Trifluoperazine Dihydrochloride Research Articles

Effect of EGTA and Trifluoperazine dihydrochloride (TFP) on conidial germination of Marssonina coronaria

Effect of EGTA and Trifluoperazine dihydrochloride (TFP) on conidial germination of Marssonina coronaria

Stonin 2 activates lysosomal-mTOR axis for cell survival in oral cancer

Aberrant expression of various genes is associated with the progression of oral squamous cell carcinoma. Stonin 2, an endocytic protein, has a prominent role in clathrin-associated endocytosis. Its position in oral cancer is still unknown. Here, we report that STON2 expression increases with an increase in the grade of the oral cancer tissue. Further, STON2 overexpressed cells possess a higher rate of proliferation and migraton in oral cancer cells. STON2 helps maintain lysosomal functions by preserving the lysosomal membrane integrity. It activates the Akt-mTOR axis and retains the mTOR on the membrane of the lysosomes. Further, we have identified an inhibitor of STON2, i.e., Trifluoperazine dihydrochloride (TFP), which targets the lysosomal axis by disrupting the Akt-mTOR pathway and causes lysosomal membrane permeabilization. Intererstingly, TFP shows a decrease in cell vaibility on the oral cancer cells and it was observed that cell viability is restored in TFP-treated STON2 overexpressed cells. Moreover, the lysosomal activity and the Akt-mTOR expression are restored in STON2 overexpressed cells co-treated with TFP, establishing TFP targets STON2 to showcase its anti-cancer effects in oral cancer. In conclusion, STON2 might serve as a potential biomarker in oral cancer, and its inhibition could functions as a novel anti-cancer mechanims against oral cancer.

Green Synthesis of Silver Nanoparticles Using Extract of Artemisia absinthium L., Humulus lupulus L. and Thymus vulgaris L., Physico-Chemical Characterization, Antimicrobial and Antioxidant Activity

The novelty of this study is twofold: AgNPs were obtained and characterized using Artemisia absinthium (A. absinthium), Humulus lupulus (H. lupulus), and Thymus vulgaris (T. vulgaris) plants extracts; moreover, a green and environmentally friendly approach for the synthesis of silver nanoparticles (AgNPs) using aqueous extracts was developed. This paper discusses new approaches about the synthesis of AgNPs. T. vulgaris, H. lupulus, and A. absinthium, which are renewable and common plants, perfect as reducing, stabilizing, and capping agent for green synthesis of silver nanoparticles (AgNPs). The extracts and synthesized AgNPs were characterized by various physico-chemical, phytochemical, morphological scanning electron microscope (SEM/EDS) and transmission electron microscope scanning (TEM), and antibacterial activity. The antioxidant activity of extracts and AgNPs were also assessed by 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+), 2,2-diphenyl-1-picrylhydrazyl (DPPH•), cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and trifluoperazine dihydrochloride (TFPH•) scavenging assays. Extracts/AgNPs showed significant antioxidant activity in all cases. A. absinthium/AgNPs, H. lupulus/AgNPs, and T. vulgaris /AgNPs displayed activities against DPPH• (0.14 ± 0.00; 0.11 ± 0.00 and 0.14 ± 0.00 mmol/g), ABTS•+ (0.55 ± 0.05; 0.86 ± 0.05 and 0.55 ± 0.05 mmol/g), respectively. TEM analysis confirmed the average particle size, it estimated t A. absinthium/AgNPs–46 nm, H. lupulus/AgNPs size of synthesized particles was 42 nm and T. vulgaris/AgNPs–48 nm. SEM analysis revealed that T. vulgaris/AgNPs showed in solitary cases as snowflake-like, branched, but in a general spheric shape, H. lupulus/AgNPs were wedge-shaped, and A. absinthium/AgNPs were the spherical shape of the synthesized AgNPs. EDS analysis confirmed the purity of the synthesized AgNPs with a strong signal at 3.2 keV. A. absinthium/AgNPs, H. lupulus/AgNPs, and T. vulgaris/AgNPs exhibited higher antibacterial activity against all tested bacterial strains compared to their respective pure extracts. It is concluded that AgNPs synthesized in extracts have a broad range of biological applications, which can be used as an eco-friendly material without having negative effects on the environment.

