- Discovery of a new autophagy inducer for A549 lung cancer cells
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Biological activities of a series of fluorescent compounds against human lung cancer cell line A549 were investigated. The results showed that (E)-1,3,3-trimethyl-2-(4-(piperidin-1-yl)styryl)-3H-indol-1-ium iodide (8) and (E)-2-(5,5-dimethyl-3-(4-(piperazin-1-yl)styryl)cyclohex-2-en-1-ylidene) malononitrile (11) could inhibit the growth of A549 cancer cells in a dose and time-dependent manner. Furthermore, compound 8 could trigger autophagy and apoptosis, but not obviously induce necrosis under the stimulatory condition. Therefore, 8 can be used as autophagy activator to investigate the regulatory mechanism of autophagy and may offer a new candidate for the treatment of lung cancer.
- Li, Na,Qu, GuoJing,Xue, JingNa,Li, Xiao,Zhao, Xuan,Yan, YeHao,Gao, DongFang,Zhang, Lu,Wang, Peng,Zhang, Ming,Zhao, BaoXiang,Miao, JunYing,Lin, ZhaoMin
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Read Online
- A mitochondria-targeted ratiometric fluorescence sensor for the detection of hypochlorite in living cells
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A new fluorescence probe based on phenothiazine-coumarin platform was rationally designed and developed for the detection of hypochlorite in a ratiometric manner in aqueous solution and living cells. The probe possessed a large pseudo Stokes shift (209 nm) and lager gap between two emissions (462/629 nm), which should avail to perform more accurate detection. The probe could respond to hypochlorite with selectivity, sensitivity and celerity. Moreover, the probe was successfully used for imaging endogenous hypochlorite in mitochondria of RAW264.7 macrophage cells with high sensitivity.
- Wang, Wei,Ning, Jun-Ya,Liu, Jin-Ting,Miao, Jun-Ying,Zhao, Bao-Xiang
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Read Online
- Poly(Pyrrole-Phenothiazine) Modified Electrodes. Application as Photoelectrodes via a Charge Transfer Complex
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Electrodes modified by a poly(pyrrole-phenothiazine) film are obtained by anodic polymerization of N-(3-pyrrol-1-ylpropyl)phenothiazine; they act as photoelectrodes via their charge transfer complex with an electron acceptor in solution.
- Deronzier, Alain,Essakalli, Mohamed,Moutet, Jean-Claude
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Read Online
- Dendritic effects on the ordered assembly and the interfacial one-electron oxidation of redox-active dendron-functionalized gold nanoparticles
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A higher generation dendron with a long-alkyl chain thiol (DA2-SH) induced the formation of nanoparticles with a small core with quite a narrow size distribution (1.5 ± 0.1 nm), the self-assembly of one-dimensional arrays of these gold nanoparticles (DA2-Au), and the stabilization for the formation of the radical cation of the phenothiazine of DA2-Au nanoparticles from the interfacial one-electron oxidation of the nanoparticles with NOBF4. The Royal Society of Chemistry 2006.
- Komine, Yusuke,Ueda, Ikuko,Goto, Tomotaka,Fujihara, Hisashi
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Read Online
- Phenothiazine compound as well as preparation method and application thereof
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The invention discloses a phenothiazine compound which has the advantages of novel structural general formula and framework, high efficiency, low toxicity and better inhibitory activity on LSD1. The invention also discloses a preparation method of the compound. The preparation method has the characteristics of mild reaction conditions, simplicity in operation and high reaction yield. According to the invention, phenothiazine is taken as a raw material, active groups are respectively introduced to a parent of phenothiazine, and new phenothiazine pharmacophores are synthesized; and phenothiazine compounds are designed and synthesized by modification with piperazine, morpholine, piperidine and other groups. The compound retains the activity of phenothiazine and also has the characteristics of modification groups, so that the biological activity of original molecules is improved, and the anti-tumor activity of target molecules is improved. The invention also discloses an application of the compound in preparation of LSD1-targeted antitumor drugs, and the compound shows good inhibitory activity on LSD1 and shows good development potential.
