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1.
Molecules ; 29(9)2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38731617

RESUMEN

In this study, a library of 3,7-di(hetero)aryl-substituted 10-(3-trimethylammoniumpropyl)10H-phenothiazine salts is prepared. These title compounds and their precursors are reversible redox systems with tunable potentials. The Hammett correlation gives a very good correlation of the first oxidation potentials with σp parameters. Furthermore, the title compounds and their precursors are blue to green-blue emissive. Screening of the salts reveals for some derivatives a distinct inhibition of several pathogenic bacterial strains (Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Aconetobacter baumannii, and Klebsiella pneumoniae) in the lower micromolar range.


Asunto(s)
Antibacterianos , Pruebas de Sensibilidad Microbiana , Fenotiazinas , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Fenotiazinas/farmacología , Fenotiazinas/química , Fenotiazinas/síntesis química , Sales (Química)/química , Sales (Química)/farmacología , Staphylococcus aureus/efectos de los fármacos , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/farmacología , Compuestos de Amonio Cuaternario/síntesis química , Escherichia coli/efectos de los fármacos , Oxidación-Reducción , Bacterias/efectos de los fármacos , Estructura Molecular , Relación Estructura-Actividad
2.
Bioorg Chem ; 148: 107458, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38788362

RESUMEN

Ferroptosis is a novel style of cell death, and studies have shown that ferroptosis is strongly associated with spinal cord injury (SCI). A large number of ferroptosis inhibitors have been reported, but so far no ferroptosis inhibitor has been used clinically. Therefore there is an urgent need to discover a better inhibitor of ferroptosis. In this study, 24 novel sulfonamide phenothiazine ferroptosis inhibitors were designed and synthesized, followed by structure-activity relationship studies on these compounds. Among them, compound 23b exhibited the best activity in Erastin-induced PC12 cells (EC50 = 0.001 µM) and demonstrated a low hERG inhibition activity (IC50 > 30 µM). Additionally, compound 23b was identified as a ROS scavenger and showed promising therapeutic effects in an SD rat model of SCI. Importantly, 23b did not display significant toxicity in both in vivo and in vitro experiments and show good pharmacokinetic properties. These findings suggest that compound 23b, a novel ferroptosis inhibitor, holds potential as a therapeutic agent for spinal cord injury and warrants further investigation.


Asunto(s)
Diseño de Fármacos , Ferroptosis , Fenotiazinas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal , Sulfonamidas , Animales , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Ratas , Relación Estructura-Actividad , Ferroptosis/efectos de los fármacos , Fenotiazinas/farmacología , Fenotiazinas/síntesis química , Fenotiazinas/química , Fenotiazinas/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Células PC12 , Estructura Molecular , Relación Dosis-Respuesta a Droga , Humanos , Masculino
3.
Bioorg Chem ; 147: 107398, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38691907

RESUMEN

Herein, we report a multifaceted nanoformulation, developed by binding thionine acetate (TA) in silica matrix to form TA loaded silica nanoparticles (STA Nps), which were characterized using various physicochemical techniques. STA NPs were spherical shaped having size 40-50 nm and exhibited good heating efficiency, improved photostability and singlet oxygen production rate than TA alone. In PDT experiment, the rate of degradation for ABDMA was enhanced from 0.1367 min-1 for TA alone to 0.1774 min-1 for STA Nps, depicting an increase in the reactive oxygen species (ROS) generation ability of STA Nps. Further, the cytotoxicity of STA Nps was investigated by carrying out the biophysical studies with Calf thymus DNA (Ct-DNA) and Human Serum Albumin (HSA). The results indicated that the binding of STA Nps to Ct-DNA causes alterations in the double helix structure of DNA and as a result, STA Nps can impart chemotherapeutic effects via targeting DNA. STA Nps showed good binding affinity with HSA without compromising the structure of HSA, which is important for STA Nps sustainable biodistribution and pharmacokinetics. Based on this study, it is suggested that because of the synergistic effect of chemo and phototherapy, STA Nps can be extensively utilized as potential candidates for treating cancer.


