química , Limite de Detecção , Lisossomos/metabolismo , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Nitrilos/síntese química , Nitrilos/toxicidade , Fenotiazinas/síntese química , Fenotiazinas/toxicidade , Células RAW 264.7 , Peixe-Zebra
5.
Chem Asian J ; 13(18): 2611-2618, 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-29963750

RESUMO

The development of effective bioanalytical methods for rapid, sensitive and specific detection of HOCl in vitro and in vivo plays a key role for better understanding the roles of this molecule in normal and diseased conditions, but remains challenging due to the highly reactive nature of HOCl and the complicated biological conditions. In this work, a new fluorescence probe, PQI, was developed for monitoring of the HOCl level in biological samples. PQI was easily synthesized by a one-step condensation reaction. Upon addition of HOCl, significant changes in the absorption spectra and the color of the solution were noticed, facilitating the "naked eye" detection of HOCl in PBS buffer. The fluorescence of PQI was found to be significantly increased within a few seconds, leading to "OFF-ON" fluorescence response towards HOCl. The sensing mechanism, oxidation of thioether by HOCl, was confirmed by HRMS titration analysis. PQI features a large Stokes shift, high sensitivity and selectivity, and rapid fluorescence response towards HOCl. Quantitative detection of HOCl in single live cells was demonstrated through fluorescence imaging and flow cytometry analysis. PQI was then successfully used in visualisation of HOCl in live zebrafish and nude mice.


Assuntos
Corantes Fluorescentes/farmacologia , Ácido Hipocloroso/análise , Fenotiazinas/farmacologia , Compostos de Quinolínio/farmacologia , Animais , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/efeitos da radiação , Humanos , Concentração de Íons de Hidrogênio , Ácido Hipocloroso/química , Luz , Limite de Detecção , Células MCF-7 , Camundongos Nus , Imagem Óptica/métodos , Oxirredução , Fenotiazinas/síntese química , Fenotiazinas/química , Fenotiazinas/efeitos da radiação , Compostos de Quinolínio/síntese química , Compostos de Quinolínio/química , Compostos de Quinolínio/efeitos da radiação , Peixe-Zebra
6.
Molecules ; 23(6)2018 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-29843370

RESUMO

We designed a series of novel phenothiazine-1,2,3-triazole hybrids by the molecular hybridization strategy and evaluated their antiproliferative activity against three cancer cell lines (MDA-MB-231, MDA-MB-468 and MCF-7). For the structure-activity relationships, the importance of 1,2,3-triazole and substituents on phenyl ring was explored. Among these phenothiazine-1,2,3-triazole hybrids, compound 9f showed the most potent inhibitory effect against MCF-7 cells, with an IC50 value of 0.8 µM. Importantly, compound 9f could induce apoptosis against MCF-7 cells by regulating apoptosis-related proteins (Bcl-2, Bax, Bad, Parp, and DR5). These potent phenothiazine-1,2,3-triazole hybrids as novel apoptosis inducers might be used as antitumor agents in the future.


Assuntos
Antineoplásicos/síntese química , Proteínas Reguladoras de Apoptose/genética , Neoplasias da Mama/genética , Fenotiazinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Estrutura Molecular , Fenotiazinas/química , Fenotiazinas/farmacologia , Relação Estrutura-Atividade
7.
Molecules ; 23(4)2018 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-29561800

RESUMO

Two new hole transporting materials, 2,7-bis(9,9-diphenylacridin-10(9H)-yl)-9,9' spirobi[fluorene] (SP1) and 2,7-di(10H-phenothiazin-10-yl)-9,9'-spirobi[fluorene] (SP2), were designed and synthesized by using the Buchwald-Hartwig coupling reaction with a high yield percentage of over 84%. Both of the materials exhibited high glass transition temperatures of over 150 °C. In order to understand the device performances, we have fabricated green phosphorescent organic light-emitting diodes (PhOLEDs) with SP1 and SP2 as hole transporting materials. Both of the materials revealed improved device properties, in particular, the SP2-based device showed excellent power (34.47 lm/W) and current (38.41 cd/A) efficiencies when compare with the 4,4'-bis(N-phenyl-1-naphthylamino)biphenyl (NPB)-based reference device (30.33 lm/W and 32.83 cd/A). The external quantum efficiency (EQE) of SP2 was 13.43%, which was higher than SP1 (13.27%) and the reference material (11.45%) with a similar device structure. The SP2 hole transporting material provides an effective charge transporting path from anode to emission layer, which is explained by the device efficiencies.