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Paragraph 0041-0044
(2021/08/19)
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- An Inhibitor of the Interaction of Survivin with Smac in Mitochondria Promotes Apoptosis
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Herein we report the first small molecule that disrupts the survivin-Smac interaction taking place in mitochondria. The inhibitor, PZ-6-QN, was identified by initially screening a phenothiazine library using a fluorescence anisotropy assay and then conducting a structure–activity relationship study. Mutagenesis and molecular docking studies suggest that PZ-6-QN binds to survivin similarly to the known Smac peptide, AVPI. The results of the effort also show that PZ-6-QN exhibits good anticancer activity against various cancer cells. Moreover, cell-based mechanistic studies provide evidence for the proposal that PZ-6-QN enters mitochondria to inhibit the survivin-Smac interaction and promotes release of Smac and cytochrome c from mitochondria into the cytosol, a process that induces apoptosis in cancer cells. Overall, the present study suggests that PZ-6-QN can serve as a novel chemical probe for study of processes associated with the mitochondrial survivin-Smac interaction and it will aid the discovery of novel anticancer agents.
- Park, Seong-Hyun,Shin, Insu,Park, Sang-Hyun,Kim, Nam Doo,Shin, Injae
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supporting information
p. 4035 - 4041
(2019/08/02)
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- Phenothiazine compound and application thereof
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The invention provides a phenothiazine compound and application thereof to preparation of drugs for curing breast cancer and melanoma. The phenothiazine compound has higher inhibitory activity on thebreast cancer cell MDA- MB- 231, SUM159, MCF- 7, SKBR- 3 and the melanoma cell A375 and B16BL6 than trifluoperazine and thioridazine, and can be applied to curing breast cancer and melanoma. The general formula of the phenothiazine compound is as following (the formula is shown in the description), wherein R1 and R2 are as shown in the description.
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Paragraph 0122-0125
(2019/06/07)
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- Reversed isoniazids: Design, synthesis and evaluation against Mycobacterium tuberculosis
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Novel reversed isoniazid (RINH) agents were synthesized by covalently linking isoniazid with various efflux pump inhibitor (EPI) cores and their structural motifs. These RINH agents were then evaluated for anti-mycobacterial activity against sensitive, isoniazid mono-resistant and MDR clinical isolates of M. tuberculosis and a selected number of compounds were also tested ex vivo for intracellular activity as well as in the ethidium bromide (EB) assay for efflux pump inhibition efficacy. The potency of some compounds against various strains of M. tuberculosis (4a–c, 7 and 8; H37Rv-MIC99 ≤1.25 μM, R5401-MIC99 ≤2.5 μM, X_61-MIC99 ≤5 μM) demonstrated the potential of the reversed anti-TB agent strategy towards the development of novel anti-mycobacterial agents to address the rapidly growing issue of resistance. Further, macrophage activity with >90% inhibition by 1a–c and 3b (MIC90 ≤13.42 μM) and inhibition of EB efflux demonstrated by these compounds are encouraging.
- Kumar, Malkeet,Singh, Kawaljit,Ngwane, Andile H.,Hamzabegovic, Fahreta,Abate, Getahun,Baker, Bienyameen,Wiid, Ian,Hoft, Daniel F.,Ruminski, Peter,Chibale, Kelly
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supporting information
p. 833 - 844
(2018/01/22)
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- Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis
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The neuroleptic drug thioridazine has been recently repositioned as possible anti-tubercular drug. Thioridazine showed anti-tubercular activity against drug resistant mycobacteria but it is endowed with adverse side effects. A small library of thioridazine derivatives has been designed through the replacement of the piperidine and phenothiazine moieties, with the aim to improve the anti-tubercular activity and to reduce the cytotoxic effects. Among the resulting compounds, the indole derivative 12e showed an antimycobacterial activity significantly better than thioridazine and a cytotoxicity 15-fold lower.
