-
Journal of Biomolecular NMR Jul 2021We used NMR to show that the antipsychotic phenothiazine drugs promazine and promethazine bind to GDP-KRAS. Promazine also binds to oncogenic GDP-KRAS(G12D), and to wild...
We used NMR to show that the antipsychotic phenothiazine drugs promazine and promethazine bind to GDP-KRAS. Promazine also binds to oncogenic GDP-KRAS(G12D), and to wild type GppNHp-KRAS. A panel of additional phenothiazines bind to GDP-KRAS but with lower affinity than promazine or promethazine. Binding is most dependent on substitutions at C-2 of the tricyclic phenothiazine ring. Promazine was used to generate an NMR-driven HADDOCK model of the drug/GDP-KRAS complex. The structural model shows the tricyclic phenothiazine ring of promazine associates with the hydrophobic pocket p1 that is bordered by the central β sheet and Switch II in KRAS. Binding appears to stabilize helix 2 in a conformation that is similar to that seen in KRAS bound to other small molecules. Association of phenothiazines with KRAS may affect normal KRAS signaling that could contribute to multiple biological activities of these antipsychotic drugs. Moreover, the phenothiazine ring represents a new core scaffold on which to design modulators of KRAS activity.
Topics: Amino Acid Substitution; Antipsychotic Agents; Humans; Models, Molecular; Mutation, Missense; Nuclear Magnetic Resonance, Biomolecular; Phenothiazines; Protein Binding; Protein Conformation, beta-Strand; Proto-Oncogene Proteins p21(ras)
PubMed: 34176062
DOI: 10.1007/s10858-021-00371-z -
Analytical Chemistry Oct 2023The uncontrollable distribution of antitumor agents remains a large obstacle for specific and efficient cancer theranostics; thus, efficient construction of...
The uncontrollable distribution of antitumor agents remains a large obstacle for specific and efficient cancer theranostics; thus, efficient construction of tumor-specific systems is highly desirable. In this work, a general design of tumor stimulus-activatable pretheranostic agents was put forward via a series of structures-tunable triphenylamine derivatives (, , and ) with phenothiazine, benzothiazine, and thiomorpholine as identifying groups of hypochlorite (HClO), respectively. Notably, the sulfur atom in phenothiazine of was more easily oxidized to sulfoxide groups by HClO, transforming into an electron acceptor to form an excellent push-pull electronic system, which was beneficial to a large redshift of absorbance and emission wavelengths. Based on this, resorted to a key of overexpressed HClO in the tumor to open "three locks", viz, NIR fluorescence, photothermal, and photoacoustic signals for multimodal diagnostic and treatment of the tumor. This study provided an elegant design to adopt tumor stimulus-triggerable pretheranostic for improving theranostic accuracy and efficiency, which was regarded as a promising candidate for precision medicine.
Topics: Humans; Neoplasms; Antineoplastic Agents; Phenothiazines; Theranostic Nanomedicine; Phototherapy; Nanoparticles
PubMed: 37824749
DOI: 10.1021/acs.analchem.3c02777 -
Neuroscience and Biobehavioral Reviews Oct 2022Over a century ago, the phenothiazine dye, methylene blue, was discovered to have both antipsychotic and anti-cancer effects. In the 20th-century, the first... (Review)
Review
Over a century ago, the phenothiazine dye, methylene blue, was discovered to have both antipsychotic and anti-cancer effects. In the 20th-century, the first phenothiazine antipsychotic, chlorpromazine, was found to inhibit cancer. During the years of elucidating the pharmacology of the phenothiazines, reserpine, an antipsychotic with a long historical background, was likewise discovered to have anti-cancer properties. Research on the effects of antipsychotics on cancer continued slowly until the 21st century when efforts to repurpose antipsychotics for cancer treatment accelerated. This review examines the history of these developments, and identifies which antipsychotics might treat cancer, and which cancers might be treated by antipsychotics. The review also describes the molecular mechanisms through which antipsychotics may inhibit cancer. Although the overlap of molecular pathways between schizophrenia and cancer have been known or suspected for many years, no comprehensive review of the subject has appeared in the psychiatric literature to assess the significance of these similarities. This review fills that gap and discusses what, if any, significance the similarities have regarding the etiology of schizophrenia.
Topics: Antipsychotic Agents; Chlorpromazine; Humans; Methylene Blue; Neoplasms; Phenothiazines; Reserpine; Schizophrenia
PubMed: 35970416
DOI: 10.1016/j.neubiorev.2022.104809 -
Veterinary Anaesthesia and Analgesia Mar 2021To evaluate the effects of incremental doses of acepromazine on hemodynamics in isoflurane-anesthetized dogs.