Repurposing of antipsychotic trifluoperazine for treating brain metastasis, lung metastasis and bone metastasis of melanoma by disrupting autophagy flux

Targeted therapies and immunotherapy have brought substantial benefits to patients with melanoma. However, brain metastases remain the biggest threat to the survival and quality of life of melanoma patients. One of the major challenges to an effective therapy is the inability of drugs to penetrate the blood-brain barrier (BBB). Anti-schizophrenic drugs can cross the BBB, and many of them have demonstrated anti-cancer effects. Repurposing existing drugs for new clinical indications is an alluring strategy for anticancer drug discovery. Herein, we applied this strategy and screened a small collection of existing anti-schizophrenic drugs to use as anti-melanoma agents. Among them, trifluoperazine dihydrochloride (TFP) exhibited promising potencies for suppressing the growth and metastasis of melanoma, both in vitro and in vivo. TFP obviously suppressed the viability of melanoma cells within the micromolar range and inhibited the growth of melanoma in the subcutaneous mice models. Notably, intraperitoneal (i.p.) administration of TFP (40 mg/kg/day) obviously inhibited the growth of intra-carotid-injection established melanoma brain metastasis and extended the survival of brain metastasis-bearing mice. Moreover, TFP significantly suppressed lung metastasis and bone metastasis of melanoma in preclinical metastasis models. Mechanistically, TFP caused G0/G1 cell cycle arrest and mitochondrial-dependent intrinsic apoptosis of melanoma cells. In addition, TFP treatment increased the expression of microtubule associated protein 1 light chain 3 beta-II (LC3B-II) and p62 in vitro, suggesting an inhibition of autophagic flux. TFP decreased LysoTracker Red uptake after treatment, indicating impaired acidification of lysosomes. Moreover, the colocalization of LC3 with lysosomal-associated membrane protein 1 (LAMP1), a lysosome marker, was also suppressed after TFP treatment, suggesting that TFP might block the fusion of autophagosomes with lysosomes, which led to autophagosome accumulation. Taken together, our data highlight the potential of repurposing TFP as a new adjuvant drug for treating melanoma patients with brain, lung, and bone metastases.

Computational Biology: Toward Early Detection of Pancreatic Cancer.

Pancreatic cancer is the eleventh most common cancer type and the seventh leading cause of cancer mortality globally. Although chemotherapy is widely employed in the treatment of any cancer type, the response rate in pancreatic cancer is very low. Hence, new and effective techniques in the treatment of pancreatic cancer are needed. Recent advances in molecular profiling as well as high-throughput sequencing technologies, for example, next-generation sequencing technologies, have revolutionized the field of cancer research. Protein-protein interaction among cancer and normal cells plays an important role in any cancer molecular mechanisms, and identifying key genes or protein via experimental technologies requires huge expenditures of capital and time. Thus, integrated computational approaches are urgently needed in cancer research. In this review, we discuss different computational approaches developed to detect novel key genes (TRIM24, CDK14, ECT2 and PSRC1), miRNA (e.g., miR-424, miR-203, miR-1266, miR-1293, and miR-4772), and pancreatic cancer drugs (e.g., trifluoperazine dihydrochloride and trifluoperazine). In the near future, the information presented here will be highly useful in the early diagnosis as well as treatment of pancreatic malignancy.

Ruthenium(II)-N-alkyl phenothiazine complexes as potential anticancer agents.

In recent years, the search for effective anticancer compounds based on transition metal complexes has been the focus of medical investigations. The synergy between the ruthenium(II) and N-alkylphenothiazine counter-ions (chlorpromazine hydrochloride, thioridazine hydrochloride and trifluoperazine dihydrochloride, respectively) through the formation of three different complexes (1-3) was investigated. We explored whether the selected counter-ions and complexes might affect redox homeostasis and genome integrity of normal human blood cells, and induce an inhibition of Na+/K+-ATPase and AChE at pharmacologically relevant doses. Our results have shown that counter-ions and complexes did not affect the activity of Na+/K+-ATPase, while AChE activity was inhibited in a dose-dependent manner. All investigated compounds disturbed the viability and redox homeostasis of lymphocytes. Complexes 1 and 2 displayed potent cytotoxic and prooxidant action while complex 3 behaved as a weaker genotoxic inducer. Still, the tested complexes appeared to be less genotoxic and more cytostatic than the corresponding counter-ions. The effects of selected complexes were also tested in PC12 and U2OS cancer cells with special attention being given to the ability of phenothiazines to affect dopamine D2 receptors. Using the confocal laser scanning microscopy, we observed that all the complexes reduced cell viability. Although all investigated complexes have been bound to the dopamine receptor D2-eGFP, only complex 3 reduced its surface density and increased its lateral mobility in investigated cell lines. Albeit the role of alternative targets for complex 3 cannot be ruled out, its effects should be further examined as potential treatment strategy against cancer cells that overexpress D2.