- Scalacci, Nicolò,Brown, Alistair K.,Pavan, Fernando R.,Ribeiro, Camila M.,Manetti, Fabrizio,Bhakta, Sanjib,Maitra, Arundhati,Smith, Darren L.,Petricci, Elena,Castagnolo, Daniele
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p. 147 - 158
(2016/12/30)
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- Phenothiazine-based CaaX competitive inhibitors of human farnesyltransferase bearing a cysteine, methionine, serine or valine moiety as a new family of antitumoral compounds
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A new family of CaaX competitive inhibitors of human farnesyltransferase based on phenothiazine and carbazole skeleton bearing a l-cysteine, l-methionine, l-serine or l-valine moiety was designed, synthesized and biologically evaluated. Phenothiazine derivatives proved to be more active than carbazole-based compounds. Phenothiazine 1b with cysteine residue was the most promising inhibitor of human farnesyltransferase in the current study.
- Dumitriu, Gina-Mirabela,B?cu, Elena,Belei, Dalila,Rigo, Beno?t,Dubois, Jo?lle,Farce, Amaury,Ghinet, Alina
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p. 4447 - 4452
(2015/10/12)
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- INHIBITORS OF MALT1 PROTEASE
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The present invention relates to compounds which are inhibitors of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALTl) and to their use in therapy, in particular in the treatment or prevention of a disease or disorder which is treatable by an inhibitor of a paracaspase. The present invention also relates to pharmaceutical compositions containing such compounds.
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Page/Page column 84-85
(2014/06/24)
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- Incorporation of triphenylphosphonium functionality improves the inhibitory properties of phenothiazine derivatives in Mycobacterium tuberculosis
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Tuberculosis (TB) is a difficult to treat disease caused by the bacterium Mycobacterium tuberculosis. The need for improved therapies is required to kill different M. tuberculosis populations present during infection and to kill drug resistant strains. Protein complexes associated with energy generation, required for the survival of all M. tuberculosis populations, have shown promise as targets for novel therapies (e.g., phenothiazines that target type II NADH dehydrogenase (NDH-2) in the electron transport chain). However, the low efficacy of these compounds and their off-target effects has made the development of phenothiazines as a therapeutic agent for TB limited. This study reports that a series of alkyltriphenylphosphonium (alkylTPP) cations, a known intracellular delivery functionality, improves the localization and effective concentration of phenothiazines at the mycobacterial membrane. AlkylTPP cations were shown to accumulate at biological membranes in a range of bacteria and lipophilicity was revealed as an important feature of the structure-function relationship. Incorporation of the alkylTPP cationic function significantly increased the concentration and potency of a series of phenothiazine derivatives at the mycobacterial membrane (the site of NDH-2), where the lead compound 3a showed inhibition of M. tuberculosis growth at 0.5 μg/mL. Compound 3a was shown to act in a similar manner to that previously published for other active phenothiazines by targeting energetic processes (i.e., NADH oxidation and oxygen consumption), occurring in the mycobacterial membrane. This shows the enormous potential of alkylTPP cations to improve the delivery and therefore efficacy of bioactive agents targeting oxidative phosphorylation in the mycobacterial membrane.
- Dunn, Elyse A.,Roxburgh, Marina,Larsen, Lesley,Smith, Robin A.J.,McLellan, Alexander D.,Heikal, Adam,Murphy, Michael P.,Cook, Gregory M.