Asunto(s)
Antineoplásicos , Rayos Láser , Nanopartículas , Fenotiazinas , Dióxido de Silicio , Humanos , Dióxido de Silicio/química , Nanopartículas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Fenotiazinas/química , Fenotiazinas/farmacología , Fenotiazinas/síntesis química , Albúmina Sérica Humana/química , ADN/química , Ensayos de Selección de Medicamentos Antitumorales , Relación Dosis-Respuesta a Droga , Estructura Molecular , Animales , Especies Reactivas de Oxígeno/metabolismo , Supervivencia Celular/efectos de los fármacos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/síntesis química , Fotoquimioterapia , Proliferación Celular/efectos de los fármacos , Bovinos , Relación Estructura-Actividad
4.
Spectrochim Acta A Mol Biomol Spectrosc ; 316: 124312, 2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-38688210

RESUMEN

The ubiquity of diverse material entities in environmental matrices renders the deployment of unifunctional fluorescent indicators inadequate. Consequently, this study introduces a ratiometric dual-emission fluorescent sensor (Probe CP), synthesized by conjugating phenothiazine coumarin to hydroxycoumarin through a piperazine linker for concurrent detection of HClO and H2S. Upon interaction with HClO, the phenothiazine unit's sulfur atom undergoes oxidation to sulfoxide, facilitating a shift from red to green fluorescence in a ratiometric manner. Concurrently, at the opposite terminus of Probe CP, 2,4-dinitroanisole serves as the reactive moiety for H2S recognition; it restores the blue emission characteristic of 7-hydroxycoumarin while maintaining the red fluorescence emanating from phenothiazine coumarin as an internal standard for ratio-based assessment. Exhibiting elevated specificity and sensitivity coupled with minimal detection thresholds (0.0506 µM for HClO and 1.7292 µM for H2S) alongside rapid equilibration periods (3 min for HClO and half an hour for H2S), this sensor was efficaciously employed in cellular environments and within zebrafish models as well as imaging applications pertaining to alcohol-induced hepatic injury in murine subjects.


Asunto(s)
Cumarinas , Colorantes Fluorescentes , Sulfuro de Hidrógeno , Fenotiazinas , Pez Cebra , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Animales , Fenotiazinas/química , Fenotiazinas/síntesis química , Cumarinas/química , Cumarinas/síntesis química , Sulfuro de Hidrógeno/análisis , Ratones , Espectrometría de Fluorescencia/métodos , Humanos
5.
Int J Mol Sci ; 25(8)2024 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-38673734

RESUMEN

Phenothiazine derivatives are widely studied in various fields such as biology, chemistry, and medicine research because of their pharmaceutical effects. The first compound used successfully in the treatment of psychosis was a phenthiazine derivative, chlorpromazine. Apart from its activity in neurons, chlorpromazine has also been reported to display anticancer and antibacterial properties. In this study, we present the synthesis and research on the activity of A549, MDA, MiaPaCa, PC3, and HCT116 cancer cell lines and of S. aureus, S. epidermidis, E. coli, and P. aeruginosa bacterial strains against a series of new tetracyclic chlorpromazine analogues containing a quinoline scaffold in their structure instead of the benzene ring and various substituents at the thiazine nitrogen. The structure of these novel molecules has been determined by 1H NMR, 13C NMR, and HRMS spectral techniques. The seven most active of the twenty-four new chlorpromazine analogues tested were selected to study the mechanism of cytotoxic action. Their ability to induce apoptosis or necrosis in cancer cells was assessed by flow cytometry analysis. The results obtained confirmed the proapoptotic activity of selected compounds, especially in terms of inducing late apoptosis or necrosis in cancer cell lines A549, MiaPaCa-2, and HCT-116. Furthermore, studies on the induction of cell cycle arrest suggest that the new chlorpromazine analogues exert antiproliferative effects by inducing cell cycle arrest in the S phase and, consequently, apoptosis.


