Journal articles: 'Phenothiazine drug structure'

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Poła, Andrzej, Anna Palko-Łabuz, and Kamila Środa-Pomianek. "Theoretical Study of 2-(Trifluoromethyl)phenothiazine Derivatives with Two Hydroxyl Groups in the Side Chain-DFT and QTAIM Computations." Molecules 26, no. 17 (August 29, 2021): 5242. http://dx.doi.org/10.3390/molecules26175242.

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Phenothiazines are known as synthetic antipsychotic drugs that exhibit a wide range of biological effects. Their properties result from the structure and variability of substituents in the heterocyclic system. It is known that different quantum chemical properties have a significant impact on drug behavior in the biological systems. Thus, due to the diversity in the chemical structure of phenothiazines as well as other drugs containing heterocyclic systems, quantum chemical calculations provide valuable methods in predicting their activity. In our study, DFT computations were applied to show some thermochemical parameters (bond dissociation enthalpy—BDE, ionization potential—IP, proton dissociation enthalpy—PDE, proton affinity—PA, and electrontransfer enthalpy—ETE) describing the process of releasing the hydrogen/proton from the hydroxyl group in the side chain of four 2-(trifluoromethyl)phenothiazine (TFMP) derivatives and fluphenazine (FLU). Additional theoretical analysis was carried out based on QTAIM theory. The results allowed theoretical determination of the ability of compounds to scavenge free radicals. In addition, the intramolecular hydrogen bond (H-bond) between the H-atom of the hydroxyl group and the N-atom located in the side chain of the investigated compounds has been identified and characterized.

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Berdyaev, S. Yu, A. I. Turilova, Z. P. Senova, A. N. Gritsenko, N. V. Kaverina, and A. P. Skoldinov. "Acyl derivatives of phenothiazine and their dibenzazepine analogs: Structure and antiarrhythmic activity." Pharmaceutical Chemistry Journal 25, no. 1 (January 1991): 1–4. http://dx.doi.org/10.1007/bf00766356.

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Mir, Shafia, Ayaz Mahmood Dar, and Bashir Ahmad Dar. "Synthetic Strategies of Benzothiazines: A Mini Review." Mini-Reviews in Organic Chemistry 17, no. 2 (February 28, 2020): 148–57. http://dx.doi.org/10.2174/1570193x16666181206101439.

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Benzothiazine is a heterocyclic compound consisting of a benzene ring attached to the 6- membered thiazine ring. The benzothiazines constitute the group of heterocyclic compounds as they have found a variety of industrial uses and show promise as herbicides. Besides this, benzothiazines play an important role in the field of drug discovery as they have the potential to act as drug candidates for the treatment of a large number of diseases including, cancer, vasorelaxant, diabetic, hypertension, mycotic infection and microbial infection. The presence of nitrogen-sulphur axis and similarity in the structure with phenothiazine drugs help the benzothiazines to act as drugs for the treatment of a number of diseases. Herein, we represent different synthetic strategies for the simple and multi-component synthesis of benzothiazine heterocyclic derivatives. The strategies mostly involve the use of 2-aminothiophenol, 1, 3-dicarbonyl compounds or α-haloketones. In almost all the strategies, the potential yields have been obtained.

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Pluta, Krystian, Małgorzata Jeleń, Beata Morak-Młodawska, Michał Zimecki, Jolanta Artym, Maja Kocięba, and Ewa Zaczyńska. "Azaphenothiazines – promising phenothiazine derivatives. An insight into nomenclature, synthesis, structure elucidation and biological properties." European Journal of Medicinal Chemistry 138 (September 2017): 774–806. http://dx.doi.org/10.1016/j.ejmech.2017.07.009.

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Shekhar, H., and Manoj Kumar. "Studies on phase diagram, thermodynamic stability and interfacial structure of solid dispersions of phenothiazine-adipic acid drug system." Molecular Crystals and Liquid Crystals 689, no. 1 (August 13, 2019): 60–71. http://dx.doi.org/10.1080/15421406.2019.1669294.

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Murray, Michael. "Inhibition of hepatic drug metabolism by phenothiazine tranquilizers: quantitative structure-activity relationships and selective inhibition of cytochrome P-450 isoform-specific activities." Chemical Research in Toxicology 2, no. 4 (July 1989): 240–46. http://dx.doi.org/10.1021/tx00010a005.

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Zarafiants, G. N., V. D. Isakov, and T. V. Gorbacheva. "QUESTIONS OF DYNAMICS, FORENSIC MEDICAL AND FORENSIC CHEMICAL DIAGNOSTICS OF METHADONE POISONING IN SAINT PETERSBURG IN 2009-2018." Toxicological Review, no. 1 (February 24, 2020): 2–7. http://dx.doi.org/10.36946/0869-7922-2020-1-2-7.