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p. 5320 - 5328
(2014/12/10)
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- Synthesis of some new 2-Oxo-N-[(10H-phenothiazin-10-yl)alkyl] derivatives of azetidine-1-carboxamides
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The synthesis of a new series of 4-aryl-3-chloro-2-oxo-N-[3-(10H- phenothiazin-10-yl)propyl]azetidine-1-carboxamides, 4a-4m, is described. Phenothiazine on reaction with Cl(CH2)3Br at room temperature gave 10-(3-chloropropyl)-10H-phenothiazine (1), and the latter reacted with urea to yield 1-[3-(10H-phenothiazin-10-yl)propyl]urea (2). Further reaction of 2 with several substituted aromatic aldehydes led to N-(arylmethylidene)-N′-[3-(phenothiazin-10-yl)propyl]ureas 3a-3m, which, on treatment with ClCH2COCl in the presence of Et3N, furnished the desired racemic trans-2-oxoazetidin-1-carboxamide derivatives 4a-4m. The structures of all new compounds were confirmed by IR, and 1H- and 13C-NMR spectroscopy, FAB mass spectrometry, and chemical methods. Copyright
- Sharma, Ritu,Samadhiya, Pushkal,Srivastava,Srivastava
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scheme or table
p. 514 - 521
(2012/05/04)
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- Synthesis and biological activity of 4-thiazolidinone derivatives of phenothiazine
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A new series of N-[3-(10H-phenothiazin-10-yl)propyl]-2-(substituted phenyl)-4-oxo-5-(substituted benzylidene)-3-thiazolidinecarboxamide, 5a-s were synthesized. The reaction of thioglycolic acid with N-[3-(10H-phenothiazin- 10-yl)propyl]-N'-[(substituted phenyl)methylidene]urea, 3a-s in the presence of anhydrous ZnCl2 afforded the new heterocyclic compounds N-[3- -(10H-phenothiazin-10-yl)propyl]-2-(substituted phenyl)-4-oxo-3- thiazolidinecarboxamide, 4a-s. The latter product on treatment with several selected substituted aromatic aldehydes in the presence of C2H5ONa underwent the Knoevenagel reaction to yield 5a-s. The structure of compounds 1, 2, 3a-s, 4a-s and 5a-s were confirmed by IR, 1H-NMR, 13C-NMR and FAB mass spectroscopy and by chemical analysis. All the above compounds were screened for their antimicrobial activity against some selected bacteria and fungi and for their antituberculosis activity, the compounds were screened against the bacterium Mycobacterium tuberculosis. Copyright 2012 (CC) SCS.
- Sharma, Ritu,Samadhiya, Pushkal,Srivastava, Savitri D.,Srivastava, Santosh K.
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experimental part
p. 17 - 26
(2012/05/05)
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- Synthesis and pharmaceutical importance of 2-azetidinone derivatives of phenothiazine
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A new series of N-[3-(10H-phenothiazin-1-yl)propyl]-4-(substituted phenyl)-3-chloro-2-oxo-1- azetidinecarboxamide 4(a-m) have been synthesized from phenothiazine in four steps. Phenothiazine on reaction with Cl(CH 2)3Br at room temperature gave 1-(3-chlorophenyl)-10H-phenothiazine, 1. The compound 1 yielded the condensation product with urea at room temperature, N-[3-(10H-phenothiazin-1-yl)propyl]urea 2. The compound 2 on further reaction with several substituted aromatic aldehydes produced N-[3-(10Hphenothiazin- 1-yl)propyl]-N'-[(substituted phenyl)methylidene]-urea 3(a-m). The compounds 3(a-m) on treatment with ClCH2COCl in the presence of Et3N furnished final products 4(a-m). The structures of all the newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR and FAB-Mass spectra and chemical methods. All the final synthesized compounds were evaluated for their antibacterial, antifungal and antitubercular activities which displayed acceptable activities. Indian Academy of Sciences.
- Sharma, Ritu,Samadhiya, Pushkal,Srivastava,Srivastava
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experimental part
p. 633 - 637
(2012/09/11)
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- Synthesis and antifungal activity of some substituted phenothiazines and related compounds
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Several phenothiazines and related compounds were synthesized and their antifungal activity was evaluated in vitro. The results observed for α-chloro-N-acetyl phenothiazine led us to choose this compound as a lead in the search of antifungal agents.