Asunto(s)
Antibacterianos , Antineoplásicos , Apoptosis , Clorpromazina , Fenotiazinas , Quinolinas , Humanos , Clorpromazina/farmacología , Clorpromazina/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Fenotiazinas/farmacología , Fenotiazinas/química , Fenotiazinas/síntesis química , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Quinolinas/química , Quinolinas/farmacología , Quinolinas/síntesis química , Pruebas de Sensibilidad Microbiana , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Células HCT116
6.
Molecules ; 27(1)2022 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-35011508

RESUMEN

The molecular hybridization approach has been used to develop compounds with improved efficacy by combining two or more pharmacophores of bioactive scaffolds. In this context, hybridization of various relevant pharmacophores with phenothiazine derivatives has resulted in pertinent compounds with diverse biological activities, interacting with specific or multiple targets. In fact, the development of new drugs or drug candidates based on phenothiazine system has been a promising approach due to the diverse activities associated with this tricyclic system, traditionally present in compounds with antipsychotic, antihistaminic and antimuscarinic effects. Actually, the pharmacological actions of phenothiazine hybrids include promising antibacterial, antifungal, anticancer, anti-inflammatory, antimalarial, analgesic and multi-drug resistance reversal properties. The present review summarizes the progress in the development of phenothiazine hybrids and their biological activity.


Asunto(s)
Desarrollo de Medicamentos , Fenotiazinas , Animales , Humanos , Fenotiazinas/síntesis química , Fenotiazinas/química , Fenotiazinas/uso terapéutico , Relación Estructura-Actividad
7.
Bioorg Med Chem ; 54: 116558, 2022 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-34915314

RESUMEN

Inhibitors of the monoamine oxidase (MAO) enzymes are important agents for the treatment of central nervous system disorders and have established roles in the therapy of neuropsychiatric diseases such as depression and in the neurodegenerative disorder, Parkinson's disease. A number of good potency MAO inhibitors consist of tricyclic ring systems as exemplified by the structures of harmine and the phenothiazine compound methylene blue. In an attempt to discover novel MAO inhibitors, 30 phenothiazine, anthraquinone and related tricyclic derivatives were selected and evaluated as potential inhibitors of human MAO-A and MAO-B. The results show that, in general, the tricyclic compounds are specific inhibitors of MAO-A over the MAO-B isoform. Quinizarin (IC50 = 0.065 µM), 2-chloro-7-methoxy-10H-phenothiazine (IC50 = 0.576 µM) and xanthone (IC50 = 0.623 µM) proved to be the most potent MAO-A inhibitors, while the most potent MAO-B inhibition was recorded with 2-chloro-7-methoxy-10H-phenothiazine (IC50 = 1.34 µM), 1,2-diaminoanthraquinone (IC50 = 2.41 µM) and emodin (IC50 = 3.24 µM). These compounds may undergo further preclinical evaluation and development, and may also serve as potential lead compounds for the future design of MAO inhibitors.


Asunto(s)
Antraquinonas/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Fenotiazinas/farmacología , Antraquinonas/síntesis química , Antraquinonas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Fenotiazinas/síntesis química , Fenotiazinas/química , Relación Estructura-Actividad
8.
ChemMedChem ; 16(24): 3763-3771, 2021 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-34536069

RESUMEN

The reactivity of phenothiazine (PS), phenoselenazine (PSE), and phenotellurazine (PTE) with different reactive oxygen species (ROS) has been studied using density functional theory (DFT) in combination with the QM-ORSA (Quantum Mechanics-based Test for Overall Free Radical Scavenging Activity) protocol for an accurate kinetic rate calculation. Four radical scavenging mechanisms have been screened, namely hydrogen atom transfer (HAT), radical adduct formation (RAF), single electron transfer (SET), and the direct oxidation of the chalcogen atom. The chosen ROS are HO. , HOO. , and CH3 OO. . PS, PSE, and PTE exhibit an excellent antioxidant activity in water regardless of the ROS due to their characteristic diffusion-controlled regime processes. For the HO. radical, the primary active reaction mechanism is, for all antioxidants, RAF. But, for HOO. and CH3 OO. , the dominant mechanism strongly depends on the antioxidant: HAT for PS and PSE, and SET for PTE. The scavenging efficiency decreases dramatically in lipid environment and remains only significant (via RAF) for the most reactive radical (HO. ). Therefore, PS, PSE, and PTE are excellent antioxidant molecules, especially in aqueous, physiological environments where they are active against a broad spectrum of harmful radicals. There is no advantage or significant difference in the scavenging efficiency when changing the chalcogen since the reactivity mainly derives from the amino hydrogen and the aromatic sites.