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Acute poisonings occupy one of the leading places in the structure of mortality due to external causes in the Russian Federation. In Saint Petersburg, there are consistently high rates of drug poisonings (especially methadone poisoning). Reports, statistical maps and other information of the Bureau of Forensic Medical Expertise for the period 2009 – 2018 were used for this study. The research methods were a selective copy of the data, including the results of a forensic chemical study, the calculation of statistical coefficients, descriptive. The analysis showed a decrease in mortality due to external causes in Saint Petersburg in 2009-2018, indicators (per 100 thousand of the population of Saint Petersburg) decreased gradually from 99,3 to 69,8. Acute poisoning of chemical etiology was in the 2nd place (24,9%) after mechanical injury. In the structure of acute poisoning of chemical etiology, the 1st place was occupied by fatal drug poisoning (45,1%). Their share was 28,7% in 2009-2011. It increased sharply up to 52,2% in the period 2012-2018 and began to change both qualitative and quantitative. In Saint Petersburg there were 19 fatal cases of methadone poisoning (0,04 per 100 thousand people) in 2009 and 599 cases (11,19 per 100 thousand people) in 2018. The number of forensic studies on the identification of methadone sharply increased (9 times). In almost half of the poisoning’s cases ethanol, other narcotic drugs (amphetamine derivatives, morphine, cocaine, etc.), as well as drugs and psychotropic substances (derivatives of barbituric acid, benzodiazepine, phenothiazine, etc.) were revealed along with methadone.Forensic medical diagnostics of methadone poisoning are based on the results of chromatography-mass spectrometry, morphological features (macro- and microscopic), analysis of the clinical picture (from medical documents), and consideration of the circumstances of the poisoning. The combined reception of methadone, ethanol and other narcotic and / or psychotropic drugs has a potentiating deprimative effect, aggravates the clinical and morphological picture of poisoning, which must be taken into account when diagnosing them.

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Mao, Meng-Xi, Fang-Ling Li, Yan Shen, Qi-Ming Liu, Shuai Xing, Xu-Feng Luo, Zhen-Long Tu, Xue-Jun Wu, and You-Xuan Zheng. "Simple Synthesis of Red Iridium(III) Complexes with Sulfur-Contained Four-Membered Ancillary Ligands for OLEDs." Molecules 26, no. 9 (April 29, 2021): 2599. http://dx.doi.org/10.3390/molecules26092599.

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Phosphorescent iridium(III) complexes have been widely researched for the fabrication of efficient organic light-emitting diodes (OLEDs). In this work, three red Ir(III) complexes named Ir-1, Ir-2, and Ir-3, with Ir-S-C-S four-membered framework rings, were synthesized efficiently at room temperature within 5 min using sulfur-containing ancillary ligands with electron-donating groups of 9,10-dihydro-9,9-dimethylacridine, phenoxazine, and phenothiazine, respectively. Due to the same main ligand of 4-(4-(trifluoromethyl)phenyl)quinazoline, all Ir(III) complexes showed similar photoluminescence emissions at 622, 619, and 622 nm with phosphorescence quantum yields of 35.4%, 50.4%, and 52.8%, respectively. OLEDs employing these complexes as emitters with the structure of ITO (indium tin oxide)/HAT-CN (dipyra-zino[2,3-f,2′,3′-h]quinoxaline-2,3,6,7,10,11-hexacarbonitrile, 5 nm)/TAPC (4,4′-cyclohexylidenebis[N,N-bis-(4-methylphenyl)aniline], 40 nm)/TCTA (4,4″,4″-tris(carbazol-9-yl)triphenylamine, 10 nm)/Ir(III) complex (10 wt%): 2,6DCzPPy (2,6-bis-(3-(carbazol-9-yl)phenyl)pyridine, 10 nm)/TmPyPB (1,3,5-tri(mpyrid-3-yl-phenyl)benzene, 50 nm)/LiF (1 nm)/Al (100 nm) achieved good performance. In particular, the device based on complex Ir-3 with the phenothiazine unit showed the best performance with a maximum brightness of 22,480 cd m−2, a maximum current efficiency of 23.71 cd A−1, and a maximum external quantum efficiency of 18.1%. The research results suggest the Ir(III) complexes with a four-membered ring Ir-S-C-S backbone provide ideas for the rapid preparation of Ir(III) complexes for OLEDs.

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Xia, Lin-Ying, Ya-Liang Zhang, Rong Yang, Zhong-Chang Wang, Ya-Dong Lu, Bao-Zhong Wang, and Hai-Liang Zhu. "Tubulin Inhibitors Binding to Colchicine-Site: A Review from 2015 to 2019." Current Medicinal Chemistry 27, no. 40 (November 26, 2020): 6787–814. http://dx.doi.org/10.2174/0929867326666191003154051.