- Sarmiento, Gabriela P.,Vitale, Roxana G.,Afeltra, Javier,Moltrasio, Graciela Y.,Moglioni, Albertina G.
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experimental part
p. 101 - 105
(2011/02/25)
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- Electrochromic compound
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A compound for use in electrochromic devices. The compound includes (1) β-(10-phenothiazyl)propoxy phosphonic acid; (2) β-(10-phenothiazyl)propyl-phosphonic acid; and (3) β-(10-phenothiazyl)propionate phosphonic acid.
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Page/Page column 9; 11; 13-15
(2008/06/13)
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- A chimeric ligand approach leading to potent antiprion active acridine derivatives: Design, synthesis, and biological investigations
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Human transmissible neurodegenerations including Creutzfeldt-Jakob disease are unique, since they are caused by prions, an infectious agent that replicates without nucleic acids but instead by inducing conversion of a host-resident normal prion protein to a misfolded conformational isoform. For pharmacotherapy of these unusual diseases, tricyclic heterocyclic compounds such as quinacrine have been considered, but with ambiguous success in vivo, so far. On the basis of the synergistic antiprion effects of quinacrine and iminodibenzyl derivatives, we introduce a novel class of potential pharmaceuticals representing structural chimeras of quinacrine and imipramine analogues. We describe the chemical synthesis and bioassays of a focused library of these compounds. The most potent target compound 2a revealed an EC50 value of 20 nM determined with a cell model of prion disease, thus substantially improving the antiprion efficacy of quinacrine.
- Dollinger, Silke,L?ber, Stefan,Klingenstein, Ralf,Korth, Carsten,Gmeiner, Peter
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p. 6591 - 6595
(2007/10/03)
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- Synthesis and pharmacological characterization of novel inverse agonists acting on the viral-encoded chemokine receptor US28
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G-protein coupled receptors encoded by viruses represent an unexplored class of potential drug targets. In this study, we describe the synthesis and pharmacological characterization of the first class of inverse agonists acting on the HCMV-encoded receptor US28. It is shown that replacement of the 4-hydroxy group of lead compound 1 with a methylamine group results in a significant 6-fold increase in affinity. Interestingly, increasing the rigidity of the spacer by the introduction of a double bond also leads to a significant increase in binding affinity compared to 1. These novel inverse agonists serve as valuable tools to elucidate the role of constitutive signaling in the pathogenesis of viral infection and may have therapeutic potential as leads for new antiviral drugs.
- Hulshof, Janneke W.,Vischer, Henry F.,Verheij, Mark H.P.,Fratantoni, Silvina A.,Smit, Martine J.,de Esch, Iwan J.P.,Leurs, Rob
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p. 7213 - 7230
(2007/10/03)
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- ADRENERGIC RECEPTOR ANTAGONISTS
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The present invention relates to α1a and/or α1b adrenergic receptor antagonists, which can be used to treat a disease or disorder mediated through α1a and/or α1b adrenergic receptors. Compounds and pharmaceutical compositions disclosed herein can be used to treat benign prostatic hyperplasia (BPH) and related symptoms thereof. Further, such compounds can be used to treat lower urinary tract symptoms that may or may not be associated with BPH. The present invention also relates to processes to prepare the disclosed compounds, pharmaceutical compositions thereof, and methods of treating BPH or related symptoms thereof.