Transcriptome Analyses Shed New Insights into Primary Metabolism and Regulation of Blumeria graminis f. sp. tritici during Conidiation.

Conidia of the obligate biotrophic fungal pathogen Blumeria graminis f. sp. tritici (Bgt) play a vital role in its survival and rapid dispersal. However, little is known about the genetic basis for its asexual reproduction. To uncover the primary metabolic and regulatory events during conidiation, we sequenced the transcriptome of Bgt epiphytic structures at 3 (vegetative hyphae growth), 4 (foot cells initiation), and 5 (conidiophore erection) days post-inoculation (dpi). RNA-seq analyses identified 556 and 404 (combined 685) differentially expressed genes (DEGs) at 4 and 5 dpi compared with their expression levels at 3 dpi, respectively. We found that several genes involved in the conversion from a variety of sugars to glucose, glycolysis, the tricarboxylic acid cycle (TAC), the electron transport chain (ETC), and unsaturated fatty acid oxidation were activated during conidiation, suggesting that more energy supply is required during this process. Moreover, we found that glucose was converted into glycogen, which was accumulated in developing conidiophores, indicating that it could be the primary energy storage molecule in Bgt conidia. Clustering for the expression profiles of 91 regulatory genes showed that calcium (Ca2+), H2O2, and phosphoinositide (PIP) signaling were involved in Bgt conidiation. Furthermore, a strong accumulation of H2O2 in developing conidiophores was detected. Application of EGTA, a Ca2+ chelator, and trifluoperazine dihydrochloride (TFP), a calmodulin (CaM) antagonist, markedly suppressed the generation of H2O2, affected foot cell and conidiophore development and reduced conidia production significantly. These results suggest that Ca2+ and H2O2 signaling play important roles in conidiogenesis and a crosslink between them is present. In addition to some conidiation-related orthologs known in other fungi, such as the velvet complex components, we identified several other novel B. graminis-specific genes that have not been previously found to be implicated in fungal conidiation, reflecting a unique molecular mechanism underlying asexual development of cereal powdery mildews.

Liraglutide restores angiogenesis in palmitate-impaired human endothelial cells through PI3K/Akt-Foxo1-GTPCH1 pathway

Glucagon-like peptide-1 (GLP-1) and its analogues have a beneficial role in cardiovascular system. Here, we aimed to investigate whether liraglutide, a GLP-1 analogue, modulated angiogenesis impaired by palmitic acid (PA) in cultured human umbilical vein endothelial cells (HUVECs). Cells were incubated with liraglutide (3–100 nmol/L) in the presence of PA (0.5mmol/L), and endothelial tube formation was observed and quantified. The protein levels of signaling molecules were analyzed and the specific inhibitors were used to identify the signaling pathways through which liraglutide affected angiogenesis. Results showed that liraglutide ameliorated endothelial tube formation impaired by PA in HUVECs in a dose-dependent manner. Meanwhile, liraglutide increased the phosphorylation of Akt and forkhead box O1 (Foxo1), and upregulated the levels of guanosine 5′-triphosphate cyclohydrolase 1 (GTPCH1) and endothelial nitric oxide synthase (eNOS) in PA-impaired HUVECs. Notably, addition of the PI3K inhibitor LY294002, Foxo1 nuclear export inhibitor trifluoperazine dihydrochloride (TFP), GTPCH1 inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP) or NOS inhibitor N-nitro-l-arginine-methyl ester (L-NAME) eliminated the angiogenic effect of liraglutide. Moreover, either LY294002 or TFP abolished the liraglutide-induced upregulation of GTPCH1 and eNOS protein levels. In conclusion, liraglutide restores angiogenesis in PA-impaired HUVECs. The effect is mediated via upregulation of GTPCH1 and eNOS levels in a PI3K/Akt-Foxo1-dependent mechanism.