OBJECTIVE
To evaluate the effects of incremental doses of acepromazine on hemodynamics in isoflurane-anesthetized dogs.
STUDY DESIGN
Prospective, experimental study.
ANIMALS
Healthy, adult, mixed-breed dogs (two male and four female) weighing 16.8 ± 5.1 kg (mean ± standard deviation).
METHODS
Dogs were anesthetized with propofol (7 mg kg) intravenously (IV) and isoflurane. Thermodilution and arterial catheters were placed for hemodynamic monitoring and arterial blood sampling for blood gas analysis. Baseline measurements were performed with stable expired concentration of isoflurane (Fe'Iso) at 1.8%. Each dog was then administered four incremental acepromazine injections (10, 15, 25 and 50 μg kg) IV, and measurements were repeated 20 minutes after each acepromazine injection with Fe'Iso decreased to 1.2%. The four acepromazine injections resulted in cumulative doses of 10, 25, 50 and 100 μg kg (time points ACP, ACP, ACP and ACP, respectively).
RESULTS
Compared with baseline, cardiac index (CI) increased significantly by 34%, whereas systemic vascular resistance index (SVRI) decreased by 25% at ACP and ACP. Arterial oxygen content (CaO) was significantly lower than baseline after all acepromazine injections (maximum decreases of 11%) and was lower at ACP and ACP than at ACP. No significant change was found in heart rate, stroke index, oxygen delivery index and systolic, mean and diastolic blood pressures. Hypotension (mean arterial pressure < 60 mmHg) was observed in one dog at baseline, ACP, ACP and ACP, and in two dogs at ACP.
CONCLUSIONS AND CLINICAL RELEVANCE
Compared with isoflurane alone, anesthesia with acepromazine-isoflurane resulted in increased CI and decreased SVRI and CaO values. These effects were dose-related, being more pronounced at ACP and ACP. Under the conditions of this study, acepromazine administration did not change blood pressure.
Topics: Acepromazine; Animals; Blood Pressure; Cross-Over Studies; Dogs; Female; Heart Rate; Hemodynamics; Isoflurane; Male; Prospective Studies
PubMed: 33388251
DOI: 10.1016/j.vaa.2020.11.003 -
Anticancer Research Nov 2016Thioridazine (TZ), an antipsychotic drug, renders multidrug-resistant (MDR) cancer cells susceptible to cytotoxic agents to which they were initially resistant, has... (Review)
Review
Thioridazine (TZ), an antipsychotic drug, renders multidrug-resistant (MDR) cancer cells susceptible to cytotoxic agents to which they were initially resistant, has anti-prolilferative activity and apoptosis-inducing properties in various tumor cell lines and cancer stem cells. Whereas the anti-proliferative activity takes place at high concentrations that ensure the intercalation of the compound between nucleic bases (especially rich in G/C bases), much lower concentrations inhibit the export function of the ABCB1 (P-glycoprotein), which is responsible for the MDR phenotype of the cancer cell. The co-administration of TZ with doxorubicin inhibits efflux of doxorubicin and, hence, increases the intracellular concentration of anticancer drug. The (+) and (-) enantiomers of TZ have the same activities as TZ. The main focus of this review is to present extensive evidence provided by our work, confirmed by much later studies, as it supports adjuvant use of TZ with an anticancer drug for MDR cancer therapy.
Topics: Antineoplastic Agents; Antipsychotic Agents; Apoptosis; DNA Damage; Drug Resistance, Neoplasm; Humans; Neoplasms; Phenothiazines; Thioridazine
PubMed: 27793891
DOI: 10.21873/anticanres.11153 -
Bioorganic Chemistry Jul 2024Ferroptosis is a novel style of cell death, and studies have shown that ferroptosis is strongly associated with spinal cord injury (SCI). A large number of ferroptosis...
Ferroptosis is a novel style of cell death, and studies have shown that ferroptosis is strongly associated with spinal cord injury (SCI). A large number of ferroptosis inhibitors have been reported, but so far no ferroptosis inhibitor has been used clinically. Therefore there is an urgent need to discover a better inhibitor of ferroptosis. In this study, 24 novel sulfonamide phenothiazine ferroptosis inhibitors were designed and synthesized, followed by structure-activity relationship studies on these compounds. Among them, compound 23b exhibited the best activity in Erastin-induced PC12 cells (EC = 0.001 μM) and demonstrated a low hERG inhibition activity (IC > 30 μM). Additionally, compound 23b was identified as a ROS scavenger and showed promising therapeutic effects in an SD rat model of SCI. Importantly, 23b did not display significant toxicity in both in vivo and in vitro experiments and show good pharmacokinetic properties. These findings suggest that compound 23b, a novel ferroptosis inhibitor, holds potential as a therapeutic agent for spinal cord injury and warrants further investigation.