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Due to the three domains of the colchicine-site which is conducive to the combination with small molecule compounds, colchicine-site on the tubulin has become a common target for antitumor drug development, and accordingly, a large number of tubulin inhibitors binding to the colchicine-site have been reported and evaluated over the past years. In this study, tubulin inhibitors targeting the colchicine-site and their application as antitumor agents were reviewed based on the literature from 2015 to 2019. Tubulin inhibitors were classified into ten categories according to the structural features, including colchicine derivatives, CA-4 analogs, chalcone analogs, coumarin analogs, indole hybrids, quinoline and quinazoline analogs, lignan and podophyllotoxin derivatives, phenothiazine analogs, N-heterocycle hybrids and others. Most of them displayed potent antitumor activity, including antiproliferative effects against Multi-Drug-Resistant (MDR) cell lines and antivascular properties, both in vitro and in vivo. In this review, the design, synthesis and the analysis of the structure-activity relationship of tubulin inhibitors targeting the colchicine-site were described in detail. In addition, multi-target inhibitors, anti-MDR compounds, and inhibitors bearing antitumor activity in vivo are further listed in tables to present a clear picture of potent tubulin inhibitors, which could be beneficial for medicinal chemistry researchers.

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Yang, Wei, Xiaolong Liu, Chunli Song, Sen Ji, Jianhong Yang, Yang Liu, Jing You, et al. "Structure-activity relationship studies of phenothiazine derivatives as a new class of ferroptosis inhibitors together with the therapeutic effect in an ischemic stroke model." European Journal of Medicinal Chemistry 209 (January 2021): 112842. http://dx.doi.org/10.1016/j.ejmech.2020.112842.

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11

Krstic, Milena, Sofija Sovilj, Suncica Borozan, Milica Rancic, Jelena Poljarevic, and Sanja Grguric-Sipka. "N-alkylphenothiazines - synthesis, structure and application as ligands in metal complexes." Chemical Industry 70, no. 4 (2016): 461–71. http://dx.doi.org/10.2298/hemind150331052k.

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Phenothiazines are a large group of heterocyclic, aromatic molecules with nitrogen and sulphur between two benzene rings. Their derivatives, N-alkylphenothiazines have supstitutient on heterocyclic nitrogen atom which gives them different properties. Also, a series of these molecules have substitution on carbon atom at place 2 of phenothiazine benzene ring. Alkylphenothiazines contain aminoalkyl substituent and their alkyl, acyl and sulphonil derivatives, as well as monocyclic and bicyclic heterocycles attached at thiazine nitrogen atom or directly linked to benzene ring. The N-alkylphenothiazines have been known as antipsychotic drugs, but they also possess antibacterial, antifungal, anticancer activity, and ability to react with macromolecules and to coordinate to the metals. Metal complexes with N-alkylphenothiazines are biological active compounds with different antimicrobial activities and cytotoxic effect against tumor cell lines. Their large field of application of N-alkylphenothiazines is very attractive in terms of synthesis of new related derivatives, metal complexes, studying their properties and applications. This article presents a review of the literature and a contemporary view at N-alkylphenothiazines - their synthesis and application, as well as their metal complexes which have promising biological effects.

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Eyk, Jennifer E. Van, and Robert S. Hodges. "Calmodulin and troponin C: affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide (residues 104–115), mastoparan, and fluphenazine binding." Biochemistry and Cell Biology 65, no. 11 (November 1, 1987): 982–88. http://dx.doi.org/10.1139/o87-128.

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The different conformations induced by the binding of Mg2+ or Ca2+ to troponin C (TnC) and calmodulin (CaM) results in the exposure of various interfaces with potential to bind target compounds. The interaction of TnC or CaM with three affinity columns with ligands of either the synthetic peptide of troponin I (TnI) inhibitory region (residues 104–115), mastoparan (a wasp venom peptide), or fluphenazine (a phenothiazine drug) were investigated in the presence of Mg2+ or Ca2+. TnC and CaM in the presence of either Ca2+ or Mg2+ bound to the TnI peptide 104–115. The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC (most likely the N-terminal helix of site III) and presumably the homologous region of CaM. Mastoparan interacted strongly with both proteins in the presence of Ca2+ but, in the presence of Mg2+, did not bind to TnC and only bound weakly to CaM. Fluphenazine bound to TnC and CaM only in the presence of Ca2+. When the ligands interacted with either proteins there was an increase in cation affinity, such that TnC and CaM were eluted from the TnI peptide or mastoparan affinity column with 0.1 M EDTA compared with the 0.01 M EDTA required to elute the proteins from the fluphenazine column. The interaction of these ligands with their receptor sites on TnC and CaM require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins. In the case of the TnI peptide, which represents a naturally occurring target protein for TnC, Mg2+ and Ca2+ can induce the correct structure in TnC or CaM for interaction, while only Ca2+ can induce the correct structure for mastoparan or fluophenazine binding.

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13

Mathur, Neha, Biplab Manna, and Arun Kumar Sharma. "Relationship between Viscosity and Micellization of Fused Chelates of Thiazine Drugs in Different Chemical Compositions." Current Physical Chemistry 9, no. 3 (November 26, 2019): 232–46. http://dx.doi.org/10.2174/1877946809666190424145506.

