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International Journal of Molecular... Jun 2017The molecular frame of the reported series of new polyheterocyclic compounds was intended to combine the potent phenothiazine and benzothiazole pharmacophoric units. The...
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 -(phenothiazin-3-yl)-thioamides and it was validated by the preparation of new 2-alkyl- and 2-aryl-thiazolo[5,4-]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-]phenothiazine and -(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-]phenothiazine was identified as the most effective of the series by displaying against THP-1 cell lines a cytotoxicity close to cytarabine antineoplastic agent.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; HL-60 Cells; Humans; Leukemia; Models, Molecular; Molecular Conformation; Molecular Structure; Phenothiazines; Spectrum Analysis; Structure-Activity Relationship
PubMed: 28672876
DOI: 10.3390/ijms18071365 -
Acta Poloniae Pharmaceutica 2001Two drugs in the form of coated tablets: Promazin (promazine hydrochloride) (1) and Thioridazin (thioridazine hydrochloride) (2), and tablets Clotrimazolum...
Two drugs in the form of coated tablets: Promazin (promazine hydrochloride) (1) and Thioridazin (thioridazine hydrochloride) (2), and tablets Clotrimazolum (clotrimazole) (3) were assayed gravimetrically and spectrophotometrically in the same process using complexes with ammonium molybdate. Stoichiometry of these complexes was established by elemental analysis and analysis of the incineration residue (MoO3). The complexes were subsequently characterized using their IR and UV spectra and melting points. The active substances of the complexes were also determined spectrophotometrically. Using this method Beers Law was found to hold for the concentration ranges of 5-40 microg/ml (complex of 1), 5-60 (microg/ml (complex of 2) and 2-10 microg/ml (complex of 3). The method was validated in terms of precision, linearity, detection limit and quantification limit. The two methods of drug determination, used in a single analytical process verify each other.
Topics: Anti-Bacterial Agents; Enzyme Inhibitors; Imidazoles; Macrolides; Phenothiazines; Spectrophotometry, Ultraviolet; Tablets; Tablets, Enteric-Coated
PubMed: 12197611
DOI: No ID Found -
The Journal of Toxicological Sciences Dec 2010The reactions of hetero-tricyclic aromatic hydrocarbons (H-TCAHs) with hypochlorite in an aqueous solution were investigated under conditions that simulate wastewater...
The reactions of hetero-tricyclic aromatic hydrocarbons (H-TCAHs) with hypochlorite in an aqueous solution were investigated under conditions that simulate wastewater disinfection. H-TCAH-hypochlorite reaction products were determined by gas chromatographic-mass spectrometric (GC-MS) analyses. For 20 µM, 10H-phenothiazine, 10H-phenoxazine, and phenoxathiin reacted rapidly with active chlorine in neutral pH (7.0), but no phenazine-hypochlorite reaction was observed over pH values of 5-9 for 1 hr. The 10H-phenothiazine-hypochlorite reaction began by oxidation with active chlorine to form its dioxides, followed by chloro-substitution in water. The extent of the reactions depended on the chlorine dose, solution pH and compound structures. Ames assays for the chlorination byproducts of 10H-phenothiazine and 10H-phenoxazine also showed to be weak mutagenicity in TA98 and TA100 strains without S9 mix, but no chlorination byproducts of phenoxathiin exhibited any mutagenicity in both tester strains with and without S9 mix.
Topics: Chlorine; Disinfection; Gas Chromatography-Mass Spectrometry; Hydrocarbons, Chlorinated; Hypochlorous Acid; Kinetics; Mutagenicity Tests; Mutagens; Phenothiazines; Salmonella typhimurium; Water Pollutants, Chemical; Water Purification
PubMed: 21139335
DOI: 10.2131/jts.35.853 -
Analytical Sciences : the International... May 2003DNA and gold nanoparticles are co-immobilized at a gold electrode through elaborate self-assembly processes. This configuration has proven to be useful as a sensor for...
DNA and gold nanoparticles are co-immobilized at a gold electrode through elaborate self-assembly processes. This configuration has proven to be useful as a sensor for phenothiazine drugs, taking advantage of the well-known, relatively large surface area of gold nanoparticles and the strong intercalation between dsDNA and phenothiazine drugs. This modified electrode has demonstrated good sensitivity and stability towards the oxidation of two model phenothiazine drugs: promethazine and chlorpromazine. A linear dependence between the concentration of phenothiazine drugs and the peak current is observed, with a concentration range of 2.0 x 10(-5)-1.6 x 10(-4) M and 1.0 x 10(-5)-1.2 x 10(-4) M, and a detection limit of 1.0 x 10(-5) M and 7.0 x 10(-6) M, for promethazine and chlorpromazine, respectively.
