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At least 19 recordsLinked to original sources
PubMedDate not supplied

Induction of a protective immunity in mice against Escherichia coli by phenothiazines, 10-[n-(phthalimido)alkyl]-2-substituted-10H-phenothiazines and 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazines-10-yl)alkyl-1 -ureas .

Abilities of five phenothiazines, six 10-[n-(phthalimido)alkyl]-2-substituted-10H-phenothiazines and six 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazines-10-yl)alkyl-1- ureas to induce anti-Escherichia coli activity in mice were compared. Seventeen compounds tested in this study had no antibacterial effect in direct contact with Escherichia coli using the disk diffusion method except chlorpromazine (4) with low growth inhibitory action. The pretreatment of mice with several phenothiazines, 10-[n-(phthalimido)alkyl]-2-substituted-10H-phenothiazines or 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazines-10-yl)alkyl-1- ureas protected the animals from lethal infection of Escherichia coli to various extents. On the basis of these experiments, we assume that the protective effect against Escherichia coli infection might be due to the immunopotentiation or macrophage inducing activity by the compounds, or inactivation of lymphokines induced by the bacteria. Since the infection preventing effect of the tested phenothiazines depends on the chemical structures, the specificity of the biological process can be assumed.

Animals↗
PubMedDate not supplied

Radical intensity and differentiation-inducing activity of benzo[a]phenothiazines and phenothiazines.

ESR spectroscopy revealed that 12H-benzo [a]phenothiazine, 9-methyl-12H-benzo[a]phenothiazine, 10-methyl-12H-benzo [a]phenothiazine, 11-methyl-12H-benzo[a]phenothiazine and 5-axo-5H-benzo[a]phenothiazine, which induced the differentiation of human myelogenous leukemic cell lines into maturing macrophages, produced radical(s) under an alkaline condition. On the other hand, 6-hydroxy-5-axo-5H-benzo [a]phenothiazine, 6-methyl-5-oxo-5H-benzo[a]phenothiazine and 5H-benzo[a][1,4]benzothiazino-[3,2-c]phenothiazine, and 13 phenothiazines, which had little or no differentiation-inducing activity, produced no detectable amounts of radical(s). Using Hückel molecular orbital (HMO) method, these active benzo[a]phenothiazines were shown to have the elevated n-spin density at the sulfur atom of their molecules. Seven out of 8 benzo[a]phenothiazines significantly enhanced the radical intensity of sodium L-ascorbate and sodium 5,6-benzylidene-L-ascorbate (SBA), whereas only 3 out of 13 phenothiazines showed similar effects. These data suggest that the induction of human leukemic cell differentiation by benzo[a]phenothiazines might be initiated by radical mediated reactions.

Cell Differentiation↗
PubMed2003

Phenothiazines suppress proliferation and induce apoptosis in cultured leukemic cells without any influence on the viability of normal lymphocytes. Phenothiazines and leukemia.