Assuntos
Acridinas/química , Eletrônica , Luminescência , Fenotiazinas/química , Compostos de Espiro/química , Acridinas/síntese química , Varredura Diferencial de Calorimetria , Simulação por Computador , Eletroquímica , Microscopia de Varredura por Sonda , Fenotiazinas/síntese química , Espectrofotometria Ultravioleta , Temperatura Ambiente
8.
Sci Rep ; 8(1): 1650, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29374224

RESUMO

Developing peripherally active cannabinoid 1 (CB1) receptor antagonists is a novel therapeutic approach for the management of obesity. An unusual phenothiazine scaffold containing CB1R antagonizing hit was identified by adopting virtual screening work flow. The hit so identified was further modified by introducing polar functional groups into it to enhance the polar surface area and decrease the hydrophobicity of the resulting molecules. CB1 receptor antagonistic activity for the designed compounds was computed by the previously established pharmacophore and three dimensional quantitative structure-activity relationship models. Docking studies of these designed compounds confirmed the existence of favourable interactions within the active site of the CB1 receptor. The designed compounds were synthesized and evaluated for their CB1 receptor antagonistic activity. Parallel artificial membrane permeability assay was performed to evaluate their potential to permeate into the central nervous system wherein it was observed that the compounds did not possess the propensity to cross the blood brain barrier and would be devoid of central nervous system side effects. In pharmacological evaluation, the synthesized compounds (23, 25, 27 and 34) showed significant decrease in food intake suggesting their potential application in the management of obesity through CB1 receptor antagonist activity.


Assuntos
Fármacos Antiobesidade/farmacologia , Fenotiazinas/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/síntese química , Comportamento Alimentar/efeitos dos fármacos , Masculino , Simulação de Acoplamento Molecular , Fenotiazinas/administração & dosagem , Fenotiazinas/síntese química , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Ratos Wistar
9.
Biosens Bioelectron ; 99: 296-302, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-28780345

RESUMO

Donor-Acceptor (D-A) structure like host-guest pair serves as an organic charge-transfer (C-T) material with pregnant electrochemical and photochemical properties. Phenothiazine, a conjugated nitrogen-sulfur heterocyclic compound with broad pharmaceutical profile, is a strong electron donating system and applied in the synthesis of various classic antipsychotic drugs. In this proposal, a novel D-A molecule, 2,3-bis(4-(10H-phenothiazin-10-yl)phenyl)fumaronitrile (PTBFN), containig a diphenylfumaronitrile as the electrophilic central core and two phenothiazines as the peripheral electron donor functional groups is first designed and synthesized. Subsequently, the C-T layer based on the PTBFN polymer, poly(PTBFN), is obtained via a straightforward electrochemical method and used as an efficient electrocatalyst for dopamine (DA) detection. The logarithm of oxidation peak currents present an outstanding linear response to that of the DA concentration varying from 0.005 to 350µM with a detection limit down to 0.70nM, wherein the interferences of uric acid (UA) and ascorbic acid (AA) could be eliminated effectively. Moreover, the biosensor displays decent stability, excellent selectivity for different interfering compounds and applicability in real samples analysis. The favorable sensing performance suggests that the nontrivial D-A architecture is one of the promising bioaffinity catalysts for electrocatalysis and expected to provide wider application potential for biosensing construction and medical diagnostics.


Assuntos
Técnicas Biossensoriais , Dopamina/isolamento & purificação , Neurotransmissores/isolamento & purificação , Fenotiazinas/química , Ácido Ascórbico/química , Catálise , Dopamina/química , Técnicas Eletroquímicas , Humanos , Limite de Detecção , Neurotransmissores/química , Nitrogênio/química , Oxirredução , Fenotiazinas/síntese química , Polímeros/química , Ácido Úrico/química
10.
Bioorg Med Chem ; 25(20): 5537-5547, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28927904

RESUMO

In an effort to identify methylene blue analogues having improved antioxidant activity, a series of new methylene violet analogues have been designed and synthesized. The analogues were prepared following a synthetic route that is more efficient than the previously reported methods, both in terms of yield and purity of the final products. The route involves the Smiles rearrangement as one of the crucial steps. Smiles rearrangement of suitably substituted diphenyl sulfide intermediates afforded the corresponding phenothiazine analogues in high yields, which were subsequently converted to the final products. The methylene violet analogues were evaluated for their ability to preserve mitochondrial function in Friedreich's ataxia (FRDA) lymphocytes. The analogues were shown to be efficient ROS scavengers, and able to protect cultured FRDA lymphocytes from oxidative stress resulting from inhibition of complex I. The analogues also preserved mitochondrial membrane potential and augmented ATP production. The analogues were found to be better antioxidants than the parent compounds methylene blue and methylene violet.