Phenothiazines solution complexity – Determination of pKa and solubility-pH profiles exhibiting sub-micellar aggregation at 25 and 37 °C

The ionization constants (pKa) and the pH-dependent solubility (log S-pH) of six phenothiazine derivatives (promazine hydrochloride, chlorpromazine hydrochloride, triflupromazine hydrochloride, fluphenazine dihydrochloride, perphenazine free base, and trifluoperazine dihydrochloride) were determined at 25 and 37°C. The pKa values of these low-soluble surface active molecules were determined by the cosolvent method (n-propanol/water at 37°C and methanol/water at 25°C). The log S-pH profiles were measured at 24h incubation time in 0.15M phosphate buffers. The log S-pH “shape-template” method, which critically depends on accurate pKa values (determined independently of solubility data), was used to propose speciation models, which were subsequently refined by rigorous mass-action weighted regression procedure described recently. Differential scanning calorimetry (DSC), UV–visible spectrophotometry, potentiometric, and high performance liquid chromatography (HPLC) measurements were used to characterize the compounds. The intrinsic solubility (S0) values of the three least-soluble drugs (chlorpromazine·HCl, triflupromazine·HCl, and trifluoperazine·2HCl) at 25°C were 0.5, 1.1, and 2.7μg/mL (resp.). These values increased to 5.5, 9.2, and 8.7μg/mL (resp.) at the physiological temperature. The enthalpies of solution for the latter compounds were exceptionally high positive (endothermic) values (99–152kJ·mol−1). Cationic sub-micellar aggregates were evident (from the distortions in the log S-pH profiles) for chlorpromazine, fluphenazine, perphenazine, and trifluoperazine at 25°C. The effects persisted at 37°C for chlorpromazine and trifluoperazine. The solids in suspension were apparently amorphous in cases where the drugs were introduced as the chloride salts.

Extraction-Free Ion-Pair Methods for the Assay of Trifluoperazine Dihydrochloride in Bulk Drug, Tablets, and Spiked Human Urine Using Three Sulfonphthalein Dyes

Three simple and sensitive extraction-free spectrophotometric methods are described for the determination of trifluoperazine dihydrochloride (TFH). The methods are based on ion pair complex formation between the nitrogenous compound trifluoperazine (TFP) converted from trifluoperazine dihydrochloride and sulfonphthalein dyes, namely, bromocresol green (BCG), bromothymol blue (BTB), and bromophenol blue (BPB) in dichloromethane medium in which all the above experimental variables were circumvented. The colored products are measured at 425 nm in the BCG method, 415 nm in the BTB method, and 420 nm in the BPB method. The stoichiometry of the ion-pair complexes formed between the drug and dye (1:1) was determined by Job’s continuous variations method, and the stability constants of the complexes were also calculated. These methods quantify TFP over the concentration ranges of 1.25–20.0 μg/ml in the BCG method, 1.5–21.0 μg/ml in the BTB method, and 1.5–18.0 μg/ml in the BPB method. The molar absorptivity (l·mol–1·cm–1) and Sandell sensitivity (ng/cm2) were calculated to be 2.06·104 and 0.0197; 1.82·104 and 0.0224; and 2.22·104 and 0.0183 for the BCG, BTB, and BPB methods, respectively. The methods were successfully applied to the determination of TFP in pure drug, pharmaceuticals, and in spiked human urine with good accuracy and precision.

Interaction of an Amphiphilic Drug Trifluoperazine Dihydrochloride with Pluronic Triblock Copolymers: A Physicochemical Study

In the present study, we report the interactional behavior of the phenothiazine drug trifluoperazine dihydrochloride (TFP) with Pluronics (L64, F68, and P123) using surface tension, cloud point and fluorescence measurements. Various micellar and interfacial parameters such as critical micellization concentration (cmc), interaction parameter (β), effectiveness of surface tension reduction (πcmc), maximum surface excess concentration (Γmax), and minimum area per molecule (Amin) at the air–water interface have been evaluated using surface tension technique. The phase separation behavior of the drug is studied in the presence of Pluronics, and the corresponding thermodynamic parameters such as Gibbs free energy (ΔG°c), standard enthalpy (ΔH°c), and entropy (TΔS°c) of clouding have been calculated. Employing the steady state fluorescence measurements, the interactions between the drug and Pluronics have been determined in terms of the number of binding sites for drug molecules (n), binding constants (Ka), and Stern–Volmer quenching constants (Ksv).