Asunto(s)
Teoría Funcional de la Densidad , Depuradores de Radicales Libres/farmacología , Peróxido de Hidrógeno/antagonistas & inhibidores , Fenotiazinas/farmacología , Relación Dosis-Respuesta a Droga , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/química , Estructura Molecular , Fenotiazinas/síntesis química , Fenotiazinas/química , Relación Estructura-Actividad
9.
Molecules ; 25(17)2020 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-32867308

RESUMEN

Acetylcholinesterase (AChE) and beta-secretase (BACE-1) are two attractive targets in the discovery of novel substances that could control multiple aspects of Alzheimer's disease (AD). Chalcones are the flavonoid derivatives with diverse bioactivities, including AChE and BACE-1 inhibition. In this study, a series of N-substituted-4-phenothiazine-chalcones was synthesized and tested for AChE and BACE-1 inhibitory activities. In silico models, including two-dimensional quantitative structure-activity relationship (2D-QSAR) for AChE and BACE-1 inhibitors, and molecular docking investigation, were developed to elucidate the experimental process. The results indicated that 13 chalcone derivatives were synthesized with relatively high yields (39-81%). The bioactivities of these substances were examined with pIC50 3.73-5.96 (AChE) and 5.20-6.81 (BACE-1). Eleven of synthesized chalcones had completely new structures. Two substances AC4 and AC12 exhibited the highest biological activities on both AChE and BACE-1. These substances could be employed for further researches. In addition to this, the present study results suggested that, by using a combination of two types of predictive models, 2D-QSAR and molecular docking, it was possible to estimate the biological activities of the prepared compounds with relatively high accuracy.


Asunto(s)
Chalconas , Inhibidores de la Colinesterasa , Fenotiazinas , Chalconas/síntesis química , Chalconas/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Simulación del Acoplamiento Molecular , Fenotiazinas/síntesis química , Fenotiazinas/farmacología , Relación Estructura-Actividad Cuantitativa
10.
Bioorg Chem ; 103: 104184, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32891861

RESUMEN

In the incessant search for innovative cancer control strategies, this study was devoted to the design, synthesis and pharmacological evaluation of dual inhibitors of farnesyltransferase and tubulin polymerization (FTI/MTIs). A series of indolizine-phenothiazine hybrids 16 (amides) and 17 (ketones) has been obtained in a 4-step procedure. The combination of the two heterocycles provided potent tubulin polymerization inhibitors with similar efficiency as the reference phenstatin and (-)-desoxypodophyllotoxin. Ketones 17 were also able to inhibit human farnesyltransferase (FTase) in vitro. Interestingly, three molecules 17c, 17d and 17f were very effective against both considered biological targets. Next, nine indolizine-phenothiazine hybrids 16c, 16f, 17a-f and 22b were evaluated for their cell growth inhibition potential on the NCI-60 cancer cell lines panel. Ketones 17a-f were the most active and displayed promising cellular activities. Not only they arrested the cell growth of almost all tested cancer cells, but they displayed cytotoxicity potential with GI50 values in the low nanomolar range. The most sensitive cell lines upon treatment with indolizine-phenothiazine hybrids were NCI-H522 (lung cancer), COLO-205 and HT29 (colon cancer), SF-539 (human glioblastoma), OVCAR-3 (ovarian cancer), A498 (renal cancer) and especially MDA-MB-435 (melanoma). Demonstrating the preclinical effectiveness of these dual inhibitors can be crucial. A single dual molecule could induce a synergy of antitumor activity, while increasing the effectiveness and reducing the toxicity of the classical combo treatments currently used in chemotherapy.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa/antagonistas & inhibidores , Indolizinas/farmacología , Fenotiazinas/farmacología , Moduladores de Tubulina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Farnesiltransferasa/química , Farnesiltransferasa/metabolismo , Humanos , Indolizinas/síntesis química , Indolizinas/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Fenotiazinas/síntesis química , Fenotiazinas/metabolismo , Unión Proteica , Relación Estructura-Actividad , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/metabolismo
11.
Anticancer Res ; 40(9): 4921-4928, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32878780