Assuntos
Mitocôndrias/efeitos dos fármacos , Fenotiazinas/farmacologia , Trifosfato de Adenosina/biossíntese , Células Cultivadas , Humanos , Interações Hidrofóbicas e Hidrofílicas , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fenotiazinas/síntese química , Fenotiazinas/química , Espécies Reativas de Oxigênio/metabolismo
11.
Mol Divers ; 21(4): 933-942, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28785928

RESUMO

Novel phenothiazine-dithiocarbamate analogues were designed by molecular hybridization strategy and synthesized and evaluated for their anticancer activity in vitro against three selected cancer cell lines (EC-109, MGC-803, and PC-3). The preliminary structure-activity relationship (SAR) for this phenothiazine-dithiocarbamate hybrids is explored. Among all analogues, 2-oxo-2-(10H-phenothiazin-10-yl)ethyl 4-ethylpiperazine-1-carbodithioate (8a) showed the most potent inhibitory activity with an [Formula: see text] value of [Formula: see text] against PC-3 cells. In addition, compound 8a could arrest the cell cycle at the G1 phase and regulate the expression of G1 checkpoint-related proteins, suggesting that phenothiazine-dithiocarbamate hybrids might be useful as cell cycle blockers.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Desenho de Drogas , Fenotiazinas/síntese química , Fenotiazinas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Fenotiazinas/química , Relação Estrutura-Atividade
12.
Int J Mol Sci ; 18(7)2017 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-28672876

RESUMO

The molecular frame of the reported series of new polyheterocyclic compounds was intended to combine the potent phenothiazine and benzothiazole pharmacophoric units. The synthetic strategy applied was based on oxidative cyclization of N-(phenothiazin-3-yl)-thioamides and it was validated by the preparation of new 2-alkyl- and 2-aryl-thiazolo[5,4-b]phenothiazine derivatives. Optical properties of the series were experimentally emphasized by UV-Vis absorption/emission spectroscopy and structural features were theoretically modelled using density functional theory (DFT). In vitro activity as antileukemic agents of thiazolo[5,4-b]phenothiazine and N-(phenothiazine-3-yl)-thioamides were comparatively evaluated using cultivated HL-60 human promyelocytic and THP-1 human monocytic leukaemia cell lines. Some representatives proved selectivity against tumour cell lines, cytotoxicity, apoptosis induction, and cellular metabolism impairment capacity. 2-Naphthyl-thiazolo[5,4-b]phenothiazine was identified as the most effective of the series by displaying against THP-1 cell lines a cytotoxicity close to cytarabine antineoplastic agent.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Fenotiazinas/química , Fenotiazinas/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Fenotiazinas/síntese química , Análise Espectral , Relação Estrutura-Atividade
13.
Eur J Med Chem ; 138: 774-806, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28734245

RESUMO

For the last two decades, classical phenothiazines have attracted attention of researchers, as the hitherto investigations have revealed many significant biological activities within this class of compounds, other than originally discovered neuroleptic ones. Important, new pharmaceutical results on phenothiazines, as 10-substituted dibenzothiazines, were recently highlighted in several reviews. Azaphenothiazines are structurally modified phenothiazines by substitution of one or both benzene rings in the phenothiazine ring system with the azine rings, such as: pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, quinoline, quinoxaline, benzoxazine and benzothiazine. They form over 50 different heterocyclic systems, of tri-, tetra-, penta- and hexacyclic structures, and contain from one to even four azine nitrogen atoms. This review summarizes the methodical knowledge on azaphenothiazines, referring to their nomenclature, synthesis, structure analysis and above all significant varied biological activities, examined in vitro and in vivo. It describes, in addition, current trends in the synthesis of azaphenothiazines. The influence of the azaphenothiazine ring system, the nature of the substituents, predominantly at the thiazine nitrogen atom, as well as at the azine nitrogen atom and carbon atom, on the biological activities, were also discussed.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Antipsicóticos/farmacologia , Neoplasias/tratamento farmacológico , Fenotiazinas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Antipsicóticos/síntese química , Antipsicóticos/química , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Humanos , Leishmania/efeitos dos fármacos , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/química
14.
Artigo em Russo | MEDLINE | ID: mdl-28638038