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Background: Phenothiazines and Triphenodithiazines are included in the class of nitrogen and sulphur donating ligands. They have a wide spectrum of biological activities and form important class of heterocyclic compounds. Both drugs are being used as, antitumors, anti-inflammatory, antiviral, anaesthetics, anticancer agents, antimalarials, antimicrobials, anti-cholinergics, growth inhibitors, and many other pharmacological agents. Objective: Present work has been initiated with a view to obtain a profile regarding structural insight of complexes of Cobalt (II), Ni (II) and Zinc (II) soaps derived from substituted phenothiazines 15 and triphenodithiazines using latest technique. It also gives an account of micelle formation in the mixed non aqueous solvents. Methods: The viscosity, specific viscosity, and fluidity of complexes of Co, Ni, and Zn Oleate with substituted phenothiazine and triphenodithiazine in methanol + benzene solvents was determined at a constant temperature of 303.15 K to study the micellar features and critical micelle concentration (CMC). In the present work benzene+ methanol have selected as co solvents due to these interact with complex molecules and thus affected aggregation of complex molecules. Results: The results were used to determine the CMC, soap complex-solvent interactions and the effect of chain length of the surfactant molecule on various parameters. The conclusions concerning solute-solute and solute-solvent interaction were discussed regarding the well-known Moulik’s and Jones-Dole equations. Conclusion: From above results it may be concluded that the micelle formation take place earlier in the case of triphenodithiazine complexes due to larger molecular structure, so a smaller number of molecules are needed to form micelle. Micellization also confirms the existence of complex aggregation in the non-aqueous mixed solvents. To conclude, it can be unveiled on the basis of the result acquired that above study of complexes conforms the presence of complex aggregation in the non - aqueous mixed solvents.

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Müller, T. "Electron microscopic demonstration of intracelluar promethazine accumulation sites by a precipitation technique: application to the cerebellar cortex of the mouse." Journal of Histochemistry & Cytochemistry 44, no. 5 (May 1996): 531–35. http://dx.doi.org/10.1177/44.5.8627010.

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A method is described that allows electron microscopic identification of the phenothiazine neuroleptic promethazine after supravital intracardiac injection of high drug concentrations (greater than or equal to 3 %). The cerebellar cortex of the mouse was used for the investigation. This procedure is based on simultaneous fixation of drug and tissue by immersion in a paraformaldehyde-glutaraldehyde solution with the addition of phosphomolybdic acid. The electron microscopic investigation revealed that the drug could easily be identified as an electron-dense precipitate. Subpopulations of neurons exhibited a higher affinity for the drug than others, but no preference for any nerve cell type was detected. Closer study showed that promethazine accumulated primarily within the cytoplasm, where it was bound to the endoplasmic reticulum. Furthermore, promethazine storage was observed within mitochondria and vesicular structures. Drug binding was also seen in the regions of synapses but without any predilection for these structures. Because this precipitation technique also appears to be well-suited for the ultrastructural identification of other drugs, it offers multiple possibilities for application.

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Luan, Yepeng, Jinyi Liu, Jianjun Gao, and Jinhua Wang. "The Design and Synthesis of Novel Phenothiazine Derivatives as Potential Cytotoxic Agents." Letters in Drug Design & Discovery 17, no. 1 (December 31, 2019): 57–67. http://dx.doi.org/10.2174/1570180816666181115112236.

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Background: Cancer incidence and mortality have been increasing and cancer is still the leading cause of death all over the world. Despite the enormous progress in cancer treatment, many patients died of ineffective chemotherapy and drug resistance. Therefore, the design and development of anti-cancer drugs with high efficiency and low toxicity is still one of the most challenging tasks. Tricyclic heterocycles, such as phenothiazine, are always important sources of scaffolds for anti-cancer drug discovery. Methods: In this work, ten new urea-containing derivatives of phenothiazine coupled with different kinds of amine motifs at the endpoint through a three carbon long spacer were designed and synthesized. The structures of the synthesized compounds were elucidated and confirmed by 1H NMR and HRMS. All the synthesized compounds were tested for their antitumor activity in vitro against the proliferation of PC-3 cells, and the compounds with best potency entered further cytotoxicity evaluations against other 22 human tumor cell lines. Mechanism was also studied. Results: From all data, it showed that among all 10 target compounds, TTi-2 showed the best effect in inhibiting the proliferation of 23 human cancer cell lines while TTi-2 without obvious inhibitory effect on normal cell. Furthermore, our results also showed that TTi-2 could inhibit migration, invasion and colony formation of MDA-MB-231 cells. Finally, TTi-2 can induce arrest of cell cycle at G0/G1 phase and cell apoptosis by activating the caspase 3 activity. Conclusion: All these results suggested that TTi-2 might be used as a promising lead compound for anticancer drug development.