Field-amplified sample injection coupled with pseudo-isotachophoresis technique for sensitive determination of selected psychiatric drugs in human urine samples after dispersive liquid–liquid microextraction

A field-amplified sample injection (FASI) technique was elaborated for fast and sensitive determination of selected central nervous system drugs in human urine samples. Factors affecting the sensitivity enhancement, such as background electrolyte (BGE) and the analytical matrix composition were optimized and discussed. Pseudo-isotachophoresis (p-ITP) mechanism contribution in preconcentration mechanism was discussed. All separations were performed in uncoated fused silica capillaries 50μm×57cm at 22kV. The optimized analytical matrix was composed of 0.25mM HCOOH in 90% (v/v) methanol, while BGE contained 45mM TRIS/HCl (pH 2.20). The head-column injection was performed in 0.25mM HCOOH water solution (3s, 3.45kPa). Sample was introduced into the capillary by electrokinetic injection (70s, 5kV) followed by short BGE plug (3s, 3.45kPa). Seven psychiatric drugs (olanzapine, prochlorperazine dimaleate, trifluoperazine dihydrochloride, perphenazine, promazine hydrochloride, clomipramine hydrochloride, and chlorprothixene hydrochloride) were separated in about 6min. The elaborated method was additionally supported with dispersive liquid–liquid microextraction (DLLME) technique which in summary with FASI provided about 8000–13,000-fold sensitivity enhancement in comparison to the capillary zone electrophoresis (CZE) method with standard hydrodynamic injection (5s, 3.45kPa).

Platinum(IV) complexes with N-alkylphenothiazines: synthesis, characterization, and antibacterial activity

Two new platinum(IV) complexes (1, trifluoperazinehydrochloride-aquapentachloridoplatinate(IV) and 2, chlorpromazine-chlorpromazinehydrochloridepentachloridoplatinate(IV)) were synthesized in the reaction of K2[PtCl6] with trifluoperazine dihydrochloride (TF·2HCl) or chlorpromazine hydrochloride (CP·HCl). The complexes were characterized by elemental analysis, molar conductivity measurement, and spectral (IR, 1H, 13C, 2D 1H–13C heteronuclear correlation spectra, 195Pt NMR, and MS) methods. Outer-coordination sphere was proposed for 1; while in 2, the ligand was coordinated to the metal. The complexes exhibit antibacterial effect on strains of Bacillus subtilis, Bacillus cereus, Bacillus pumilus, and methicillin-resistant Staphylococci as Gram-positive bacteria and an Escherichia coli as Gram-negative bacteria, as well as the reference strains.

Extractive spectrophotometric determination of chlorpromazine and trifluoperazine hydrochloride in pharmaceutical preparations

A simple, accurate, and rapid extraction spectrophotometric procedure has been developed for the determination of some phenothiazine drugs such as chlorpromazine hydrochloride (CPH) and trifluoperazine dihydrochloride (TFPH) in pure form and their pharmaceutical preparations. The procedures are based on the reaction between the examined drugs (CPH and TFPH) and Alizarin Red S (AR), Bromocresol Purple (BCP), Chlorophenol Red (CPR) and Cresol Red (CR) producing ion-pair complexes which can be measured at the optimum wavelengths. The optimizations of the reaction conditions were investigated. Beer’s law is obeyed in the concentration ranges 1.77–96μgml−1. The molar absorptivity and Sandell sensitivity are also calculated. The correlation coefficient for both drugs was ⩾0.9995 (n=5) with a relative standard deviation (R.S.D.) ⩽0.38. The methods are successfully applied to determine CPH and TFPH in pharmaceutical formulations.