RESUMEN

BACKGROUND/AIM: Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research. MATERIALS AND METHODS: Three phenothiazines (promethazine, chlorpromazine and thioridazine) have been tested in combination with 11 active selenocompounds against MDR (ABCB1-overexpressing) mouse T-lymphoma cells to investigate their activity as combination chemotherapy and as antitumor adjuvants in vitro with a checkerboard combination assay. RESULTS: Seven selenocompounds showed toxicity on mouse embryonic fibroblasts, while three showed selectivity towards tumor cells. Two compounds showed synergism with all tested phenothiazines in low concentration ranges (1.46-11.25 µM). Thioridazine was the most potent among the three phenothiazines. CONCLUSION: Phenothiazines belonging to different generations showed different levels of adjuvant activities. All the tested phenothiazines are already approved medicines with known pharmacological and toxicity profiles, therefore, their use as adjuvants in cancer may be considered as a potential drug repurposing strategy.


Asunto(s)
Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Compuestos de Organoselenio/farmacología , Fenotiazinas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/patología , Ratones , Estructura Molecular , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/química , Fenotiazinas/síntesis química , Fenotiazinas/química
12.
Eur J Med Chem ; 201: 112420, 2020 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-32526553

RESUMEN

Targeting energy metabolism in Mycobacterium tuberculosis (Mtb) is a new paradigm in the search for innovative anti-TB drugs. NADH:menaquinone oxidoreductase is a non-proton translocating type II NADH dehydrogenase (NDH-2) that is an essential enzyme in the respiratory chain of Mtb and is not found in mammalian mitochondria. Phenothiazines (PTZs) represent one of the most known class of NDH-2 inhibitors, but their use as anti-TB drugs is currently limited by the wide range of potentially serious off-target effects. In this work, we designed and synthesized a series of new PTZs by decorating the scaffold in an unconventional way, introducing various halogen atoms. By replacing the sulfur atom with selenium, a dibromophenoselenazine 20 was also synthesized. Among the synthesized poly-halogenated PTZs (HPTZs), dibromo and tetrachloro derivatives 9 and 11, along with the phenoselenazine 20, emerged with a better anti-TB profile than the therapeutic thioridazine (TZ). They targeted non-replicating Mtb, were bactericidal, and synergized with rifampin and bedaquiline. Moreover, their anti-TB activity was found to be related to the NDH-2 inhibition. Most important, they showed a markedly reduced affinity to dopaminergic and serotonergic receptors respect to the TZ. From this work emerged, for the first time, as the poly-halogenation of the PTZ core, while permitting to maintain good anti-TB profile could conceivably lead to fewer CNS side-effects risk, making more tangible the use of PTZs for this alternative therapeutic application.


Asunto(s)
Antituberculosos/farmacología , Compuestos de Organoselenio/farmacología , Fenotiazinas/farmacología , Animales , Antituberculosos/síntesis química , Antituberculosos/metabolismo , Antituberculosos/toxicidad , Chlorocebus aethiops , Sinergismo Farmacológico , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/toxicidad , Células HEK293 , Humanos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , NADH Deshidrogenasa/antagonistas & inhibidores , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/metabolismo , Compuestos de Organoselenio/toxicidad , Pruebas de Sensibilidad Parasitaria , Fenotiazinas/síntesis química , Fenotiazinas/metabolismo , Fenotiazinas/toxicidad , Unión Proteica , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Relación Estructura-Actividad , Células Vero
13.
Curr Org Synth ; 17(2): 151-159, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32418517

