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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.
Bioorg Chem ; 87: 810-820, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981160

RESUMO

We present efficient synthesis of isomeric types of angularly fused diquinothiazines in the reactions of 2,2'-dichloro-3,3'-diquinolinyl disulfide and diquinodithiin with 3-, 5-, 6- and 8-aminoquinolines. The pentacyclic diquinothiazine ring systems were identified as diquino[3,2-b;3',4'-e][1,4]thiazine, diquino[3,2-b;5',6'-e][1,4]thiazine, diquino[3,2-b;6',5'-e][1,4]thiazine and diquino[3,2-b;8',7'-e][1,4]thiazine with advanced two-dimensional 1H and 13C NMR techniques (COSY, ROESY, HSQC and HMBC) of N-methyl derivatives. The identification of pentacyclic ring system was confirmed by X-ray diffraction analysis of selected N-alkyl derivatives. The X-ray analysis revealed different spatial structures of the ring system (planar and folded). NH-diquinothiazines were further transformed into N-alkyl and N-dialkylaminoalkyl derivatives. Most of diquinothiazines exhibited significant cancer cell growth inhibition against the human glioblastoma SNB-19, colorectal carcinoma Caco-2, breast cancer MDA-MB-231 and lung cancer A549 cell lines with the IC50 values < 3 µM. This anti-proliferative activity was found to be more than for cisplatin. The most promising compound, 7-dimethylaminopropyldiquino[3,2-b;6',5'-e]thiazine, was used for gene expression analysis by reverse transcription-quantitative real-time PCR (RT-QPCR) method. The expression of H3, TP53, CDKN1A, BCL-2 and BAX genes revealed that this compound inhibited the proliferation in all cells (H3) and activated mitochondrial events of apoptosis (BAX/BCL-2) in two cancer cell lines (SNB-19 and Caco-2).

3.
Immunol Lett ; 208: 1-7, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30825456

RESUMO

Azaphenothiazines are predominantly immunosuppressive compounds. We evaluated the efficacy of an azaphenothiazine derivative, 6-chloroethylureidoethyldiquino[3,2-b;2',3'-e][1,4]thiazine (DQT) in prolongation of survival of skin allografts between BALB/c and C57Bl/6 mice. The mice were treated intraperitoneally (i.p.) with 100 µg of DQT on alternate days, on days 1-13 of the experiment (7 doses). The effect of DQT on a two-way mixed lymphocyte reaction (MLR) in the human model, as well as its effect on production of TNF α and IL-10 in a whole blood cell culture, stimulated by lipopolysaccharide (LPS), were evaluated. In addition, DQT effects were investigated regarding the proportion of T cell subsets in human peripheral blood lymphocytes (PBMC) by flow cytometry. Lastly, the effect of DQT on expression of signaling molecules involved in pro apoptotic pathways was determined by RT PCR. The results showed that DQT significantly extended skin graft survival. The compound also strongly suppressed two-way MLR in the human model at a concentration range of 2.5-5.0 µM. In addition, DQT inhibited LPS-inducible TNF α, but not IL-10 production. The compound preferentially caused a loss of the CD3-CD8+CD11b + PBMC cell subset, and transformed CD3+CD8+high into CD3+CD8+low cells. Lastly, we demonstrated significant increases in expression of caspases (in particular caspase 8) and of p53 in a culture of Jurkat T cells. We conclude that the immunosuppressive actions of the compound in allograft rejection may be predominantly associated with induction of cell apoptosis and inhibition of TNF α production. The apoptosis could be predominantly selective for the CD3-CD8+CD11b + cell phenotype.

4.
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
5.
Molecules ; 23(10)2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30250011

RESUMO

An azaphenothiazine derivative, 6-chloroethylureidoethyldiquino[3,2-b;2',3'-e][1,4]thiazine (DQT), has recently been shown to exhibit immunosuppressive activities in mouse models. It also inhibited the expression of CXCL10 at the protein level, at non-toxic concentrations, in the culture of KERTr cells treated with double-stranded RNA, poly(I:C). In this report, we demonstrated that DQT inhibits the transcription of the CXCL10 gene. Although CXCL10 is an IFNγ-inducible protein, we found that the CXCL10 protein was induced without the detectable release of IFNγ or IκB degradation. Hence, we concluded that IFNγ or NFκB was not involved in the regulation of the CXCL10 gene in KERTr cells transfected with poly(I:C), nor in the inhibitory activity of DQT. On the other hand, we found that IFNß was induced under the same conditions and that its expression was inhibited by DQT. Kinetic analysis showed that an increase in IFNß concentrations occurred 4⁻8 h after poly(I:C) treatment, while the concentration of CXCL10 was undetectable at that time and started to increase later, when IFNß reached high levels. Therefore, DQT may be regarded as a new promising inhibitor of IFNß expression and IFNß-dependent downstream genes and proteins, e.g., CXCL10 chemokine, which is implicated in the pathogenesis of autoimmune diseases.