Topics: Animals; Spinal Cord Injuries; Rats; Structure-Activity Relationship; Ferroptosis; Drug Design; Phenothiazines; Sulfonamides; PC12 Cells; Molecular Structure; Rats, Sprague-Dawley; Dose-Response Relationship, Drug; Humans; Male
PubMed: 38788362
DOI: 10.1016/j.bioorg.2024.107458 -
Journal of Enzyme Inhibition and... Dec 2023Carbonic anhydrases (CAs) are important regulators of pH homeostasis and participate in many physiological and pathological processes. CA activators (CAAs) are becoming...
Antihistamines, phenothiazine-based antipsychotics, and tricyclic antidepressants potently activate pharmacologically relevant human carbonic anhydrase isoforms II and VII.
Carbonic anhydrases (CAs) are important regulators of pH homeostasis and participate in many physiological and pathological processes. CA activators (CAAs) are becoming increasingly important in the biomedical field since enhancing CA activity may have beneficial effects at neurological level. Here, we investigate selected antihistamines, phenothiazine-based antipsychotics, and tricyclic antidepressants (TCAs) as potential activators of human CAs I, II, IV, and VII. Our findings indicate that these compounds are more effective at activating hCA II and VII compared to hCA I and IV. Overall, hCA VII was the most efficiently activated isoform, particularly by phenothiazines and TCAs. This is especially relevant since hCA VII is the most abundant isoform in the central nervous system (CNS) and is implicated in neuronal signalling and bicarbonate balance regulation. This study offers additional insights into the pharmacological profiles of clinically employed drugs and sets the ground for the development of novel optimised CAAs.
Topics: Humans; Antipsychotic Agents; Antidepressive Agents, Tricyclic; Carbonic Anhydrases; Protein Isoforms; Phenothiazines; Histamine Antagonists; Carbonic Anhydrase Inhibitors; Structure-Activity Relationship; Molecular Structure
PubMed: 36912265
DOI: 10.1080/14756366.2023.2188147 -
Journal of Molecular Modeling Aug 2015Ommochromes are colored substances that apparently function as biological signals among arthropods and insects. These substances may prevent oxidative stress by...
Ommochromes are colored substances that apparently function as biological signals among arthropods and insects. These substances may prevent oxidative stress by scavenging free radicals. Two principal mechanisms exist for scavenging free radicals: the electron transfer and hydrogen atom transfer. In this investigation, a theoretical study of the antiradical capacity of five ommochromes was performed within the density functional theory framework. Vertical ionization energy and vertical electron affinity were used to study the electron transfer mechanism between ommochromes and four free radicals: CH3O•, NO2•, HO•, and HOO•. For the hydrogen transfer mechanism, dissociation energy (D0) and Gibbs free energy were calculated, taking into account hydrogen atoms at different positions in the ommochromes. Both mechanisms are thermodynamically possible. The best antiradical is ommatin D. The UV/VIS spectra for ommochromes were obtained with ommatin D registering as the ommochrome with the greatest λmax value. In summary, ommatin D is the best antiradical and also the redder molecule. These results are important and may help to elucidate the function of these molecules in the animal kingdom. Graphical abstract Ommochromes are red and yellow substances present in arthropods and insects. According with computational chemistry, these substances present the capacity of prevent oxidative stress since they scavenge free radicals. These results may help to elucidate the function of these molecules in the animal Kingdom.
Topics: Animals; Arthropods; Free Radical Scavengers; Free Radicals; Phenothiazines; Thermodynamics
PubMed: 26238086
DOI: 10.1007/s00894-015-2773-3 -
Journal of Chromatography. A Aug 2023In this study, a simple, rapid, and ultrasensitive technique was developed to identify five pairs of phenothiazine drugs by using ultrasound-enhanced and...
Ultrasensitive determination of 10 phenothiazine derivatives and their enantiomers in biological fluids by capillary electrophoresis with contactless conductivity detection.