An investigation of binding ability of ionic surfactants with trifluoperazine dihydrochloride: insights from surface tension, electronic absorption and fluorescence measurements

This work deals with the effect of the ionic surfactants, sodium dodecylsulphate (SDS), dioctylsulphosuccinate sodium salt (AOT), dodecyltrimethylammonium bromide (DTAB) and didodecyldimethylammonium bromide (DDAB), on the physicochemical properties of the antidepressant phenothiazine drug, trifluoperazine dihydrochloride (TFP). Surface tension, fluorescence and electronic absorption measurements have been done in order to study the nature of interactions between drug–ionic surfactant mixtures. Various interfacial, micellar, spectroscopic and corresponding thermodynamic parameters have been calculated from these techniques. The values of the interaction parameter (β) suggest that cationic surfactants exhibit less synergistic interactions with TFP compared to anionic surfactants. To confirm this we further performed fluorescence quenching and electronic absorption titrations of ionic surfactants with TFP. Anionic surfactants (SDS, AOT) have been observed to bind preferentially with TFP over cationic surfactants (DTAB, DDAB), which supports the presence of a cationic charge on the head group of the drug and signifies that anionic surfactants can act as better drug-carriers than cationic surfactants even at very low concentrations. The blue shift and decrease in fluorescence intensity observed in fluorescence quenching methods for TFP + SDS/AOT mixtures confirms the formation of a new complex between interacting species. Also the number of binding sites for drug molecule has been estimated, which helps to give an insight into the mechanism of the drug–surfactant complexes formed. The results indicate that among electrostatic, hydrophobic and van der Waals forces, the former ones are the predominant intermolecular forces between TFP and ionic surfactants.

Thermal decomposition of new chlorido(p-cymene) ruthenium(II) complexes containing N-alkylphenothiazines

The thermal decomposition of [RuCl2(η6-p-cymene)]2 (1) and its biologically active N-alkylphenothiazine compounds of composition L[RuCl3(η6-p-cymene)] where L = CPH+ (2), TFH+·HCl (3), and TRH+ (4) (chlorpromazine hydrochloride, CP·HCl; trifluoperazine dihydrochloride, TF·2HCl; and thioridazine hydrochloride, TR·HCl, respectively) has been studied. The crystal and molecular structure of compound 3 was determined earlier by single crystal X-ray diffraction analysis. The thermal data were collected by simultaneous TG/DSC measurements. For evolved gas detection, the qualitative reaction of chlorides with AgNO3 in an acidic solution was applied. The measurements were carried out in the temperature range to 700 °C in nitrogen atmosphere. Compounds of L[RuCl3(η6-p-cymene)] crystallize with water or water/2-propanole. On the basis of thermal data, the trend in the solvent bonding energies was assessed.

Solubility and pKa determination of six structurally related phenothiazines

Solubilities of six structurally related phenothiazines, namely chlorpromazine hydrochloride, fluphenazine dihydrochloride, promazine hydrochloride, thioridazine hydrochloride, trifluoperazine dihydrochloride, and triflupromazine hydrochloride at constant pH were measured in the temperature range from 290K to 350K in three important drugs solvents: water, ethanol and 1-octanol using the dynamic method and UV–vis method. Dissociation constants and corresponding pKa values of drugs were obtained with Bates–Schwarzenbach method at temperature 298.15K in the buffer solutions. Our experimental pKa values for chlorpromazine hydrochloride, fluphenazine dihydrochloride, promazine hydrochloride, thioridazine hydrochloride, trifluoperazine dihydrochloride, and triflupromazine hydrochloride are 9.15, 10.01, 9.37, 8.89, 8.97, and 9.03, respectively. The basic thermal properties of pure drugs i.e. melting and solid–solid phase transition as well as glass-transition temperatures, the enthalpy of melting and phase transitions and the molar heat capacity at glass transition (at constant pressure) were measured with differential scanning microcalorimetry (DSC) technique. Molar volumes were calculated with Barton group contribution method. The experimental solubility data were correlated by means of three commonly known GE equations: the Wilson, NRTL and UNIQUAC with the assumption that the systems studied here have revealed simple eutectic mixtures. The root-mean-square deviations of temperature were used for the precision of the correlation. The activity coefficients of drugs at saturated solutions in each correlated binary mixture were calculated from the experimental data. These new data will help in all prediction-methods and their precision.