RESUMO

Based on the analysis of the original literature, the author for the first time systemizes the data on the story of atypical antipsychotic drugs. The history of introduction of the first atypical neuroleptics - clozapine and sulpiride, which launched the dichotomic development of psychopharmacology of atypical antipsychotics, is described. Historical facts on the introduction into practice of different sulpiride- and clozapine-like neuroleptics as well as the relationship of their history with the elaboration of dopamine and serotonin hypotheses of mechanisms of action of antipsychotics are presented. The author analyzes the efficacy and tolerability of treatment with different atypical neuroleptics. An importance of evidence-based medicine principles in the history of atypical antipsychotics is described. A significance of the history of some atypical and typical (pericyazine) neuroleptics in the evolution of conceptions on the validity of evidence-based medicine in psychiatry is evaluated. Main stages in the history of typical and atypical antipsychotics are determined.


Assuntos
Antipsicóticos/história , Clozapina/história , Sulpirida/história , Antipsicóticos/síntese química , Antipsicóticos/farmacologia , Clozapina/síntese química , Clozapina/farmacologia , História do Século XX , Humanos , Fenotiazinas/síntese química , Fenotiazinas/história , Sulpirida/síntese química , Sulpirida/farmacologia
15.
J Mol Recognit ; 30(7)2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28101950

RESUMO

In this paper, the comparative binding behavior of antimalarial drug azure A, azure B and azure C with bovine serum albumin (BSA) has been studied. The interaction has been confirmed by multispectroscopic (UV, fluorescence, Fourier transform infrared (FT-IR), and circular dichroism) and molecular docking techniques. The experimental results show that azure B has the highest BSA binding affinity followed by azure A and azure C. The experimental evidence of binding showed a static quenching mechanism in the interaction azures with BSA. The isothermal titration calorimetry result reveals that the binding was exothermic with positive entropy contribution in each case. The thermodynamic parameters ΔH, ΔG, and ΔS at 25°C were calculated, which indicates that the weak van der Waals forces and hydrogen bonding rather than the hydrophobic effect played an important role in the interaction. According to the theory of Förster nonradiative energy transfer, the distance (r) between the donor (BSA) and acceptor azures found to be <7 nm in all the case. The circular dichroism and FT-IR studies show that the content of α-helix structure has increased for the azures-BSA system. Overall, experimental studies characterize the interaction dynamics and energetics of the binding of three toxic analogs towards the physiologically relevant serum albumins. We hope, the outcome of this work will be most helpful for synthesizing a new type of phenothiazinium derivatives of the better therapeutic application.


Assuntos
Fenotiazinas/química , Ligação Proteica , Soroalbumina Bovina/química , Termodinâmica , Animais , Calorimetria , Bovinos , Dicroísmo Circular , Simulação por Computador , Ligações de Hidrogênio , Simulação de Acoplamento Molecular , Fenotiazinas/síntese química , Fenotiazinas/uso terapêutico , Espectroscopia de Infravermelho com Transformada de Fourier
16.
ACS Chem Neurosci ; 8(4): 798-806, 2017 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-28097868

RESUMO

Early detection of Alzheimer's disease (AD) is imperative in enabling the understanding and clinical treatment of this disorder, as well as in preventing its progression. Imaging agents specifically targeting Aß plaques in the brain and the retina may lead to the early diagnosis of AD. Among them, near-infrared fluorescent (NIRF) imaging has emerged as an attractive tool to noninvasively identify and monitor diseases during the preclinical and early stages. In the present study, we report the design, synthesis, and evaluation of a series of new near-infrared fluorescent probes. Most of these probes displayed maximum emission in PBS (>650 nm), which falls in the good range for NIRF probes. Among them, 4a1 showed the highest affinity toward Aß aggregates (Kd = 7.5 nM) and an excellent targeting ability for Aß plaques in slices of brain and retina tissue from double transgenic mice. These compounds are also found to effectively prevent Aß fibril formation and disaggregate preformed Aß fibrils, showing a promising potential as theranostic agents for the diagnosis and therapy of AD.


Assuntos
Doença de Alzheimer/diagnóstico , Diagnóstico Precoce , Neuroimagem/métodos , Imagem Óptica/métodos , Fenotiazinas/farmacologia , Animais , Modelos Animais de Doenças , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Camundongos , Camundongos Transgênicos , Fenotiazinas/síntese química , Fenotiazinas/química , Placa Amiloide/diagnóstico , Espectroscopia de Luz Próxima ao Infravermelho , Nanomedicina Teranóstica/métodos
17.
Org Biomol Chem ; 14(48): 11488-11501, 2016 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-27886311

RESUMO

Efficient syntheses of cell-penetrating peptide-porphyrin conjugates are described using a variety of bioconjugation chemistries. This provides a flexible means to convert essentially hydrophobic tetrapyrolle photosensitisers into amphiphilic derivatives which are well-suited for use in light-triggered drug delivery by photochemical internalisation (PCI) and targeted photodynamic therapy (PDT).