6.
Int Immunopharmacol ; 59: 276-286, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29674255

RESUMO

The therapeutic efficacy of topically applied azaphenothiazine derivatives: 9-chloro-6-acetylaminobutylquinobenzo[3,2-b][1,4]thiazine (compound 4) and 6-chloroethylureidoethyldiquino[3,2-b;2';3'-e][1,4]thiazine (compound 5) in the amelioration of inflammatory symptoms of imiquimod-induced psoriasis in mice was investigated. Clobederm®, containing clobetasol propioniate, served as a reference drug. The application of the compounds led to thinning of the epidermis and reduction of the cell layers. The suppressive actions of the compounds were even stronger with regard to pathological changes of the dermis. The compounds also exerted generalized, anti-inflammatory effects by decreasing the number of circulating leukocytes, lowering subiliac lymph node weight and partially normalizing an altered blood cell composition. The changes in the composition of main cell types in the epidermis and dermis were less affected by the compounds. In addition, both compounds inhibited to a similar degree production of tumor necrosis factor α (TNF α) in human whole blood cell culture. Whereas compound 5 strongly inhibited IL-8 and CXCL10 chemokines in human keratinocytes - KERTr cell line, transfected with poly(I:C), the suppressive action of compound 4 in this model was weak. In addition, compound 5, but not compound 4, exhibited at low doses proapoptotic properties with regard to colonic cell lines. In summary, we demonstrated the therapeutic potential of two selected azaphenotiazines in the amelioration of the skin pathology elicited in a mouse experimental model of psoriasis.


Assuntos
Anti-Inflamatórios/uso terapêutico , Fenotiazinas/uso terapêutico , Psoríase/tratamento farmacológico , Administração Tópica , Aminoquinolinas , Animais , Anti-Inflamatórios/farmacologia , Caspases/metabolismo , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células HCT116 , Humanos , Imiquimode , Células Jurkat , Contagem de Leucócitos , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Fenotiazinas/farmacologia , Psoríase/induzido quimicamente , Psoríase/imunologia , Psoríase/patologia , Pele/efeitos dos fármacos , Pele/patologia , Receptor fas/metabolismo
7.
J Chromatogr Sci ; 56(4): 376-381, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29425266

RESUMO

The lipophilicity of new two series of anticancer active 10-substituted 1,6- and 3,6-diazaphenothiazines has been investigated using reversed-phase thin-layer chromatography. Their lipophilicity (RM0 and log PTLC) was determined with mixtures of acetone and Tris buffer as mobile phases. The relative lipophilicity parameter RM0 and specific hydrophobic surface area b were significantly intercorrelated showing congeneric classes of diazaphenothiazines. The parameter RM0 was transformed into parameter log PTLC by use of the calibration curve. The parameter log PTLC was compared with computationally calculated lipophilic parameters log Pcalcd. The lipophilicity was discussed with the structure elements and was correlated with molecular descriptors, ADME properties and in vitro anticancer activities.


Assuntos
Antineoplásicos/análise , Antineoplásicos/química , Cromatografia de Fase Reversa/métodos , Cromatografia em Camada Delgada/métodos , Fenotiazinas/análise , Fenotiazinas/química , Interações Hidrofóbicas e Hidrofílicas
8.
Histol Histopathol ; 33(2): 223-236, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28748525

RESUMO

In this work we investigated the efficacy of two topically applied azaphenothiazine derivatives, 9-chloro-6-acetylaminobutylquinobenzo[3,2-b][1,4]thiazine (compound 4) and 6-chloroethylureidoethyldiquino[3,2-b;2';3'-e][1,4]thiazine (compound 5), in the amelioration of inflammatory symptoms of contact sensitivity (CS) to oxazolone in mice, in relation to the commercial ointment Protopic® (tacrolimus), the reference drug. The compounds were administered 24 h following elicitation of CS and, 24 h later, the parameters of inflammation, such as ear edema, blood composition, leukocyte level, numbers of cells in the draining lymph nodes, histological picture of the inflamed tissue, and the morphometric analysis, were analyzed. The study showed that the effectiveness of the studied azaphenothiazines applied as a 0.1% ointment was comparable to the reference drug regarding suppression of the inflammatory process, when all the investigated histological parameters are taken into account.