Synthesis, structural and spectroscopic characterization, in vitro cytotoxicity and in vivo activity as free radical scavengers of chlorido( p-cymene) complexes of ruthenium(II) containing N-alkylphenothiazines

Three new ruthenium(II) complexes 1– 3 containing N-alkylphenothiazine molecules were synthesized by reaction of [RuCl 2(η 6- p-cymene)] 2 with chlorpromazine hydrochloride ( 1), trifluoperazine dihydrochloride ( 2) or thioridazine hydrochloride ( 3). The compounds of the general formula L[RuCl 3(η 6- p-cymene)] were characterized by elemental analysis and spectroscopic methods (FT-IR, UV–Vis, 1H and 13C NMR). Complex 2 was structurally characterized by single crystal X-ray diffraction. In vitro cytotoxic activity of complexes 1– 3 were assayed in four human carcinoma cell lines MCF-7, MDA-MB-453 (breast carcinoma), SW-480 (colon carcinoma) and IM9 (myeloma multiple cells). The highest cytotoxicity (12.1 ≤ IC 50 ≤ 17.3 μM) and induced a total (SW-480) or almost total cell death (MCF-7, MDA-MB-453) at 25 μM in 48 h of treatment were observed for complex 2. The influence of three different doses (0.4, 4.5 and 90.4 μM/kg bw) of complex 2 on activities of antioxidants enzymes (superoxide dismutase (SOD) and catalase (CAT)) and lactate dehydrogenase (LDH) were investigated under physiological conditions. The effects on nitrite production ( NO 2 − ) and level of erythrocytes malondialdehyde (MDA) in rats blood were evaluated, too.

Thermal decomposition of new ruthenium(II) complexes containing N-alkylphenothiazines

Thermal decomposition of chlorpromazine hydrochloride (CPHCl), trifluoperazine dihydrochloride (TF� 2HCl) and thioridazine hydrochloride (TRHCl), and the ruthenium complexes with dimethyl sulfoxide (dmso) of composition (RuCl2(dmso)4) and L(RuCl3(dmso)3)� xEtOH, L = CPHCl, TF� 2HCl or TRHCl is described. The phe- nothiazines are stable to temperature range of 200-280 C with an increasing stability order of TF� 2HCl \ CPHCl \ TRHCl. The decomposition of all the com- pounds takes place in superposing steps. For detection of chlorides and sulfides, EGD analysis was performed. The decomposition pattern of the complexes, due to their similar structure, is similar. The thermal data unambiguously resolve the contradiction between the elemental analysis and X-ray structural data for (TF� 2HCl)(RuCl3(dmso)3)ClEtOH. The compound crystallizes with one EtOH, evaporating in part at room temperature.

Evaluation of Peakmaster for computer‐aided multivariate optimisation of a CE separation of 17 antipsychotic drugs using minimal experimental data

The computer-assisted development of a CE method for compliance monitoring of a group of 17 antipsychotic drugs (chlorpromazine hydrochloride, clozapine, droperidol, flupenthixol dihydrochloride, fluphenazine dihydrochloride, haloperidol, pimozide, thioridazine hydrochloride, trifluoperazine dihydrochloride, prochlorperazine dimaleate, amisulpride, aripiprazole, olanzapine, quetiapine fumarate, risperidone, ziprasidone, and zuclopenthixol dihydrochloride) was performed. Peakmaster, a free simulation program for CE, was employed in a multivariate optimisation approach to determine suitable BGE conditions with minimal experimentation. However, analyte input parameters (pK(a) and limiting ionic mobility) were not included within the software and required determination. Limiting ionic mobility was determined experimentally, while pK(a) values were calculated using ACD Labs software. A modified chromatographic response factor, which identified the BGE providing the greatest resolution between each pair of peaks within 10 min, was used and determined a pH 2.5 and an ionic strength of 50 mM as optimal. Marked disparities were apparent between experimentally determined and computer-simulated results, due to error associated with pK(a) values calculated using ACD Labs. These results confirm that Peakmaster analyses are highly sensitive to pK(a) values, especially where the pH of the BGE is in the proximity of the analyte pK(a); but also that Peakmaster does allows a rational approach to dramatically reduce the amount of experimental work required for multivariate optimisation of conditions for CE.