RESUMEN

A series of novel 1,3-thiazole derivatives (5a-i) with a modified phenothiazine moiety were synthesized and tested against cancer cell line MCF-7 for their cytotoxicity. Most of them (5a-i) were less cytotoxic or had no activity against MCF-7 cancer cell line. MATERIAL AND METHODS: The IC50 value of compound (4) was 33.84 µM. The compounds (5a-i) were also evaluated for antimicrobial activities, but no significant activity was observed. The antioxidant activity was conducted for target compounds (5a-i). The IC50 value of compound (5b) was 0.151mM. RESULTS: The total amount of energy, ACE (atomic contact energy), energy of receptor (PDB: 5G5J), and ligand interaction of structure (4) were found to be 22.448 Kcal.mol-1 , -247.68, and -91.91 Kcal.mol-1, respectively. The structure (4) is well binded with the receptor because the values of binding energy, steric energy, and the number of hydrogen bondings are -91.91, 22.448 kcal.mol-1, and 2, respectively. It shows that structure (4) has good cytotoxicity with MCF-7 in vitro. CONCLUSION: The increasing of docking ability of structures (5a-i) with the receptor is presented in increasing order as (5f)>(5e)>(5g)>(5a)>(5b)>(5d)>(5c)>(5i)>(5h). The structure bearing substitution as thiosemicarbazone (4), nitrogen heterocyclic (5f), halogen (5e), and azide (5g) showed good cytotoxicity activity in vitro.


Asunto(s)
Antineoplásicos/farmacología , Antioxidantes/farmacología , Fenotiazinas/farmacología , Tiazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antioxidantes/síntesis química , Antioxidantes/metabolismo , Citocromo P-450 CYP3A/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Fenotiazinas/síntesis química , Fenotiazinas/metabolismo , Unión Proteica , Tiazoles/síntesis química , Tiazoles/metabolismo
14.
J Med Chem ; 63(9): 4896-4907, 2020 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-32267685

RESUMEN

Development of new photosensitizers (PSs) with high photodynamic efficacy and minimal side effects is of great interest in photodynamic therapy (PDT). In this work, we reported several pyridine-embedded phenothiazinium (pyridophenothiazinium) dyes, which could be conveniently synthesized in a few short steps and acted as highly efficient and potent PSs to selectively localize to lysosomes and photosensitively kill cancer cells. Among them, compound 5, which possessed the ability of promoting intracellular reactive oxygen species (ROS) upon light irradiation by almost 40-fold higher than that of methylene blue (MB, a general phenothiazinium-based PS), exhibited a remarkable phototherapeutic index (PI = 53.8) against HT29 cancer cells, leading to eradication of large solid tumors (∼300 mm3) in a xenograft mouse model without apparent side effects. These results suggest that the pyridophenothiazinium dyes developed herein, especially compound 5, may serve as promising lysosome-targeted PSs for efficient photodynamic antitumor therapy.


Asunto(s)
Antineoplásicos/uso terapéutico , Colorantes/uso terapéutico , Lisosomas/metabolismo , Neoplasias/tratamiento farmacológico , Fenotiazinas/uso terapéutico , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Antineoplásicos/efectos de la radiación , Línea Celular Tumoral , Colorantes/síntesis química , Colorantes/farmacocinética , Colorantes/efectos de la radiación , Femenino , Humanos , Luz , Masculino , Ratones Endogámicos BALB C , Fenotiazinas/síntesis química , Fenotiazinas/farmacocinética , Fenotiazinas/efectos de la radiación , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/efectos de la radiación , Piridinas/síntesis química , Piridinas/farmacocinética , Piridinas/efectos de la radiación , Piridinas/uso terapéutico , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
15.
ACS Appl Mater Interfaces ; 12(18): 20281-20286, 2020 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-32279482

RESUMEN

Traditional organic fluorophores generally have hydrophobic conjugated backbones and exhibit an aggregation-caused quenching emission property, which limits greatly their applications in the biological field. Aggregation-induced emission (AIE) fluorophores can breakthrough this shortcoming and are more promising in biological imaging. In this paper, we synthesized three novel donor-acceptor-donor-type second near-infrared (NIR-II) fluorophores and studied their geometric and electronic structures and photophysical properties by both theoretical and experimental studies. All the three fluorophores had typical AIE characteristics, and their emission wavelength spanned the traditional near-infrared and NIR-II regions. They exhibited much stronger fluorescence after being encapsulated in polymer nanoparticles (NPs) than in solutions, and the fluorophore-loaded NPs had desirable biosafety and significant tumor accumulation, indicating that they have great application potentials in tumor detection.