Topics: Animals; DNA; Electrodes; Gold; Microscopy, Electron; Nanotechnology; Phenothiazines; Surface Properties
PubMed: 12769359
DOI: 10.2116/analsci.19.653 -
Theranostics 2021The tumor suppressor protein p53 remains in a wild type but inactive form in ~50% of all human cancers. Thus, activating it becomes an attractive approach for targeted...
The tumor suppressor protein p53 remains in a wild type but inactive form in ~50% of all human cancers. Thus, activating it becomes an attractive approach for targeted cancer therapies. In this regard, our lab has previously discovered a small molecule, Inauhzin (INZ), as a potent p53 activator with no genotoxicity. To improve its efficacy and bioavailability, here we employed nanoparticle encapsulation, making INZ-C, an analog of INZ, to nanoparticle-encapsulated INZ-C (n-INZ-C). This approach significantly improved p53 activation and inhibition of lung and colorectal cancer cell growth by n-INZ-C and while it displayed a minimal effect on normal human Wi38 and mouse MEF cells. The improved activity was further corroborated with the enhanced cellular uptake observed in cancer cells and minimal cellular uptake observed in normal cells. pharmacokinetic evaluation of these nanoparticles showed that the nanoparticle encapsulation prolongates the half-life of INZ-C from 2.5 h to 5 h in mice. These results demonstrate that we have established a nanoparticle system that could enhance the bioavailability and efficacy of INZ-C as a potential anti-cancer therapeutic.
Topics: Animals; Antineoplastic Agents; Biological Availability; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Humans; Indoles; Lung Neoplasms; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Nanoparticles; Phenothiazines; Spectroscopy, Fourier Transform Infrared; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays
PubMed: 34093867
DOI: 10.7150/thno.57404 -
Canadian Medical Association Journal Mar 1962
Topics: General Practitioners; Phenothiazines; Tranquilizing Agents
PubMed: 14464787
DOI: No ID Found -
Organic & Biomolecular Chemistry Jul 2022A two-step synthesis of phenothiazines has been developed using a dual-catalytic -thioarylation reaction of anilines as the key step. Activation of...
A two-step synthesis of phenothiazines has been developed using a dual-catalytic -thioarylation reaction of anilines as the key step. Activation of -(2-bromophenylthio)succinimide was achieved using the super Lewis acid, iron(III) triflimide and the Lewis base, diphenyl selenide, resulting in an accelerated and efficient -thioarylation reaction of various protected aniline derivatives and less reactive, unprotected analogues. The thioarylated adducts were then cyclised to the desired phenothiazines using either an Ullmann-Goldberg or Buchwald-Hartwig coupling reaction. The dual catalytic thioarylation and copper(I)-catalysed cyclisation approach was used for the four-step synthesis of methopromazine, a neuroleptic agent with antipsychotic activity.
Topics: Aniline Compounds; Catalysis; Copper; Ferric Compounds; Phenothiazines
PubMed: 35796590
DOI: 10.1039/d2ob01082h -
Potential of phenothiazines to synergistically block calmodulin and reactivate PP2A in cancer cells.PloS One 2022Phenothiazines (PTZ) were developed as inhibitors of monoamine neurotransmitter receptors, notably dopamine receptors. Because of this activity they have been used for...