Assuntos
Adjuvantes Imunológicos/toxicidade , Dermatite de Contato/prevenção & controle , Pomadas/farmacologia , Oxazolona/toxicidade , Fenotiazinas/farmacologia , Administração Tópica , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C
9.
Drug Des Devel Ther ; 11: 3045-3063, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29123378

RESUMO

The asymptomatic properties and high treatment resistance of ovarian cancer result in poor treatment outcomes and high mortality rates. Although the fundamental chemotherapy provides promising anticancer activities, it is associated with severe side effects. The derivative of phenothiazine, namely, 10H-3,6-diazaphenothiazine (PTZ), was synthesized and reported with ideal anticancer effects in a previous paper. In this study, detailed anticancer properties of PTZ was examined on A2780 ovarian cancer cells by investigating the cytotoxicity profiles, mechanism of apoptosis, and cell invasion. Research outcomes revealed PTZ-induced dose-dependent inhibition on A2780 cancer cells (IC50 =0.62 µM), with significant less cytotoxicity toward HEK293 normal kidney cells and H9C2 normal heart cells. Generation of reactive oxygen species (ROS) and polarization of mitochondrial membrane potential (ΔΨm) suggests PTZ-induced cell death through oxidative damage. The RT2 Profiler PCR Array on apoptosis pathway demonstrated PTZ-induced apoptosis via intrinsic (mitochondria-dependent) and extrinsic (cell death receptor-dependent) pathway. Inhibition of NF-κB and subsequent inhibition of (BIRC6-XIAP) complex activities reduced the invasion rate of A2780 cancer cells penetrating through the Matrigel™ Invasion Chamber. Lastly, the cell cycle analysis hypothesizes that the compound is cytostatic and significantly arrests cell proliferation at G2/M phase. Hence, the exploration of the underlying anticancer mechanism of PTZ suggested its usage as promising chemotherapeutic agent.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Fenotiazinas/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/toxicidade , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HEK293 , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Concentração Inibidora 50 , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/metabolismo , Invasividade Neoplásica , Fenotiazinas/administração & dosagem , Fenotiazinas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
10.
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
11.
Med Chem Res ; 25(11): 2425-2433, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27818603

RESUMO

New phenothiazine derivatives as 10-substituted dipyridothiazines of the 1,6-diazaphenothiazine structure were obtained in the cyclization reaction of 3-amino-3'-nitro-2,2'-dipyridinyl sulfide and 3,3'-dinitro-2,2'-dipyridinyl disulfide, and in the reaction of 2-chloro-3-ntropyridine with sodium 3-amino-2-pyridinethiolate followed by various alkylation and arylation reactions. The reaction of the thiazine ring formation ran via the Smiles rearrangement of the S-N type. As the alkylation reactions could proceed at the thiazine, azine or both nitrogen atoms, the product structure elucidation was based on the 2D NMR (Rotating-frame Overhauser Effect Spectroscopy, Correlated Spectroscopy, Heteronuclear Single Quantum Coherence, and Heteronuclear Multiple Bond Correlation) spectra of the N-methylated product. Some 10-substituted 1,6-diazaphenothizines (5, 10, 12, 13) were at least anticancer active against melanoma C-32 and breast cancer MCF-7 cell lines as a reference drug - cisplatin. The monoazaphenothiazine drug, prothipendyl, turned out to be less active than least 6 derivatives of the 1,6-diazaphenothiazine structure.

12.
Int Immunopharmacol ; 40: 265-268, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27632704

RESUMO

Several, previously selected azaphenothiazines, as strongly antiproliferative agents in in vitro models, were subjected to evaluation for their potential immunosuppressive effects in the model of delayed type hypersensitivity (DTH) to ovalbumin (OVA) in BALB/c mice and in foot pad inflammation induced by carrageenan in CBA mice. In the DTH model the compounds were given to mice intraperitoneally (i.p.) in 50µg or 250µg doses, 1h before the elicitation of the response. In the carrageenan-induced foot pad inflammation the compounds were given i.p. in 50µg or 250µg doses, 24h and 2h before administration of carrageenan. Among the compounds, the significantly suppressive activities in both models were exhibited only by compound 5 (6-chloroethylureidoethyldiquino[3,2-b;2',3'-e][1,4]thiazine) and compound 4 (6-acetylaminobutyl-9-chloroquino[3,2-b]benzo[1,4]thiazine). Structure-activity relationship, plausible mechanism of action and potential application in therapy of the compounds are discussed.