Asunto(s)
Colorantes Fluorescentes/química , Fenotiazinas/química , Quinoxalinas/química , Tiadiazoles/química , Animales , Línea Celular Tumoral , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/toxicidad , Humanos , Masculino , Ratones Endogámicos ICR , Ratones Desnudos , Micelas , Neoplasias/diagnóstico por imagen , Imagen Óptica , Fenotiazinas/síntesis química , Fenotiazinas/toxicidad , Poloxámero/química , Quinoxalinas/síntesis química , Quinoxalinas/toxicidad , Tiadiazoles/síntesis química , Tiadiazoles/toxicidad
16.
J Am Chem Soc ; 142(11): 5380-5388, 2020 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-32105455

RESUMEN

Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O2 delivery approaches, here we describe an innovative binary photodynamic O2-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O2•-) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O2 consumption and down-regulate HIF-1α expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O2 for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O2•- through type-I photochemistry, and the generated O2•- can further trigger a biocascade to reduce the PDT's demand for O2 in an O2-recycble manner. Furthermore, SORgenTAM also serves to activate the AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O2-economical strategy, under relatively low light dose irradiation, excellent therapeutic responses toward hypoxic tumors are achieved. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutics.


Asunto(s)
Neoplasias/tratamiento farmacológico , Fenotiazinas/uso terapéutico , Fármacos Fotosensibilizantes/uso terapéutico , Hipoxia Tumoral/efectos de los fármacos , Animales , Respiración de la Célula/efectos de los fármacos , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Luz , Células MCF-7 , Ratones Endogámicos BALB C , Mitocondrias/efectos de los fármacos , Fenotiazinas/síntesis química , Fenotiazinas/efectos de la radiación , Fotoquimioterapia , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/efectos de la radiación , Superóxidos/metabolismo
17.
Luminescence ; 35(4): 608-617, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31916343

RESUMEN

A new typical phenothiazine compound functionalized with thienyl-indandione derivative (PTZTID) was synthesized and characterized using spectral analysis (ultraviolet-visible (UV-vis) light, infrared (IR), 1 H nuclear magnetic resonance (NMR) and 13 C NMR tools). The UV-vis absorption spectra of the PTZTID solution in 1,4-dioxane showed two absorption bands attributed to localized aromatic π-π* transitions of conjugated aromatic moieties and intramolecular charge transfer with the characteristics of a π-π* transition. The fluorescence spectra exhibited a maximum emission wavelength at 580 nm. The effect of concentration on photophysical properties took the form of a minor hypsochromic shift, which was attributed to some extent to the occurrence of H-type aggregation of the PTZTID derivative. Binary solvent effects on the spectroscopic behaviour of PTZTID were measured at different H2 O/1,4-dioxane ratios. Similarly, when increasing the water content, a hypsochromic shift was observed that resulted from H-type aggregation. Furthermore, geometry and electronic configurations of PTZTID were studied at density functional theory /B3LYP level and indicated that the compound had a nonplanar (butterfly structure).


Asunto(s)
Colorantes Fluorescentes/química , Indanos/química , Fenotiazinas/química , Teoría Funcional de la Densidad , Colorantes Fluorescentes/síntesis química , Estructura Molecular , Fenotiazinas/síntesis química , Procesos Fotoquímicos , Espectrometría de Fluorescencia
18.
Luminescence ; 35(5): 738-747, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31970874

RESUMEN

A new A-π-D-π-A phenothiazine derivative, 2,2'-((10-octyl-10H-phenothiazine-3,7-diyl)bis (ethene-2,1-diyl))bis(1-ethyl-3,3-dimethyl-3H-indol-1-ium)iodide (PTZ-BEI) was prepared and fully characterized using infra-red (IR), 1 H nuclear magnetic resonance (NMR), 13 C NMR, ultraviolet-visible light and mass spectra. Electronic spectra of PTZ-BEI solutions in solvents with different polarities displayed absorption bands (λmax ) related to intramolecular charge transfer. In addition, the emission spectra of PTZ-BEI solutions were strongly solvent dependent for both wavelength and intensity. Stokes' shift ( Δ ν ¯ ) increased with increasing solvent polarity up to 4105 cm-1 in the most polar solvent, dimethylformamide. The linear solvation-energy relationship was utilized to investigate solvent dependency of the Stokes' shifts. Relative quantum yield (φ) of PTZ-BEI was calculated. Finally, density functional theory was employed at the B3LYP level for geometrical optimization and simulation of electron spectra for the PTZ derivative in gaseous and solvated states to explore the solvent effect.