In this study, a simple, rapid, and ultrasensitive technique was developed to identify five pairs of phenothiazine drugs by using ultrasound-enhanced and surfactant-assisted dispersive liquid-liquid microextraction (UESA-DLLME), field-amplified sample injection with capillary electrophoresis (FASI-CE), and capacitively coupled capacitively coupled contactless conductivity detection (CD). During the CE separation process, UESA-DLLME was used for sample clean-up and offline concentration, and FASI-CE was used for the online concentration of phenothiazine enantiomers. At baseline, the five pairs of phenothiazine enantiomer drugs required 18 min for separation. UESA-DLLME was then used to extract 0.01 mM Tween 80 at pH 10 from a sample solution (extraction solvent, 100 mL of dichloromethane). Subsequently, FASI was used to stack the sample solution (buffer, 30 mM 2-(N-morpholino)ethanesulfonic acid/aspartic acid, additive 4 mM hydroxypropyl-γ-cyclodextrin, pH 2.5), and CD was used for signal detection (amplitude, 2 Vpp; frequency, 400 kHz). The results indicated that the linear range for quantifying all analyte enantiomers was 1.0-150 nM, with a coefficient of determination exceeding 0.99. In addition, the relative standard deviations in the migration time and peak areas for the 10 analytes were less than 3.2% and 7.2%, respectively. The proposed system has a limit of detection (LOD) for the 10 analytes at a signal-to-noise ratio of 3, ranging from 0.24 to 0.28 nM. The sensitivity enhancement, which compares the LOD (limit of detection in the normal method) to LOD (limit of detection achieved using the proposed UESA-DLLME-FASI-CE-CD method), varies between approximately 1200 and 2000 for the 10 analytes. Analysis of the 10 separated analytes spiked in urine and serum samples revealed recovery rates of 88%-106% and 89%-105%, respectively. Therefore, this highly sensitive advanced technique was successfully used to analyze phenothiazine enantiomers in urine and serum samples.
Topics: Phenothiazines; Solvents; Limit of Detection; Antipsychotic Agents; Electrophoresis, Capillary; Electric Conductivity
PubMed: 37487301
DOI: 10.1016/j.chroma.2023.464212 -
International Journal of Oncology Aug 2019Gastrointestinal stromal tumors (GISTs) are gastrointestinal tract sarcomas that commonly contain a mutation in the tyrosine kinases, KIT and platelet‑derived growth...
Gastrointestinal stromal tumors (GISTs) are gastrointestinal tract sarcomas that commonly contain a mutation in the tyrosine kinases, KIT and platelet‑derived growth factor receptor A (PDGFRA). Imatinib, sunitinib and regorafenib are all effective tyrosine kinase inhibitors; however, acquired resistance is inevitable. The E26 variant 1 (ETV1) pathway has been found to be a key downstream effector of KIT and is therefore a reasonable therapeutic target for this disease. In this study, we explored the potential agents targeting ETV1 in GISTs by uploading an ETV1 knockout gene signature of GIST cell lines to the pattern‑matching software 'Connectivity Map'. The activity and mechanisms of identified agents were examined using an in vitro model. Four drugs were identified: Suberanilohydroxamic acid and trichostatin [two histone deacetylase inhibitors (HDACIs)] and trifluoperazine and thioridazine (two phenothiazine‑class drugs). Western blot analysis demonstrated that all four drugs had ETV1‑downregulating effects. As HDACIs have been previously studied in GISTs, we focused on phenothiazine. Phenothiazine was found to exert cytotoxicity and to induce apoptosis and autophagy in GISTs. Treatment with phenothiazine had little effect on the KIT/AKT/mammalian target of rapamycin (mTOR) pathway, but instead upregulated extracellular‑signal‑regulated kinase (ERK) activity. A combination of phenothiazine and a MEK inhibitor had a synergistic cytotoxic effect on GISTs. Western blot analysis indicated that ELK1 and early growth response 1 (EGR1) were activated/upregulated following phenothiazine treatment, and the MEK inhibitor/phenothiazine combination downregulated the ERK/ELK1/EGR1 pathway, resulting in diminished autophagy, as well as enhanced apoptosis. On the whole, the findings of this study established phenothiazine as a novel class of therapeutic agents in GIST treatment and demonstrate that a combination of phenothiazine and MEK inhibitor has great potential for use in the treatment of GISTs.
Topics: Antineoplastic Agents; Antiprotozoal Agents; Apoptosis; Biomarkers, Tumor; Connectome; DNA-Binding Proteins; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Phenothiazines; Prognosis; Signal Transduction; Transcription Factors
PubMed: 31268158
DOI: 10.3892/ijo.2019.4829