Thioridazine

Thioridazine can be synthesized through various methods. One common synthetic route involves the reaction of 2-methylmercapto-10-(2-(N-methyl-2-piperidyl)ethyl)phenothiazine with appropriate reagents . The synthesis of optically pure enantiomers of this compound has been achieved using an auxiliary-based strategy, which allows for high optical purity and good overall yield . Industrial production methods often involve large-scale synthesis using similar reaction conditions but optimized for efficiency and cost-effectiveness .

Thioridazine undergoes several types of chemical reactions, including oxidation, reduction, and substitution . Common reagents used in these reactions include oxidizing agents like potassium permanganate and reducing agents such as lithium aluminum hydride . Major products formed from these reactions include various sulfoxides and sulfone derivatives . For example, this compound can be oxidized to form mesoridazine, a metabolite with similar pharmacological properties .

Thioridazine is an antipsychotic drug that has been identified as having potential applications beyond its original psychiatric use. Research has explored its efficacy in treating various conditions, including cancer, tuberculosis, and inflammatory diseases .

Scientific Research Applications

Cancer Therapy:

• This compound has demonstrated anti-cancer properties in several studies. It can reduce the viability of glioblastoma multiforme (GBM) cells and GBM stem cells, induce autophagy, and affect the expression of related proteins .
• In vitro experiments have shown that this compound reduces the cell viability of gastric cancer cells, inhibits colony formation, and induces apoptosis through the mitochondrial pathway .
• In vivo studies indicate that this compound pretreatment can inhibit the growth of tumors derived from NCI-N87 gastric cancer cells in mice .
• This compound has shown more effectiveness than fluphenazine against GBM stem-like cells .
• This compound may be an effective drug for cancer therapy by targeting cancer stem cells (CSCs), which play a vital role in drug resistance, cancer relapse, and metastasis .

Tuberculosis Treatment:

• This compound has shown promise in treating both susceptible and multidrug-resistant tuberculosis (TB) .
• This compound treatment resulted in a significant reduction of colony-forming units of both susceptible and multidrug-resistant tuberculosis bacilli in the lungs of mice .
• When this compound was added to a regimen containing rifampicin, isoniazid, and pyrazinamide for susceptible tuberculosis, a significant synergistic effect was achieved .

Anti-inflammatory Agent:

• This compound has been identified as a potential anti-inflammatory agent .
• It blocks IκBα protein degradation and subsequent NF-κB activation, which inhibits inflammation .
• In LPS-injected mice, this compound demonstrated anti-inflammatory efficacy .

Data Tables and Case Studies

While the provided documents do not contain comprehensive data tables and well-documented case studies, they do offer specific experimental findings that can be summarized.

Gastric Cancer Study (in vivo):

• NCI-N87 cells were pretreated with either DMSO or 5 μM this compound for 24 hours before being injected into nude mice .
• Pretreatment with 5 μM this compound inhibited the growth of NCI-N87 cell-derived tumors .
• Tumors derived from this compound-pretreated cells were smaller and weighed less than those from DMSO-pretreated cells .

Tuberculosis Study (in vivo):

• This compound was tested as a monotherapy in a Balb/c mouse model for both susceptible and multidrug-resistant tuberculosis .
• Treatment with this compound resulted in a significant reduction in colony-forming units of both susceptible and multidrug-resistant tuberculosis bacilli in the lung .
• The dose of 70 mg/kg of this compound significantly reduced CFUs at 30 and 60 days after initiation of treatment in mice infected with an MDR-TB strain .

Safety and Adverse Effects

• Over 50% of individuals on regular this compound experienced adverse events during or following drug withdrawal .
• The most common substituted drug during withdrawal was chlorpromazine .
• This compound alone was associated with sudden unexplained death, with drug-induced arrhythmia as the likely mechanism .
• Adverse events during or after withdrawal included re-emergence of psychosis or mood disturbance, escalation of behavioral disturbance, and tardive dyskinesia .

Thioridazine exerts its effects by blocking postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain . It also blocks alpha-adrenergic receptors, depresses the release of hypothalamic and hypophyseal hormones, and affects the reticular activating system, which influences basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis . These actions contribute to its antipsychotic and anxiolytic effects .

Comparison with Structural Analogs

Mesoridazine

• Structural Similarity: Mesoridazine is a thioridazine analog with identical phenothiazine cores but differing side chains.
• Target Profiles : Both are multi-target ligands (MTLs) acting on dopamine, serotonin, and histamine receptors. However, in a screen of 227 targets, this compound was active against 15 unique targets (e.g., specific GPCRs), while mesoridazine acted on two distinct targets (unidentified kinases) .
• Clinical Use : Both are antipsychotics, but mesoridazine lacks this compound’s antimicrobial and anticancer applications.