Assuntos
Anti-Inflamatórios/uso terapêutico , Hipersensibilidade Tardia/tratamento farmacológico , Fenotiazinas/uso terapêutico , Alérgenos , Animais , Carragenina , Feminino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Ovalbumina
13.
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
14.
J Enzyme Inhib Med Chem ; 31(sup3): 83-88, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27404955

RESUMO

Azaphenothiazines containing the quinoline ring, 8-10-substituted 6H-quinobenzothiazines and 6H-diquinothiazine were transformed into new 6-propargyl and 6-dialkylaminobutynyl derivatives containing the triple bond. Most of them displayed strong antiproliferative actions against human peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin A (PHA), strongly suppressed lipopolysaccharide (LPS)-induced TNF-α production by whole blood human cell cultures, and exhibited low cytotoxicity. Three propargylquinobenzothiazines with the bromine, trifluoromethyl, and methylthio groups at position 9 and propargyldiquinothiazine exhibited comparable actions to cisplatin against the L-1210 and SW-948 tumor lines. 6-Propargyl-9-trifluoromethylquinobenzothiazine was shown to block caspase 3 expression and inhibit expression of caspase 8 and 9 in Jurkat cells indicating its possible mechanism of action. These derivatives could be promising, potential therapeutics for treatment of neoplastic diseases and autoimmune disorders.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Doenças Autoimunes/tratamento farmacológico , Leucócitos Mononucleares/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Pargilina/farmacologia , Tiazinas/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias/patologia , Pargilina/síntese química , Pargilina/química , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/química
15.
J Enzyme Inhib Med Chem ; 31(6): 1512-9, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26950280

RESUMO

3,6-Diazaphenothiazines were obtained in cyclization of 3-amino-3'-nitro-2,4'-dipyridinyl sulfide and the reaction of sodium 3-amino-2-pyridinethiolate with 4-chloro-3-nitropyridine followed by alkylation and heteroarylation. The thiazine ring formation ran via the Smiles rearrangement. The structure elucidation was based on 2D NMR and X-ray analysis of N-methylated product. 3,6-Diazaphenothiazines were investigated for antitumor activity using glioblastoma SNB-19, melanoma C-32 and breast cancer MCF-7 cells. 10H-3,6-diazaphenothiazine was 10 times more active (IC50 < 0.72 µg/mL) than cisplatin. Two diazaphenothiazines with the 2-pyrimidinyl and dimethylaminopropyl substituents were selectively active against MCF-7 and C-32 cells. The expressions of H3 (proliferation marker), TP53, CDKN1A (cell cycle regulators), BAX and BCL-2 (proapoptopic and antiapoptopic genes) were detected by RT-QPCR method. The expression analysis suggests the cell cycle arrest and the mitochondrial apoptosis pathway activation in MCF-7 and SNB-19 cells.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Fenotiazinas/síntese química , Fenotiazinas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenotiazinas/química , Espectroscopia de Prótons por Ressonância Magnética
16.
Med Chem Res ; 24(4): 1408-1418, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25750499

RESUMO

A new type of tricyclic azaphenothiazines-1,8-diazaphenothiazines-was obtained in the reaction of 2,3- and 3,4-disubstituted pyridines. The reaction ran as the Smiles rearrangement. The 1,8-diazaphenothiazine system was determined using NOE experiment and 2D NMR spectra (COSY, HSQC, HMBC). 10H-1,8-diazaphenothiazine was transformed into 10-derivatives with alkyl, aminoalkyl, amidoalkyl, sulfonamidoalkyl, and nitrogen half-mustard groups. The compounds were tested for their effects on phytohemagglutinin A-induced proliferative response of human peripheral blood mononuclear cells (PBMC) and lipopolysaccharide-induced tumor necrosis factor alpha production by human whole blood cultures. The compounds exhibited differential, dose-dependent inhibitory activities in these tests. All the compounds were low toxic against PBMC. The compounds showing the highest antiproliferative activity strongly inhibited the growth of leukemia L-1210 and colon cancer SW-948 cell lines, similarly as cisplatin, a reference drug.

17.
Med Chem Res ; 24(4): 1725-1732, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25750501

RESUMO

New tetracyclic and pentacyclic azaphenothiazines containing one or two quinoline rings instead of benzene rings were obtained in the original reactions of isomeric diquinodithiins, dichlorodiquinolinyl sulfides, and disulfide with aromatic amines. The type of ring fusion in the azaphenothiazine system was concluded from the 1H NMR spectra. The obtained azaphenothiazines were evaluated in vitro for their antioxidant activity on rat hepatic microsomal membranes for protection of non-enzymatic lipid peroxidation promoted by the Fe2+/ascorbic acid redox system. Most compounds exhibited a very significant antioxidant activity with IC50 values between 1 and 23 µM. The degree of antioxidant activity depends on the lipophilicity and molecular size as well as the (non)substitution of the thiazine nitrogen atom and type of ring system fusion. It is the first time to our knowledge that azaphenothiazines are shown to exhibit such potent antioxidant activity.