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Lilius, Esa-Matti, Marta Bakay, Klara Berencsi, I. Petri, S. Földeak, and J. Molnar. "Immunomodulating Effects of Various Phenothiazines and Related Tricyclic Compounds in Vitro and in Vivo." International Journal of Immunopathology and Pharmacology 5, no. 1 (January 1992): 31–41. http://dx.doi.org/10.1177/039463209200500104.

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A biotechnological approach to the immunomodulating ability of various phenothiazines and related tricyclic compounds in vitro and in vivo was made. The effect of these compounds was studied on various mononuclear leukocyte functions such as antibody-dependent cell-mediated cytotoxicity, blast transformation of lymphocytes by three mitogens, phytohemagglutinin, concanavalin A and pokeweed mitogen (PWM), rosette formation with erythrocytes and with antibody coated erythrocytes (EA), as well as on polymorphonuclear leukocyte functions including phagocytosis and chemiluminescence emission. Moreover, the ability of these compounds to modulate the bioluminescence emission capacity of Escherichia coli cloned with lux genes was measured. Also in vivo studies were made by measuring the number of haemolytic plaque forming cells in the spleen of mice after drug administration. The electrochemical structure of these tricyclic compounds was shown to be in good correlation with their immunomodulating activity on all the functions except EA rosette formation and on blast transformation by PWM showing the role of charge transfer complex formation in the drug-target cell interaction. These results suggest that the biological effectiveness of phenothiazines and related tricyclic compounds can be presumed from their electrochemical properties and a tricyclic compound with a given biological effect can be theoretically designed.

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Benson, T. J., J. H. McKie, J. Garforth, A. Borges, A. H. Fairlamb, and K. T. Douglas. "Rationally designed selective inhibitors of trypanothione reductase. Phenothiazines and related tricyclics as lead structures." Biochemical Journal 286, no. 1 (August 15, 1992): 9–11. http://dx.doi.org/10.1042/bj2860009.

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Trypanothione reductase, an essential component of the anti-oxidant defences of parasitic trypanosomes and Leishmania, differs markedly from the equivalent host enzyme, glutathione reductase, in the binding site for the disulphide substrate. Molecular modelling of this region suggested that certain tricyclic compounds might bind selectively to trypanothione reductase without inhibiting host glutathione reductase. This was confirmed by testing 30 phenothiazine and tricyclic antidepressants, of which clomipramine was found to be the most potent, with a K(i) of 6 microM, competitive with respect to trypanothione. Many of these compounds have been noted previously to have anti-trypanosomal and anti-leishmanial activity and thus they can serve as lead structures for rational drug design.

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18

Swarnkar, Pawan Kumar, P. Kriplani, G. N. Gupta, and K. G. Ojha. "Synthesis and Antibacterial Activity of Some New Phenothiazine Derivatives." E-Journal of Chemistry 4, no. 1 (2007): 14–20. http://dx.doi.org/10.1155/2007/402673.

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A series of some new phenothiazine derivatives were synthesized with the objective for evaluation as antimicrobials. The title compounds were prepared by a five step synthesis scheme. 2-Amino-6-substituted benzothiazoles (1) on diazotization afford 6-substituted benzothiazolyl-2-diazonium chlorides (2). Reaction of 2 with cold solution ofβ-naphthol in dilute NaOH furnishesα-(2-diazo-6-substituted benzothiazolyl)-β-sodionaphthoxides (3) which on acidification with concentrated HCl givesα-(2-diazo-6-substituted benzothiazolyl)-β-naphthols (4). Reaction of 4 with p-substituted anilines givesα-(2-diazo-6-substituted benzothiazolyl)-β-(p-substituted anilino) naphthalenes (5). This synthesis besides by using conventional methods was also attempted using microwave. Fusion of 5 with sulphur in presence of iodine results inα-(2-diazo-6-substituted benzothiazolyl)-6- substituted [2, 3-b] benzophenothiazines(6). The structures of all these compounds have been supported by elemental analysis and their spectral studies. All synthesized compounds were tested for their antibacterial activity using standard drugs.

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Hough, E., M. Hjorth, and S. G. Dahl. "The structures of (dimethylaminopropyl)phenothiazine drugs and their metabolites. II. Chlorpromazine sulphoxide, C17H19ClN2OS, at 120 K." Acta Crystallographica Section C Crystal Structure Communications 41, no. 3 (March 15, 1985): 383–86. http://dx.doi.org/10.1107/s0108270185003997.

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Morita, Ken, Shuning He, Radosław P. Nowak, Jinhua Wang, Nathanael Gray, Eric S. Fischer, and A. Thomas Look. "Targeting T-ALL Cells with Potent Activators of the PP2A Protein Phosphatase Tumor Suppressor." Blood 134, Supplement_1 (November 13, 2019): 406. http://dx.doi.org/10.1182/blood-2019-123573.