Comparison with Other Phenothiazines

Chlorpromazine and Trifluoperazine

• Antipsychotic Efficacy : All three are dopamine antagonists, but this compound has higher affinity for serotonin receptors .
• Cardiotoxicity: this compound causes pronounced QT prolongation and T-wave abnormalities in 100% of patients at high doses, whereas chlorpromazine and trifluoperazine induce similar changes in 50% and 17% of patients, respectively .

Promethazine and Methdilazine

• Primary Use : Both are antihistamines; this compound is primarily an antipsychotic.
• Antitubercular Activity: this compound’s efficacy against M. tuberculosis is attributed to its neuroleptic use, which may drive resistance via prolonged exposure.

Antimicrobial Activity Compared to Non-Phenothiazines

• Mechanism : this compound disrupts bacterial membranes and inhibits efflux pumps (e.g., adeB in A. baumannii), enhancing antibiotic efficacy .
• Efficacy :
  • Salmonella enterica: (–)-enantiomer reduces bacterial load by 90% in murine models, outperforming racemic mixtures .
  • Staphylococcus aureus: Racemic this compound shows MIC values 2–4× lower than standard antibiotics like ciprofloxacin .

Cardiotoxicity Profile

• Enantiomer-Specific Effects : The (+) enantiomer of this compound inhibits hERG potassium channels, causing fatal arrhythmias. The (–) enantiomer retains antimicrobial activity without cardiotoxicity .
• Metabolites : this compound-5-sulfoxide, a major metabolite, prolongs Q-T intervals at 12 µM in rat hearts, mimicking clinical cardiotoxicity .
• Comparison: this compound vs. Haloperidol: Haloperidol (a butyrophenone) lacks hERG inhibition, making it safer for cardiac patients . this compound vs. Quetiapine: Quetiapine, an atypical antipsychotic, has negligible ECG effects compared to this compound’s high-risk profile .

Derivatives and Modified Compounds

• T5 Derivative :
  • Design : A permanently charged derivative of this compound HCl with 51% synthesis yield. Reduces blood-brain barrier (BBB) penetration by 70% compared to the parent compound .
  • Safety : Predicted to lack mutagenicity but retains hERG inhibition risk unless synthesized using the (–) enantiomer .

Metabolic and Analytical Considerations

• Metabolites : this compound-5-sulfoxide exists as diastereoisomers, detectable via HPLC. Light exposure during analysis causes degradation artifacts, complicating pharmacokinetic studies .
• Comparison with Clozapine : Clozapine is light-stable, unlike this compound, simplifying its analytical protocols .

Thioridazine is an antipsychotic medication that has gained attention for its diverse biological activities, particularly in the fields of oncology and pharmacology. Originally developed for the treatment of schizophrenia, recent studies have revealed its potential in inducing apoptosis in various cancer cell lines and enhancing the efficacy of chemotherapy agents.

1. Anticancer Properties
this compound exhibits significant anticancer activity through several mechanisms:

• Induction of Apoptosis : Research indicates that this compound can induce apoptosis in various cancer types, including neuroblastoma, glioma, leukemia, and breast cancer. It achieves this by downregulating anti-apoptotic proteins such as Mcl-1 and c-FLIP, which are critical for cell survival .
• Cell Cycle Regulation : this compound has been shown to affect cell cycle regulators. It downregulates cyclin D1 and CDK4 while upregulating p21 and p16, leading to G0/G1 phase arrest in ovarian cancer cells .
• Synergistic Effects with Chemotherapy : In studies combining this compound with carboplatin, a chemotherapeutic agent, it was found that this combination enhances sensitivity to treatment by promoting apoptosis through proteasomal degradation of Mcl-1 and c-FLIP. This approach also involves the upregulation of proteasome subunit alpha 5 (PSMA5) via Nrf2 activation .

Case Studies

Several case studies highlight this compound's effectiveness in cancer treatment:

• Breast Carcinoma and Glioma : A study demonstrated that the combination of this compound with carboplatin significantly increased apoptosis in MDA-MB231 (breast carcinoma) and U87MG (glioma) cells compared to treatment with carboplatin alone .
• Gastric Cancer : this compound has shown potent anti-gastric cancer effects both in vitro and in vivo. It was found to significantly inhibit cell proliferation and induce cell death through apoptosis mechanisms .