18.
Eur J Med Chem ; 89: 411-20, 2015 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-25462256

RESUMO

6-Substituted 9-fluoroquino[3,2-b]benzo[1,4]thiazines - a new type of tetracyclic azaphenothiazines-were obtained from of 6H-9-fluoroquinobenzothiazine by the introduction of appropriate substituents to the thiazine nitrogen atom (alkyl, aminoalkyl, amidoalkyl, sulfonamidoalkyl and nitrogen half-mustard groups). The compounds displayed differential cytotoxic as well as antiproliferative actions against human peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin A (PHA). In addition, they suppressed lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) production by whole blood human cell cultures. Two compounds (4 and 15, with the propargyl and methanesulfonamidopropyl groups) were selected for further experiments because of lack of cytotoxicity and strong antiproliferative actions. Compound 4 showed strong suppressive actions on growth of L1210, SW948, A-431 and CX-1 tumor cell lines which were close to those of cisplatin, the reference drug (e.g. GI50 of 2.28 µg/mL vs. 1.86 µg/mL for L1210 cells). Further, the compound appeared to be equally effective as cyclosporine A (CsA) in the inhibition of human two-way mixed lymphocyte reaction (MLR). The compound did not significantly inhibit interleukin 2 (IL-2)-induced growth of CTLL-2 cell line. In addition, inhibition of prostaglandin (PG) synthesis by indomethacin or block of PG receptors did not interfere with the inhibitory effect of the compound on PHA-induced cell proliferation. Therefore, it is likely that the compound acts by inhibiting cell cycle as proposed for other phenothiazines. Further studies are required for the elucidation of the mechanism of action and therapeutic utility of these compounds in more advanced in vivo models.


Assuntos
Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Fluoroquinolonas/síntese química , Fenotiazinas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Drogas , Fluoroquinolonas/química , Fluoroquinolonas/farmacologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/patologia , Estrutura Molecular , Fenotiazinas/química , Fenotiazinas/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/sangue
19.
J Enzyme Inhib Med Chem ; 30(1): 98-106, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24666296

RESUMO

The study presents the discovery of novel butyrylcholinesterase (BuChE) inhibitors among derivatives of azaphenothiazines by application of in silico and in vitro screening methods. From an in-house library of compounds, 143 heterocyclic molecules derived from the azaphenothiazine scaffold were chosen for virtual screening. Based on results of the docking procedure, 15 compounds were identified as exhibiting the best fit for the two screening complexes (ligand - AChE and ligand - BuChE). Five compounds displayed moderate AChE and good BuChE inhibitory activity at screening concentrations of 10 µM. The IC50 values for active BuChE inhibitors were in the 11.8-122.2 nM range. Three of the most active inhibitors are tetra- or pentacyclic derivatives of azaphenothiazines with the same N-methyl-2-piperidinethyl substituent.


Assuntos
Acetilcolinesterase/química , Compostos Aza/química , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Fenotiazinas/química , Acetilcolinesterase/isolamento & purificação , Animais , Compostos Aza/síntese química , Butirilcolinesterase/isolamento & purificação , Inibidores da Colinesterase/síntese química , Descoberta de Drogas , Electrophorus , Ensaios Enzimáticos , Ensaios de Triagem em Larga Escala , Cavalos , Cinética , Simulação de Acoplamento Molecular , Fenotiazinas/síntese química , Piperidinas/química , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Interface Usuário-Computador
20.
J Chromatogr Sci ; 53(4): 462-6, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24981982

RESUMO

The lipophilicity of anticancer and immunosuppressant active 1,8-diazaphenothiazine derivatives ( 1: - 16: ) has been investigated. Their lipophilicity (RM0 and log PTLC) was determined by reversed-phase thin-layer chromatography with mixtures of acetone and TRIS buffer as mobile phases. The parameter RM0 and specific hydrophobic surface area b were significantly intercorrelated showing congeneric classes of dipyridothiazines. The parameter RM0 was discussed in the terms of the structure-lipophilicity relationships and transformed into parameter log PTLC by use of the calibration curve. The lipophilicity was correlated with molecular and biomolecular descriptors (human intestinal absorption, blood-brain barrier, plasma protein binding, MDCK) and in vitro tumor necrosis factor alpha inhibition and antiproliferative activity.


Assuntos
Antineoplásicos/química , Imunossupressores/química , Fenotiazinas/química , Cromatografia de Fase Reversa , Interações Hidrofóbicas e Hidrofílicas
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