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Background Protein phosphatase 2A (PP2A) represents a family of potent tumor suppressors that are often suppressed in human cancers by upregulation of proteins that inhibit subunit assembly into active enzyme complexes. Thus, restoration of PP2A has assumed increasing importance for cancer treatment. In earlier work, we found that perphenazine (PPZ) kills leukemic T cells by activating PP2A (Gutierrez et al. 2014. J Clin Invest.). PPZ also acts to inhibit dopamine D2 receptor (DRD2) in the basal ganglia, which causes movement disorders at dosages less than those needed to kill T-ALL cells, effectively precluding "repurposing" of PPZ for the therapy of T-ALL. Hypothesis We sought to identify PPZ analogues that activate PP2A and induce apoptosis in T-ALL cells but lack the ability to bind and inhibit DRD2. Such analogues would not induce the movement disorders that have limited the usefulness of PPZ as an anti-leukemic drug. Methods PP2A is a heterotrimeric phosphatase that is assembled from three classes of subunits, encoded by two possible "A" genes, 15 "B" genes and 2 "C" genes, providing 60 distinct PP2A holoenzymes that can potentially form in the cell. To identify the key subunits of PP2A required for the antitumor activity of PPZ in T-ALL cells, we knocked out each subunit in human T-ALL cell lines and treated these cells with PPZ. Biochemical reporter assays were established to identify a phenothiazine derivative, iHAP1, that efficiently reactivates PP2A but does not inhibit dopamine signaling. iHAP1 preclinical studies included in vivo efficacy and toxicity in T-ALL xenograft models and in vitro efficacy in 248 cancer cell lines from 35 distinct tumor types. Results Using this approach, we found that knockout of each of three specific subunit genes of PP2A - PPP2R1A, PPP2CA and PPP2R5E - uniquely conferred resistance to PPZ treatment in T-ALL cell lines,. An independent Immunoprecipitation followed by western blotting indicated that all three subunits form a functional PP2A heterotrimeric holoenzyme complex in response to PPZ treatment. Narla and coworkers have published extensively about a series of compounds called "small molecule PP2 activators" or SMAPs (Sangodkar et al. 2017 J Clin Invest.). Intriguingly, we showed that activities of SMAP compounds depend on a different "B subunit" - PPP2R2A - and target different signal transduction pathways. Based on this finding, we sought to identify analogues of PPZ that more potently activate PP2A through this mechanism and kill T-ALL cells but lack inhibitory activity against DRD2. Testing more than 80 analogues of PPZ revealed a highly potent PP2A activator, iHAP1 (improvedHeterocyclic Activators of PP2A 1). iHAP1 is ten times more potent than PPZ in its ability to activate PP2A and kill tumor cells, but does not measurably inhibit dopamine signalling. iHAP1 is highly active as an antitumor drug human T-ALL xenograft models, without causing untoward movement disorders or other toxicity in vivo. Phosphoproteomics analysis followed by detailed biochemical assays revealed that the potent antitumor activity of PPZ and iHAP1 is mediated by dephosphorylation of MYBL2, a transcription factor that is essential for expression of genes whose products mediate prometaphase, and thus for cancer cell growth and survival. SMAP compounds do not dephosphorylate the same transcription factor and rather target other phosphoproteins. Thus, the potent PP2A activator iHAP1 drives three specific PP2A subunits into an active trimeric phosphatase and this drug is highly active against T-ALL and other hematologic malignancies. iHAP1 did not exhibit measurable toxicity up to 80 mg/kg/day PO or IM for 30 days in preclinical studies of human leukemia xenografts growing in immunosuppressed mice, providing a therapeutic index for this lead compound in preclinical studies. Conclusions Our findings show that small molecules promote the assembly of unique PP2A complexes with different regulatory subunits and substrates, allowing detailed structure and function studies of PP2A family members. A goal is to identify small molecules that assemble PP2A enzymes containing each of the remaining 13 regulatory PP2A subunits, thereby targeting a diverse array of substrates crucial to the pathogenesis of cancer and other diseases. Disclosures Gray: Gatekeeper: Equity Ownership; Syros: Equity Ownership; Petra: Equity Ownership; C4: Equity Ownership; B2S: Equity Ownership; Soltego: Equity Ownership; Novartis: Research Funding; Takeda: Research Funding; Astellas: Research Funding; Taiho: Research Funding; Janssen: Research Funding; Kinogen: Research Funding; Voronoi: Research Funding; Her2llc: Research Funding; Deerfield: Research Funding; Sanofi: Research Funding. Fischer:C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Deerfield: Consultancy, Research Funding; Astellas: Research Funding.

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Hartshorn, Edward A., Gary M. Levin, and C. Lindsay DeVane. "A Review of Cyclic Antidepressant-Induced Blood Dyscrasias." Annals of Pharmacotherapy 26, no. 3 (March 1992): 378–83. http://dx.doi.org/10.1177/106002809202600313.