PURPOSE: The purpose of the present study was to investigate the effects of phenothiazines (at clinically relevant doses) on the viability and proliferation of leukemic cell lines and normal lymphocytes, and to investigate the possibility of specific induction of apoptosis in leukemic cells. METHODS: Phenothiazines with different chemical structure and hydrophobicity were used: chlorpromazine (CPZ); levomepromazine (LVPZ); prometazine (PMZ); trifluoperazine (TFPZ); thioridazine (TRDZ). The leukemic cell lines used were: Daudi and Raji (derived from Burkitt's lymphoma), K-562 (derived from myelogenous leukemia), and BALL-1, MOLT-4, HPB-ALL and CCRF-HSB-2 (derived from acute lymphoblastic leukemia). The cytotoxicity of the phenothiazines was determined by a CellTiter-Glo luminescent cell viability assay, using ATP bioluminescence as a marker of cell viability as well as a marker of mitochondrial activity. The proliferation of leukemic cells was determined using a CellTiter-AQ cell proliferation assay which is based on the reduction of a methyl-tetrazolium compound to the formazan product. Apoptosis induction was estimated using phosphatidylserine (PSer) translocation to the cell surface and DNA fragmentation as characteristics of the process. RESULTS: Phenothiazines (at concentrations in the range 0.1-10 micro M) did not affect the viability of normal lymphocytes during a 24-h incubation. Moreover, about 15-20% increase in ATP bioluminescence was observed in normal cells during treatment with 40 micro M phenothiazines. In contrast, the phenothiazines manifested strong cytotoxicity and antiproliferative activity against leukemic cells. The most powerful drugs were TFPZ and TRDZ, followed by CPZ. They showed a significant cytotoxic effect against leukemic cells even at 5-10 micro M. The most sensitive cell lines were MOLT-4 and Raji, and the most resistant were HPB-ALL and CCRF-HSB-2. All phenothiazines induced PSer exposure on the surface of leukemic cells, but not of normal lymphocytes. TFPZ, TRDZ and CPZ also induced DNA fragmentation in almost all leukemic cell lines during a 48-h incubation. The strongest apoptotic agent was TRDZ. The apoptosis induction was not accompanied by a significant release of cytochrome c from the mitochondria into the cytoplasm of native cells. Moreover, the drugs markedly suppressed Ca(2+)-induced cytochrome c release in isolated mitochondria of leukemic cells. CONCLUSIONS: The results suggest that in clinically relevant doses (up to 20 micro M) some phenothiazines (TFPZ, TRDZ, CPZ) expressed a selective cytotoxicity and antiproliferative activity, and induced apoptosis in leukemic cells without any influence on the viability of normal lymphocytes. It is considered that the mechanism of apoptosis induction in phenothiazine-treated leukemic cells is associated with inhibition of mitochondrial DNA polymerase and decreased ATP production, which are crucial events for the viability of cancer cells.

Adenosine Triphosphate↗
PubMedDate not supplied

Cytotoxicity and differentiation-inducing activity of phenothiazine and benzo[a]phenothiazine derivatives.

The effects of 13 phenothiazines, and 8 benzo[a]phenothiazines on the growth and differentiation of various human cultured cell lines were investigated. Perphenazine dimaleate and chlorpromazine hydrochloride were more cytotoxic against human normal fibroblasts and glioma cells than 19 other related compounds. The differentiation of three human myelogenous leukemic cell lines (ML-1, U-937, THP-1) into maturing monocytes/macrophages was potently induced by 12H- benzo[a]phenothiazine and 5-oxo-5H-benzo[a]phenothiazine. The differentiation--inducing activity of phenothiazine, and other benzo[a]phenothiazine derivatives was much less, and that of phenothiazine derivatives without the benzyl group was undetectable. Simultaneous treatment with 12H- benzo[a]phenothiazine and tumor necrosis factor produced additive, but not synergistic differentiation--induction of these cells.

Cell Differentiation↗
PubMedDate not supplied

Diverse biological activities displayed by phenothiazines, benzo[a]phenothiazines and benz[c]acridins (review).

This review summarizes our experiments which are investigating the relationship between the structure and activity of mainly phenothiazines, benzo[a]phenothiazines and benz[c]acridines. Phenothiazines had potent antiplasmid and antibacterial activities, but induced weak antimicrobial activity in vivo. Their antiplasmid activity seemed to be enhanced by Cl- or CF3- substitution at the 2C position of phenothiazines and modified by the side-chain length and hydrophobicity. Benzo[a]phenothiazines did not show any significant antiplasmid or antibacterial activity, but stimulated the differentiation of human myelogenous leukemic cell lines and natural killing activity of human peripheral blood mononuclear cells in vitro, and induced antimicrobial activity in vivo. Circuit current energy (CRE), circuit current (CC), bond current (BC), diatropic and paratropic properties of benzo[a]phenothiazines might be correlated with their biological activity. Benz[a]acridine showed both in vitro and in vivo antimicrobial activities, and carcinogenic activity for skin tumor. The carcinogenic benz[c]acridines showed out-of-phase in the L-region and their energy was accumulated in the K-region of the molecular orbitals. The results suggest the involvement of different molecular orbitals for the expression of various biological activities by phenothiazines, benzo[a]phenothiazines and benz[c]acridines.