Safety Profile

Despite its promising biological activities, this compound is associated with several side effects, particularly at high doses. These include:

• Cardiac Arrhythmias : this compound has been linked to serious cardiac side effects such as dysrhythmia and sudden death, especially when used in combination with other medications .
• Drug Resistance Overcoming : this compound has been noted to overcome drug resistance mechanisms by inhibiting P-glycoprotein, which is often responsible for reduced efficacy of chemotherapeutic agents .

Summary Table of Biological Activities

Basic Research Questions

Q. What are the primary molecular targets of thioridazine, and how do they influence its antipsychotic and anticancer activities?

this compound primarily antagonizes dopamine D2 and D4 receptors, contributing to its antipsychotic effects by modulating dopaminergic signaling in the central nervous system . Additionally, it inhibits the PI3K-Akt-mTOR pathway, which is critical for its anti-angiogenic and pro-apoptotic effects in cancer cells. Researchers should validate these targets using receptor-binding assays (e.g., radioligand displacement) and pathway inhibition studies (e.g., immunoblotting for phosphorylated Akt/mTOR) .

Q. What pharmacokinetic properties of this compound are critical for designing in vivo studies?

this compound has a hepatic half-life of 21–25 hours, with extensive metabolism into active metabolites like N-desmethylthis compound and sulfoxides. Its hydrophilicity results in high plasma concentrations (hundreds of ng/mL), and it accumulates in melanin-rich tissues (e.g., eyes). Researchers should monitor hepatic function and metabolite levels using HPLC or LC-MS, particularly in chronic dosing studies .

Q. What in vitro assays are commonly used to assess this compound’s dopaminergic antagonism?

Dopamine receptor binding assays (using radiolabeled ligands like [³H]-spiperone) and functional cAMP modulation tests are standard. For example, D2 receptor antagonism can be quantified via inhibition of dopamine-induced cAMP reduction in transfected cell lines .

Advanced Research Questions

Q. How does this compound induce apoptosis in cancer cells, and what key signaling pathways are involved?

this compound upregulates pro-apoptotic PDCD4 and downregulates BCL2, CCND1, and c-MYC, inducing mitochondrial-mediated apoptosis. It also inhibits PI3K-Akt-mTOR signaling, reducing phosphorylation of downstream targets like p70S6K and 4E-BP1. Methodologies include flow cytometry (annexin V/PI staining), qPCR for gene expression, and immunoblotting for caspase-3/9 cleavage .

Q. How can researchers reconcile conflicting data on this compound’s efficacy in dementia-related psychosis across clinical trials?

Meta-analyses (e.g., ) show no superiority over placebo in elderly dementia patients, possibly due to heterogeneous study designs, unblinded allocation, or inconsistent outcome measures (e.g., behavioral vs. cognitive scales). Future trials should prioritize concealed allocation, standardized dementia assessments (e.g., ADAS-Cog), and stratification by dementia subtype .

Q. What methodological approaches are recommended for studying this compound’s anti-angiogenic effects in tumor models?

Use in vivo xenograft models to quantify CD31⁺ blood vessels via immunohistochemistry. Complement with immunoblotting for VEGF, HIF-1α, and VEGFR-2 phosphorylation. In vitro, endothelial tube formation assays and matrigel plug assays can validate anti-angiogenic activity .

Q. How does this compound’s inhibition of the PI3K-Akt-mTOR pathway contribute to its dual role in antipsychotic and anticancer effects?

In schizophrenia, PI3K-Akt-mTOR modulation may mitigate synaptic plasticity deficits. In cancer, pathway inhibition suppresses proliferation and angiogenesis. Researchers should employ phospho-specific antibodies to track pathway activity in dual-purpose studies, comparing neuronal and cancer cell lines .

Q. What experimental strategies can mitigate this compound’s cardiotoxicity while preserving therapeutic efficacy?

Computational modeling of hERG channel interactions and enantiomer-specific testing (e.g., isolated rabbit papillary muscle assays) can identify less cardiotoxic derivatives. Concurrent ECG monitoring in preclinical studies is advised to detect QTc prolongation .

Q. How can transcriptomic and survival data from platforms like DRUGSURV inform this compound’s repositioning in oncology?

DRUGSURV links this compound’s off-target effects (e.g., EGFR inhibition) to survival-associated genes in cancers like leukemia and myeloma. Researchers should validate these targets using CRISPR/Cas9 knockout models and correlate findings with patient survival data from TCGA or GEO datasets .

Q. Methodological Guidance

Q. What are the recommended quality control parameters for preparing this compound solutions in experimental settings?

Use HPLC-certified reference standards (purity >98%) and prepare stock solutions in DMSO at 10 mM. Validate stability via UV-Vis spectrophotometry and store aliquots at -80°C to prevent oxidation. Include COA (Certificate of Analysis) and SDS documentation for reproducibility .