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OBJECTIVE: To review the literature for cases of blood dyscrasias associated with cyclic antidepressants. Several types of blood dyscrasias are discussed. DATA SOURCES: All references were selected through the use of MEDLINE. Indexing terms were blood, abnormalities, dyscrasias, antidepressants, agranulocytosis, and eosinophilia. The only constraints were English language and human subjects. STUDY SELECTION: All cases were included except for letters to the editor of various journals when pertinent data such as doses and additional medications were omitted. DATA SYNTHESIS: The review provides a table listing the different blood dyscrasias and the drug the patient was receiving. The table also includes time of onset, time to recovery, and several symptoms for each patient. CONCLUSIONS: Common symptoms of various blood dyscrasias are discussed. The chemical structures of the antidepressants are related to phenothiazines, which are also implicated in causing blood dyscrasias. Recommendations for treatment of both the dyscrasia and depression are discussed.

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Hough, E., E. Wold, and S. G. Dahl. "The structures of (dimethylaminopropyl)phenothiazine drugs and their metabolites. III. Monode-N-methylchlorpromazine sulphoxide, C16H17ClN2OS, at 120 K." Acta Crystallographica Section C Crystal Structure Communications 41, no. 3 (March 15, 1985): 386–89. http://dx.doi.org/10.1107/s0108270185004000.

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Mansilla, Alicia, Antonio Chaves-Sanjuan, Nuria E. Campillo, Ourania Semelidou, Loreto Martínez-González, Lourdes Infantes, Juana María González-Rubio, et al. "Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome." Proceedings of the National Academy of Sciences 114, no. 6 (January 24, 2017): E999—E1008. http://dx.doi.org/10.1073/pnas.1611089114.

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The protein complex formed by the Ca2+ sensor neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor protein Ric8a coregulates synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses, such as fragile X syndrome (FXS), the most common heritable autism disorder. Using crystallographic data and the virtual screening of a chemical library, we identified a set of heterocyclic small molecules as potential inhibitors of the NCS-1/Ric8a interaction. The aminophenothiazine FD44 interferes with NCS-1/Ric8a binding, and it restores normal synapse number and associative learning in a Drosophila FXS model. The synaptic effects elicited by FD44 feeding are consistent with the genetic manipulation of NCS-1. The crystal structure of NCS-1 bound to FD44 and the structure–function studies performed with structurally close analogs explain the FD44 specificity and the mechanism of inhibition, in which the small molecule stabilizes a mobile C-terminal helix inside a hydrophobic crevice of NCS-1 to impede Ric8a interaction. Our study shows the drugability of the NCS-1/Ric8a interface and uncovers a suitable region in NCS-1 for development of additional drugs of potential use on FXS and related synaptic disorders.

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Mosnaim, Aron D., Javier Puente, Rolando Saavedra, Seymour Diamond, and Marion E. Wolf. "In vitro Human Plasma Leucine⁵-Enkephalin Degradation Is Inhibited by a Select Number of Drugs with the Phenothiazine Molecule in Their Chemical Structure." Pharmacology 67, no. 1 (December 4, 2002): 6–13. http://dx.doi.org/10.1159/000066781.

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Lahav, M., H. Rennert, K. Sabag, and D. Barzilai. "Calmodulin inhibitors and 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate do not prevent the inhibitory effect of prostaglandin F2α on cyclic AMP production in isolated rat corpora lutea." Journal of Endocrinology 113, no. 2 (May 1987): 205–12. http://dx.doi.org/10.1677/joe.0.1130205.

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ABSTRACT In the rat corpus luteum, prostaglandin F2α (PGF2α) rapidly inhibits LH-induced cyclic AMP (cAMP) production when given in vivo or to isolated corpora lutea, but not to broken-cell preparations. The suggestion that increased cytosolic calcium concentration mediates PGF2α action was investigated in corpora lutea of pseudopregnancy induced in immature rats by administration of pregnant mare serum gonadotrophin (15 i.u.). Isolated 10-day-old corpora lutea were incubated for 90 min with LH (5 μg/ml), PGF2α (10 μmol/l) and other additions, and cAMP concentration in the tissue was estimated. The putative inhibitor of intracellular calcium release or action, 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8; 30 or 150 μmol/l), did not abolish the effect of PGF2α. Similarly ineffective was the combination of TMB-8 (150 μmol/l) and calcium-depleted medium (free ionized calcium concentration, 30 nmol/l). Calmodulin inhibitors of three different chemical structures were then tested. The phenothiazine trifluoperazine, at 300 as well as 30 μmol/l, did not interfere with the inhibitory effect of PGF2α on cAMP, while suppressing (at 300 μmol/l) progesterone secretion in LH-treated tissue. Furthermore, inhibition by PGF2α was not impaired by pimozide, a diphenylbutylpiperidine (25 and 50 μmol/l) nor by N-(6-aminohexyl)-5-chloro-1-naphthalene sulphonamide (W-7; 15 and 45 μmol/l). In the presence of LH alone, W-7 (45 μmol/l) inhibited and TMB-8 (30 μmol/l augmented cAMP accumulation, indicating that the luteal tissue was effectively exposed to these compounds. Thus, drugs known to inhibit calcium- and calmodulin-dependent processes in a variety of tissues did not abolish the inhibitory action of PGF2α on luteal cAMP production. J. Endocr. (1987) 113, 205–212