Acridines↗
PubMed1985

Interaction of phenothiazine drugs with human ceruloplasmin. Relation between activation of catecholamine neurotransmitter oxidation and electron donating ability of phenothiazine drugs.

The influence has been studied of 11 phenothiazine drugs on the oxidation of the catecholamine neurotransmitters noradrenaline and dopamine, catalyzed by human ceruloplasmin. The phenothiazine drugs were not transformed by the enzyme. This makes participation of free phenothiazine radical cations in the oxidation of the catecholamines unlikely. A relation between the electron donating capacity of the phenothiazine drugs and the activating effect on the enzyme has been observed. It is proposed that in the interaction of phenothiazine drugs with ceruloplasmin, charge transfer complexes between the phenothiazines and Cu2+ of the enzyme, are involved. The possible relevance of charge transfer complexes as a model for the receptor interactions of phenothiazine drugs is discussed.

Catecholamines↗
PubMedDate not supplied

Induction of anti-Escherichia coli activity in mice by phenothiazines, benzo[a]phenothiazines and benz[c]acridines.

The abilities of 14 phenothiazines, 8 benzo[a]phenothiazines and 12 benz[c]acridines to induce anti-Escherichia coli activity in mice were compared. Pretreatment with several benzo[a]phenothiazines or benz[c]acridines protected mice from lethal infection of Escherichia coli in a dose-dependent manner, whereas most of the phenothiazines induced much weaker anti-Escherichia coli activity. However, direct contact of Escherichia coli with these compounds or their administration just after bacterial inoculation were ineffective. These data suggest the immunopotentiation activity of benzo[a]phenothiazines and benz[c]acridines.

Acridines↗
PubMedDate not supplied

Antimicrobial activity of phenothiazines, benzo[a]phenothiazines and benz[c]acridines.

The abilities of 14 phenothiazines, 8 benzo[a]phenothiazines and 12 benz[c]acridines to induce an antibacterial effect against Escherichia coli K12 were compared. Several phenothiazines, which showed antiplasmid activity, displayed the most potent antibacterial activity. All benz[c]acridine derivatives were moderately antibacterial, whereas benzo[a]phenothiazines were inactive. The active phenothiazine derivatives had more potent inhibitory activity against fungi, including phytopathogen filamentous, human pathogen filamentous fungi and yeasts, than against gram-positive and -negative bacteria. Taken together with previously reported data, the induction mechanism of antimicrobial and antiplasmid activity by these compounds seems to be different from that of antitumor, differentiation-inducing and carcinogenic activity.

Acridines↗
PubMedDate not supplied

Effect of phenothiazines, benzo[a] phenothiazines, benz[c]acridines and Pentaglobin on endotoxin.

The endotoxin neutralizing effects of several phenothiazines, benzophenothiazines and Pentaglobin (control) were investigated by spectrophotometry, tumor necrosis factor (TNF) induction and the conventional Limulus test. In animal experiments, some beneficial effects of complex forming compounds were found, however, the compounds could not completely inactivate the biological effect of endotoxin in the Limulus test. The complex formation between endotoxin and the compounds were revealed in spectrophotometry. The TNF inducing effect of compound-endotoxin complexes was markedly reduced by some phenothiazines and benzo[a]phenothiazines in leukocytes. Benz[c]acridines and Pentaglobin could not neutralize completely the TNF induction of E. coli endotoxin. The recent findings indicate that multifocal effects of phenothiazines and benzophenothiazines can be responsible for anti-endotoxin action in vivo. Hypotensive action in experimental animals was reduced by some phenothiazines in some preliminary experiments.

Acridines↗
PubMed2003

Since phenothiazines alter antibiotic susceptibility of microorganisms by inhibiting efflux pumps, are these agents useful for evaluating similar pumps in phenothiazine-sensitive parasites?