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Page/Page column 55
(2010/11/24)
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- Ultrafast electrochromic windows based on redox-chromophore modified nanostructured semiconducting and conducting films
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Described is the construction of an ultrafast electrochromic window. One electrode of this window is based on a transparent nanostructured TiO2 (anatase) film (4.0 μm thick) supported on conducting glass (F-doped tin oxide, 10 Ω cm-2, 0.5 μm thick) and modified by chemisorption of a monolayer of the redox chromophore bis(2-phosphonoethyl)-4,4′-bipyridinium dichloride. The other electrode is based on a transparent nanostructured SnO2 film (3.0 μm thick) supported on conducting glass (F-doped tin oxide, 10 Ω cm-2, 0.5 μm thick) and modified by chemisorption of a monolayer of the redox chromophore [β-(10-phenothiazyl)propoxy]phosphonic acid. The electrolyte used is LiClO4 (0.2 mol dm-3) in γ-butyrolactone. The excellent performance of a 2.5 cm × 2.5 cm window over 10000 electrochromic test cycles-switching times (coloring and bleaching) of less than 250 ms, coloration efficiency of 270 cm2 C-1, steady-state currents (colored and bleached) of less than 6 μA cm-2, and memory of greater than 600 s (time required for low end transmittance to increase by 5%) - suggest a practical technology.
- Cummins, David,Boschloo, Gerrit,Ryan, Michael,Corr, David,Rao, S. Nagaraja,Fitzmaurice, Donald
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p. 11449 - 11459
(2007/10/03)
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- Identification of a non peptidic RANTES antagonist
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A series of phenothiazines demonstrating inhibition of RANTES binding to THP-1 cell membranes has been identified. The lead compound RP23618 (IC50 = 3 μM) was found to inhibit specific binding of 125I-RANTES, but not 125I-MCP-1 to THP-1 cell membranes and furthermore to antagonise RANTES, but not MCP-1-induced chemotaxis of THP-1 cells.
- Bright, Colin,Brown, Thomas J.,Cox, Paul,Halley, Frank,Lockey, Peter,McLay, Iain M.,Moore, Una,Porter, Barry,Williams, Robert J.
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p. 771 - 774
(2007/10/03)
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- Method of reducing blood glucose
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The present invention relates to the use of compounds of the general formula STR1 for reducing blood glucose and/or inhibit the secretion, circulation or effect of insulin antagonizing peptides like CGRP or amylin. Hence the compound can be used in the treatment of insulin resistance related to NIDDM (non-insulin-dependent diabetes mellitus) or aging.
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- N-substituted azaheterocyclic carboxylic acids and esters thereof
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The present invention relates to novel N-substituted azaheterocyclic carboxylic acids and esters thereof in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation.
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- Tests of a Piperidino Mask for the Protection of Functionalized Carbon Sites in Multistep Syntheses
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Primary alkyl chlorides (R-Cl) are easily isolated in excellent yield after treatment of the appropriate N-alkylpiperidines (R-NC5H10) with α-chloroethyl chloroformate.The method is exemplified by the conversion of a variety of alkylpiperidines, including systems with other sensitive functionalities, to the respective chlorides in yields varying from 90 to 97percent.The potential significance of this process in drug congener preparation and in total synthesis is outlined.Similar fragmentations of N-sec-alkylpiperidines are described.
- Olofson, R. A.,Abbott, Duain E.
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p. 2795 - 2799
(2007/10/02)
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- Heterocyclic Free Radicals. Part 10. Phenothiazine Cation-Radicals as Probes of the Inductive Effect
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Phenothiazine cation-radicals, functionalised at nitrogen by polymethylene chains which terminate in polar substituents, exhibit nitrogen hyperfine splittings which vary regularly with the length of the polymethylene chain and with the polarity of the terminal substituent, as measured by ?1.The cation-radicals are thus probes of the inductive effect which give quantitative insight into its transmisson mechanisms and its attenuation by intervening bonds.For chain-lengths longer than a single methylene group, the field effects of the polar terminal substituents are correlated by a cosθ/r3 function which implies that any terminal substituent may be modelled as a point-dipole whose mean orientation and mean separation from the radical aminium centre are determined by the conformational preferences of the polymethylene chain.Literature values of ?1 for certain substituents are questioned in the light of the results obtained and inductive substituent constants, in general, are discussed.
- Hanson, Peter,Isham, William J.,Lewis, Robin J.,Stockburn, William A.
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p. 1492 - 1500
(2007/10/02)
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