Assuntos
Peptídeos Catiônicos Antimicrobianos/síntese química , Sistemas de Liberação de Medicamentos , Luz , Fenotiazinas/síntese química , Fotoquimioterapia , Porfirinas/síntese química , Peptídeos Catiônicos Antimicrobianos/química , Estrutura Molecular , Fenotiazinas/química , Porfirinas/química
18.
Bioorg Med Chem ; 24(22): 6021-6030, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27707624

RESUMO

The phenothiazine group has been identified as a suitable A ring in the structure of tubulin polymerization inhibitors. In our search to identify more potent inhibitors, a study of different isosteric tricyclic groups as new potential A rings was first realized and permitted to identify 1-azaphenothiazine and iminodibenzyl as favorable modulations providing compounds with improved activity against tubulin. An investigation of the methylene group as the connector between the A and B rings revealed that the "CH2" bridge was tolerated, improving the biological potency when the A unit was of phenothiazine, 1-azaphenothiazine or iminodibenzyl type. Molecules 6-8 and 12 showed increased biological activity in comparison to parent phenstatin 2 on COLO 205 colon cancer cell line. The most antineoplastic agent in the current study was phenothiazine 5 displaying a GI50 of 25nM against the melanoma MDA-MB-435 cell line.


Assuntos
Antineoplásicos/farmacologia , Fenotiazinas/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/química , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade
19.
J Enzyme Inhib Med Chem ; 31(6): 1132-8, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27677322

RESUMO

New derivatives of two isomeric types of azaphenothiazines, 1,8- and 2,7-diazaphenothiazine, containing the triple bond substituents and additionally tertiary cyclic and acyclic amine groups, were synthesized and tested for their anticancer activity. The compounds exhibited differential inhibitory activities. Better results were obtained when the acetylenic group was transformed via the Mannich reaction to the dialkylaminobutynyl groups. The most active was 2,7-diazaphenothiazine with the N-methylpiperazine-2-butynyl substituent against the human ductal breast epithelial tumor cell line T47D, more potent than cisplatin. The 2,7-diazaphenothiazine system turned out to be more active than isomeric 1,8-diaza one. For the most active compound, the expression of TP53, CDKN1A, BCL-2 and BAX genes was detected by the RT-QPCR method. The gene expression ratio BACL-2/BAX suggests the mitochondrial apoptosis in T47D cells. The synthesis makes possible to obtain many new bioactive phenothiazines with the dialkylaminoalkynyl substituents inserting various tertiary cyclic and acyclic amine moieties to the substituents.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Fenotiazinas/síntese química , Fenotiazinas/farmacologia , Linhagem Celular Tumoral , Humanos , Fenotiazinas/química , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas de Bombardeamento Rápido de Átomos
20.
Mater Sci Eng C Mater Biol Appl ; 66: 215-220, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27207057

RESUMO

In this work, we reported a rather facile method for fabrication of ultrabright, well dispersible and biocompatible fluorescent organic nanoparticles (FONs) with aggregation-induced emission (AIE) properties through combination of esterification and ring-opening reaction. The hydroxyl groups of Pluronic F127 was first reacted with the chloride of trimellitic anhydride chloride (TMAC), and its anhydride groups were further reacted with the amino groups of amino-terminated AIE dye (PhNH2) through ring-opening reaction. The optical properties, biocompatibility as well as cell uptake behavior of these obtained AIE-active nanoparticles (F127-TMAC-PhNH2 FONs) were examined by a series of characterization techniques and assays. We demonstrated that uniform organic nanoparticles with high water dispersibility, strong luminescence and desirable biocompatibility can be facilely obtained, which are promising for biological imaging applications. More importantly, a number of carboxyl groups were introduced into these AIE-active nanoparticles, which can be further utilized for further conjugation reaction and carrying anticancer drugs such as cisplatin. Therefore, the strategy of described in this work should be a simple and useful route for fabrication of multifunctional AIE-active luminescent nanotheranostic systems.


Assuntos
Materiais Biocompatíveis/síntese química , Polímeros/química , Células A549 , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Corantes Fluorescentes/química , Humanos , Espectroscopia de Ressonância Magnética , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Fenotiazinas/síntese química , Fenotiazinas/química , Poloxâmero/química , Polímeros/síntese química
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