Phenothiazines have activity against Schistosoma mansoni, Trypanosoma brucei, Trypanasoma gambiensi, Molinema dessetae, Leishmania spp., Plasmodium falciparum and free-living protozoa. These organisms and other parasitic infections are prevalent in HIV-infected humans. These infections are becoming more frequently resistant to commonly employed antibiotics, and due to the absence of economic motivation, new and effective compounds against these infections are not anticipated in the near future. Resistance of prokaryotes and eukaryotes to antibiotics is now known to be also due to the presence of efflux pumps that extrude the antibiotic prior to the agent reaching its target. Because phenothiazines are known to inhibit some efflux pumps and therefore alter the susceptibility of the organism to an antibiotic to which it is resistant, and also because of the sensitivity of the above parasites to phenothiazines, efflux pumps may play a role in emerging antibiotic resistance of these organisms. Furthermore, their prevalence is known to be greatest in areas that have high rates of HIV infection; therefore, it would be necessary that these agents should receive close scrutiny. This review concerns the attributes afforded by phenothiazines related to their effective activity against a wide range of parasites. Because these agents are inexpensive and many are no longer protected by patent, they may be exploited as anti-parasitic agents in the poorer areas of the world.

Animals↗
PubMedDate not supplied

Antiplasmid activity of phenothiazines, benzo[a]phenothiazines and benz[c]acridines.

Various synthetic derivatives of phenothiazines, benzo[a]phenothiazines and benz[c]acridines were compared for their abilities to induce antiplasmid activity against E. coli F'lac plasmid. Several phenothiazine derivatives were much more potent in antiplasmid activity than benzo[a]phenothiazine- or benz[c]acridine derivatives. Their antiplasmid activity seemed to be enhanced by Cl- or CF3- substitution at 2 C atom, and modified by the side chain length and charge at the L-region of the molecules, as well as by hydrophilicity.

Acridines↗
PubMedDate not supplied

Immunomodulating activities on cellular cytotoxicity and the blast transformation of human lymphocytes by 10-[n-(phthalimido)alkyl-2-substituted-10H-phenothiazines and 1-(2-chloroethyl)-3-(2-substituted-10 H-phenothiazin-10-yl)alkyl-1-ureas.

Phenothiazines, 10-[n-(phthalimido)alkyl-2-substituted-10H- phenothiazines, and 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alkyl-1- ureas were investigated for their effects on antibody-dependent cellular cytotoxicity (ADCC), natural killer (NK) cells and the blast transformation of human peripheral blood mononuclear cells. All of the compounds dose-dependently suppressed mitogen-stimulated T cell proliferation. In contrast, a strong enhancing effect on NK cell activity was detected mostly in the case of 1-(2-choroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alk yl-1-ureas and their related compounds. The stimulating effect directly influenced the NK cells and was demonstrated at all tested concentrations.

Adjuvants, Immunologic↗
PubMedDate not supplied

Study of the metabolism of phenothiazines: determination of N-demethylated phenothiazines in urine.

When phenothiazine drugs (chlorpromazine, promazine, promethazine, propiomazine, propionylpromazine, trifluoperazine and trimeprazine) were reacted with m-chloroperbenzoic acid, N-demethylated phenothiazines were obtained in moderate yield. The mass spectra of the N-demethylated phenothiazines showed either m/z 44 and 72 or m/z 58 as characteristic ions depending on their side chain. The N-demethylated propiomazine was identified as a metabolite of propiomazine from the urine of a rat which was given propiomazine orally.

Animals↗
PubMed1988

Determination of low levels of phenothiazine sulphoxides in phenothiazine drug substances and formulations by thin-layer chromatography-second-derivative spectrofluorimetry.

A thin-layer chromatographic-second derivative spectrofluorimetric procedure has been developed for low levels of sulphoxide (down to 0.01%, w/w) in phenothiazine drug substances and formulations. The method has been applied to prochlorperazine maleate, chlorpromazine hydrochloride and promethazine hydrochloride. It has also been applied to pharmaceutical formulations of promethazine hydrochloride and comparison of the results with those obtained by a published difference spectrophotometric procedure for promethazine sulphoxide showed that there was good agreement. The method is simple, rapid, accurate and precise and seems to have general application to the determination of low levels of sulphoxide in phenothiazine drug substances or formulations.

Chromatography, Thin Layer↗
PubMedDate not supplied

Immunomodulation activity of phenothiazines, benzo[a]phenothiazines and benz[c]acridines.