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Mason, Nigel J., William J. Geary, Leslie A. Nixon, and Ian W. Nowell. "Interactions between phenothiazine drugs and metal ions. Part 2. Crystal and molecular structure of protonated trichloro[2-chloro-10-(3′-dimethylaminopropyl)phenothiazine-S]palladium(II), [Pd(cpzH)Cl3]; hydrogen-1 and carbon-13 nuclear magnetic resonance data for the chlorpromazine complexes [M(cpzH)Cl3](M = Pd or Pt)." J. Chem. Soc., Dalton Trans., no. 7 (1986): 1347–50. http://dx.doi.org/10.1039/dt9860001347.

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González-González, Alonzo, Lenci K. Vazquez-Jimenez, Alma D. Paz-González, María Laura Bolognesi, and Gildardo Rivera. "Recent Advances in the Medicinal Chemistry of Phenothiazines. New Anticancer and Antiprotozoal Agents." Current Medicinal Chemistry 28 (April 5, 2021). http://dx.doi.org/10.2174/0929867328666210405120330.

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Background: Molecules that have a phenothiazine scaffold have been considered versatile organic structures with a wide variety of biological activities: antipsychotic, anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial, and trypanocidal, among others. First discovered in the 19th century as a histochemical dye, methylene blue, phenothiazine derivatives have been studied, discovering their activities, and repurposing them. Objective: This review is aimed at describing the main synthetic routes of phenothiazines and, particularly, the anticancer and antiprotozoal activities that have been reported during the second decade of the 2000’s (2010-2020) Results: A variety of studies of phenothiazines against cancer and protozoa have revealed that these compounds show IC50 values in the micromolar and near nanomolar range. Structure analyses have revealed that compounds bearing halogens or electron-withdrawing groups at 2-position have favorable anticancer activity. Phenothiazine dyes have shown a photosensitizing activity against trypanosomatids at a micromolar range. Tetra and pentacyclic azaphenothiazines are structures with a high broad-spectrum anticancer activity. Conclusion: The phenothiazine scaffold is favorable for developing of anticancer agents, especially those bearing halogens and electron withdrawing groups bound at 2-position with enhanced biological activities with a variety of aromatic, aliphatic and heterocyclic substituents in the thiazine nitrogen. Further studies are warranted along these investigation lines to attain more active anticancer and antiprotozoal compounds with minimal to negligible cytotoxicity.

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Moschou, Elizabeth A., Nitin Chopra, Santoshkumar L. Khatwani, Jason D. Ehrick, Sapna K. Deo, Leonidas G. Bachas, and Sylvia Daunert. "Stimuli-Responsive Hydrogels Based on the Genetically Engineered Proteins: Actuation, Drug Delivery and Mechanical Characterization." MRS Proceedings 952 (2006). http://dx.doi.org/10.1557/proc-0952-f05-02.

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ABSTRACTHerein, we describe a biomimetic approach aimed at the development of synthetic biohybrid materials inspired by nature's sensing and actuating mechanism of action. The biomaterials are based on the incorporation of the hinge-motion binding protein calmodulin (CaM) and its low affinity ligand phenothiazine (TAPP) within the bulk of an acrylamide hydrogel network, which is accomplished through covalent binding. At the initial state and in the presence of Ca2+ ions, CaM interacts with TAPP creating chemical (non-covalent) cross-links within the bulk of the hydrogel, forcing the material to assume a constrictive configuration. Upon the removal of Ca2+, CaM releases TAPP, breaking the non-covalent cross-links within the bulk of the hydrogel and letting the material relax into a swollen state. The same type of effect is observed when a higher affinity ligand for CaM, like chlorpromazine (CPZ), is employed. In the presence of CPZ, the protein releases TAPP and binds CPZ, allowing the biomaterial to swell into a relaxed state. This swelling response of the biomaterial is reversible, and is directly related to the levels of CPZ used. The sensing and subsequent actuating mechanism of the CaM-based stimuli-sensitive hydrogels makes them suitable for a variety of applications, including sensing, mechanical actuation, high-throughput screening, and drug delivery. Additionally, it is shown that the CaM-based stimuli-sensitive hydrogels developed present unique mechanical properties, suitable for integration within microfluidics and MEMS structures. It is envisioned that these biomaterials will find a number of applications in a variety of fields, including drug delivery.

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Journal articles on the topic 'Phenothiazine drug structure'

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