Phenothiazines (PTZ) were developed as inhibitors of monoamine neurotransmitter receptors, notably dopamine receptors. Because of this activity they have been used for decades as antipsychotic drugs. In addition, they possess significant anti-cancer properties and several attempts for their repurposing were made. However, their incompletely understood polypharmacology is challenging. Here we examined the potential of the PTZ fluphenazine (Flu) and its mustard derivative (Flu-M) to synergistically act on two cancer associated targets, calmodulin (CaM) and the tumor suppressor protein phosphatase 2A (PP2A). Both proteins are known to modulate the Ras- and MAPK-pathway, cell viability and features of cancer cell stemness. Consistently, we show that the combination of a CaM inhibitor and the PP2A activator DT-061 synergistically inhibited the 3D-spheroid formation of MDA-MB-231 (K-Ras-G13D), NCI-H358 (K-Ras-G12C) and A375 (B-raf-V600E) cancer cells, and increased apoptosis in MDA-MB-231. We reasoned that these activities remain combined in PTZ, which were the starting point for PP2A activator development, while several PTZ are known CaM inhibitors. We show that both Flu and Flu-M retained CaM inhibitory activity in vitro and in cells, with a higher potency of the mustard derivative in cells. In line with the CaM dependence of Ras plasma membrane organization, the mustard derivative potently reduced the functional membrane organization of oncogenic Ras, while DT-061 had a negligible effect. Like DT-061, both PTZ potently decreased c-MYC levels, a hallmark of PP2A activation. Benchmarking against the KRAS-G12C specific inhibitor AMG-510 in MIA PaCa-2 cells revealed a higher potency of Flu-M than combinations of DT-061 and a CaM inhibitor on MAPK-output and a strong effect on cell proliferation. While our study is limited, our results suggest that improved PTZ derivatives that retain both, their CaM inhibitory and PP2A activating properties, but have lost their neurological side-effects, may be interesting to pursue further as anti-cancer agents.
Topics: Calmodulin; Cell Line, Tumor; Cell Survival; Neoplasms; Phenothiazines; Protein Phosphatase 2
PubMed: 35617282
DOI: 10.1371/journal.pone.0268635 -
European Journal of Pharmacology Nov 2020In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not... (Review)
Review
In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not seen such mobilization towards one topic in this century. The whole situation makes clear that progress needs to be made in antiviral drug development. The first step to do it is to characterize the potential antiviral activity of new or already existed drugs on the market. Phenothiazines are antipsychotic agents used previously as antiseptics, anthelminthics, and antimalarials. Up to date, they are tested for a number of other disorders including the broad spectrum of viruses. The goal of this paper was to summarize the current literature on activity toward RNA-viruses of such drugs like chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine. We identified 49 papers, where the use of the phenothiazines for 23 viruses from different families were tested. Chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine possess anti-viral activity towards different types of viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Additionally, since the drugs display activity at nontoxic concentrations they have therapeutic potential for some viruses, still, further research on animal and human subjects are needed in this field to verify cell base research.
Topics: Animals; Antipsychotic Agents; Antiviral Agents; Betacoronavirus; COVID-19; Chlorpromazine; Coronavirus Infections; Fluphenazine; Humans; Pandemics; Perphenazine; Phenothiazines; Pneumonia, Viral; Prochlorperazine; RNA Viruses; SARS-CoV-2; Thioridazine; COVID-19 Drug Treatment
PubMed: 32949606
DOI: 10.1016/j.ejphar.2020.173553 -
Journal of Orthopaedic Research :... Sep 2018The integration of osteochondral grafts to native articular cartilage is critical as the lack of graft integration may lead to continued tissue degradation, poor load...
The integration of osteochondral grafts to native articular cartilage is critical as the lack of graft integration may lead to continued tissue degradation, poor load transfer and inadequate nutrient transport. Photochemical bonding promotes graft integration by activating a photosensitizer at the interface via a light source and avoids negative effects associated with other bonding techniques. We hypothesized that the bond strength depends on photosensitizer type and concentration in addition to light exposure. Photochemical bonding was evaluated using methylene blue (MB), a cationic phenothiazine photosensitizer, and two phthalocyanine photosensitizers, Al(III) phthalocyanine chloride tetrasulfonic acid (CASPc) and aluminum phthalocyanine chloride (AlPc). Exposure was altered by varying irradiation time for a fixed irradiance or by varying irradiance with a fixed irradiation time. MB was ineffective at producing bonding at the range of concentrations tested while CASPc produced a peak twofold bond strength increase over controls. AlPc produced substantial bonding at all concentrations with a peak 3.9-fold bond strength increase over controls. Parametric tests revealed that bond strength depended primarily on the total energy delivered to the bonding site rather than the rate of light delivery or light irradiance. Bond strength persisted for 1 week of in-vitro culture, which warrants further exploration for clinical applications. These studies indicate that photochemical bonding is a viable strategy for enhancing articular cartilage graft integration. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2406-2415, 2018.
Topics: Animals; Cartilage; Cartilage, Articular; Cattle; Chondrocytes; Femur; Indoles; Isoindoles; Light; Methylene Blue; Phenothiazines; Photochemical Processes; Photosensitizing Agents; Shear Strength; Surface Properties; Tissue Adhesives; Transplants
PubMed: 29575046
DOI: 10.1002/jor.23898