Some non-differentiation-induction benzo[a]phenothiazines and mutagenic benz[c]acridines more potently inhibited the mitogen-induced blast transformation of human-peripheral blood lymphocytes than differentiation-induction and non-mutagenic counterparts and phenothiazines. Differential absorption spectrophotometry revealed tight complex formation between these drugs and bacterial endotoxin or mitogens. All of these compounds only slightly affected antibody dependent cellular cytotoxicity and natural killer cell activity, but significantly inhibited the endotoxin-or heat-killed Staphylococcus aureus induced tumor necrosis factor production by human mononuclear cells. Pretreatment of mice with these drugs protected them from lethal E. coli infection. Quantumchemical analysis suggests a correlation between the biological activity of these compounds and some molecular orbital parameters such as the charge at C7, and the ratio of polar/total surface areas.

Acridines↗
PubMed1985

Photoinduced free radicals from chlorpromazine and related phenothiazines: relationship to phenothiazine-induced photosensitization.

Chlorpromazine and several other related phenothiazines are known to cause both phototoxic and photoallergic reactions in the skin and eyes of patients receiving these drugs. While the detailed mechanisms of photosensitization are not known, it is obvious that the first step must be the absorption of light by the drug, its metabolites, or photoproducts, or possibly an induced endogenous chemical. In this review, the free-radical photochemistry of phenothiazines is described, and the evidence for the involvement of photoinduced free radicals in photosensitization is examined. Upon irradiation chlorpromazine yields a variety of free radicals including the corresponding cation radical (via photoionization), the neutral promazinyl radical and a chlorine atom (Cl.) (via homolytic cleavage), and a sulfur-centered peroxy radical. The chlorpromazine cation radical is probably responsible for some of the observed in vitro phototoxic effects of this drug. However, it seems unlikely that the cation radical is involved in phototoxicity in vivo, since photoionization only occurs when chlorpromazine is excited into the S2 level (lambda ex less than 280 nm). The promazinyl radical is a more likely candidate for the phototoxic species both in vivo and in vitro. In addition, this radical can react covalently with proteins and other macromolecules to yield antigens which could be responsible for the photoallergic response to chlorpromazine. Neither oxygen-derived radicals nor singlet oxygen (1O2*), appear to be important in chlorpromazine photosensitization. In contrast, it would seem that promazine-induced phototoxicity may result in part from the generation of superoxide (O2-.).(ABSTRACT TRUNCATED AT 250 WORDS)

Antipsychotic Agents↗
PubMed1992

A kinetic study of the generation and decomposition of some phenothiazine free radicals formed during enzymatic oxidation of phenothiazines by peroxidase-hydrogen peroxide.

A kinetic study of the oxidation of four different phenothiazines (Pts) by peroxidase-hydrogen peroxide was carried out. The free radical formed during the enzymatic oxidation suffers a non-enzymatic breakdown and the overall system was analysed and characterized. The non-enzymatic breakdown of the cation radical does not occur through a disproportionation mechanism but through a more complex mechanism. The kinetic parameters of the overall system were determined for the different Pts. These experimental data may serve in the understanding of the pharmacological action of Pts.

Buffers↗
PubMed1980

Conformationally restricted phenothiazine neuroleptics. 1. 3-(Dimethylamino)-1,2,3,4-tetrahydroazepino[3,2,1-kl]phenothiazine.

A rigid analogue of promazine, 3-(dimethylamino)-1,2,3,4-tetrahydroazepino[3,2,1-kl]phenothiazine (1), was prepared by reductive amination of the corresponding ketone 4. An X-ray crystallographic study revealed that the seven-membered ring of the hydrochloride salt of 1 exists as a half-chair-like form with the dimethylammonium group in an equatorial-like conformation. Compound 1 was approximately one-half as active as promazine as an inhibitor of [3H]spiperone binding in rat corpus striatal homogenates. In homogenates obtained from calf caudate tissue, however, 1 was only about one-twentieth as active as promazine as an inhibitor of [3H] spiperone binding. As a stimulator of homovanilic acid (HVA) synthesis in rat corpus striatum in vivo, it was about one-tenth as active as promazine.

Animals↗