Asunto(s)
Fenotiazinas/química , Modelos Moleculares , Estructura Molecular , Fenotiazinas/síntesis química , Teoría Cuántica , Solubilidad , Solventes/química , Espectrometría de Fluorescencia
19.
Spectrochim Acta A Mol Biomol Spectrosc ; 228: 117724, 2020 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-31753645

RESUMEN

By taking advantage of phenothiazine moiety as an electron-donating group, a novel donor-acceptor (D-A) type coumarin dye, PTZ-Et, was developed. The introduction of phenothiazine moiety not only caused emission red-shifting and Stokes shift enlarging, but also endowed PTZ-Et with significant aggregation-enhanced emission (AEE) features, thereby enabled PTZ-Et as a robust ratiometric fluorescent probe for HClO detection. Upon oxidation of the sulfur atom on phenothiazine into sulfoxide, PTZ-Et displayed remarkable ratiometric fluorescence response (over 150 folds variations of F534/F626) toward HClO with rapid response time (<30 s) and ultra-sensitivity (LOD = 15 nM). Additionally, the corresponding sensing mechanism of PTZ-Et for HClO was fully elucidated through the successful purification and well characterization (1H NMR, 13C NMR, HRMS, and single crystal data) of the corresponding reaction product between PTZ-Et and HClO. Significantly, PTZ-Et was capable of monitoring both exogenous and endogenous HClO in living RAW 264.7 cells by ratiometric fluorescence imaging.


Asunto(s)
Cumarinas/química , Colorantes Fluorescentes/química , Ácido Hipocloroso/análisis , Fenotiazinas/química , Animales , Cumarinas/síntesis química , Fluorescencia , Colorantes Fluorescentes/síntesis química , Ratones , Microscopía Fluorescente , Modelos Moleculares , Imagen Óptica , Fenotiazinas/síntesis química , Células RAW 264.7
20.
Molecules ; 24(24)2019 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-31817838

RESUMEN

Phenothiazines are one of the more common dye scaffolds for dye-sensitized solar cells. However, these sensitizers are exclusively based on a 3,7-substitution pattern. Herein, we have synthesized and characterized novel 3,8-substituted phenothiazine dyes in order to evaluate the effect of auxiliary donor groups on the performance of this new dye class. The power conversion efficiency increased by 7%-10% upon insertion of an auxiliary donor in position 8 of the phenothiazine, but the structure of the auxiliary donor (phenyl, naphthyl, pyrene) had a low impact when electrodes were stained with chenodeoxycholic acid (CDCA) additive. In the absence of CDCA, the highest power conversion efficiency was seen for the phenyl-based sensitizer attributed to a higher quality dye-monolayer. By comparing the novel dyes to their previously reported 3,7- analogues, only subtle differences were seen in photophysical, electrochemical, and performance measurements. The most notable difference between the two geometries is a lowering of the oxidation potentials of the 3,8-dyes by 40-50 mV compared to the 3,7-analogues. The best auxiliary donor for the 3,8-phenothiazine dyes was found to be pyrenyl, with the best device delivering a power conversion efficiency of 6.23% (99 mW cm-2, 10 eq. CDCA, JSC = 10.20 mA cm-2, VOC = 791 mV, and FF = 0.765).


Asunto(s)
Ácido Quenodesoxicólico/química , Colorantes/química , Fenotiazinas/química , Energía Solar , Ácido Quenodesoxicólico/síntesis química , Colorantes/síntesis química , Suministros de Energía Eléctrica , Electroquímica , Oxidación-Reducción , Fenotiazinas/síntesis química
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