Tamoxifen

Synthetic Routes and Reaction Conditions: Tamoxifen can be synthesized through various methods. One efficient route involves the direct carbolithiation of diphenylacetylenes followed by cross-coupling with alkenyllithium reagents. This method employs a palladium nanoparticle-based catalyst, achieving high selectivity and yield .

Industrial Production Methods: In industrial settings, this compound is typically produced through a multi-step synthesis processThe reaction conditions often involve the use of strong bases and transition metal catalysts to ensure high efficiency and purity .

Metabolism Pathways

Tamoxifen is extensively metabolized in the liver, primarily through cytochrome P450 (CYP) enzymes. Key reactions include:

Primary Metabolites

• N-Desmethylthis compound : Formed via CYP3A4/3A5-mediated N-dealkylation. This metabolite is further oxidized by CYP2D6 to endoxifen (4-hydroxy-N-desmethylthis compound), a potent anti-estrogenic agent .
• 4-Hydroxythis compound (Afimoxifene) : Generated by CYP2D6/CYP2B6/CYP3A4 hydroxylation. This metabolite undergoes glucuronidation or sulfation to enhance clearance .

Elimination Routes

• Fecal Excretion : 75% of radiolabeled this compound is recovered in feces, with minor urinary excretion (24.7%). The terminal half-life is 5–7 days, while endoxifen has a shorter half-life (50–70 hours) .

Non-Estrogen Receptor (ER) Mediated Reactions

This compound exhibits ER-independent anticancer effects, particularly through metal complexation and redox modulation:

Metal Complexes

• Au(III)-Tamoxifen Complexes : Target thioredoxin reductase (TrxR), disrupting mitochondrial function and inducing apoptosis. Binding free energies to ERα:

  Compound	ΔG (kcal/mol)
  4-Hydroxythis compound	–21.3 ± 4.3
  [AuTAML(OH)Cl]	–23.3 ± 5.0
  [CuTAML(OH)₂]	–21.7 ± 3.8

  These complexes inhibit TrxR, leading to reactive oxygen species (ROS) accumulation and mitochondrial membrane permeabilization .

This compound Analogs and Derivatives

Structural modifications aim to enhance ER binding and reduce toxicity:

Reactivity Parameters

• Electrophilicity Index (ω) : TAM-Amide (>1.5 eV) shows highest reactivity, correlating with ER-binding affinity .
• Molecular Polar Surface Area (PSA) : TAM-Sulfhydryl (9.63 Ų) exhibits optimal membrane permeability, adhering to Lipinski’s Rule of Five .

Environmental Impact

This compound and its hydroxylated metabolites (e.g., 4-hydroxythis compound) persist in the environment. Their structural similarity to the parent compound retains biological activity, necessitating wastewater treatment considerations .

Breast Cancer Treatment

Tamoxifen is primarily indicated for the treatment of estrogen receptor-positive (ER+) breast cancer in both men and women. It is used in various settings, including:

• Adjuvant Therapy : Following surgery and radiation, this compound reduces the risk of cancer recurrence in patients with early-stage ER+ breast cancer .
• Metastatic Breast Cancer : It is effective in treating advanced stages of breast cancer, providing significant survival benefits .

Prophylactic Use

This compound is also utilized as a prophylactic agent to reduce the risk of breast cancer in women at high risk. Studies indicate that it can lower the incidence of invasive breast cancer by approximately 50% over five years .

Cardioprotective Effects

Research suggests that this compound may offer cardioprotective benefits, potentially reducing the risk of coronary artery disease . This application is particularly relevant for postmenopausal women who are at increased risk for cardiovascular issues.

Bone Health

This compound has been shown to increase bone mineral density, making it beneficial for postmenopausal women at risk for osteoporosis .

Other Medical Conditions

Emerging studies have explored this compound's role in various other conditions, including:

• Multiple Sclerosis : Investigations are underway to assess its potential benefits in managing symptoms or progression .
• Alzheimer's Disease and Parkinson's Disease : The compound's neuroprotective properties are being studied for possible applications in these neurodegenerative disorders .
• Gynecomastia : this compound can be effective in treating gynecomastia and associated breast pain in men .
• Fertility Treatments : It has been used off-label to induce ovulation in women with infertility issues .

Breast Cancer Prevention Trials

Numerous randomized clinical trials have demonstrated this compound's efficacy in preventing breast cancer among high-risk populations:

• The Breast Cancer Prevention Trial showed a significant reduction in breast cancer incidence among participants taking this compound compared to placebo .
• Long-term follow-up studies indicate that the protective effects can last for up to 20 years after treatment cessation .

Combination Therapies

Recent studies have examined this compound's effectiveness when combined with other agents:

• Research involving flaxseed demonstrated enhanced anti-tumor effects when used alongside this compound in preclinical models of breast cancer .
• Investigations into hybrid therapies combining this compound with other compounds are ongoing, aiming to overcome resistance seen in some breast cancer cases .

Data Table: Summary of this compound Applications

Tamoxifen exerts its effects by binding to estrogen receptors, particularly estrogen receptor alpha. This binding prevents estrogen from activating the receptor, thereby inhibiting the growth of estrogen-dependent cancer cells. This compound also undergoes metabolic activation to form active metabolites such as 4-hydroxy-tamoxifen and endoxifen, which have higher affinity for estrogen receptors .

Toremifene

Toremifene, a structurally related triphenylethylene derivative, shares tamoxifen’s SERM mechanism but differs in pharmacokinetics. However, toremifene demonstrates a marginally better safety profile in reducing endometrial hyperplasia risk .

This compound Derivatives

Derivatives like 4-hydroxythis compound (4-OHT) and OHTAM2–3 exhibit enhanced cytotoxicity. In A. baumannii, 4-OHT binds OmpW with high affinity, disrupting membrane integrity . Synthetic derivatives (e.g., P15, P41) show superior anti-proliferative effects in MCF-7 and MDA-MB-231 cells, with IC₅₀ values ≤10 μM .

Combination Therapies

• This compound + Vitamin D3 : Synergistic anti-proliferative effects in MCF-7 cells. At 20 μM this compound + 100 nM vitamin D3, cell viability drops by 70% (vs. 50% for this compound alone) .
• This compound + Ceramide : Induces apoptosis in HL-60/VCR leukemia cells via ceramide pathway activation, overcoming chemoresistance .

Structural and Functional Analogues

• U18666A : A cholesterol biosynthesis inhibitor sharing this compound’s binding site on EBP (emopamil-binding protein). Both compounds exhibit similar conformational binding but differ in hydrophobicity .
• Synthetic 1,3-Diphenylpropanones: Designed to mimic this compound’s aromatic backbone. Compound 4h shows 60% lower cytotoxicity in fibroblasts compared to this compound, suggesting improved selectivity .

Pharmacokinetic and Pharmacodynamic Contrasts

• Metabolism : this compound relies on CYP2D6 for activation, whereas toremifene is CYP3A4-dependent. Polymorphisms in CYP2D6 reduce endoxifen levels by ~50%, though clinical impact remains debated .
• Transport : this compound is a substrate for P-glycoprotein (ABCB1), limiting brain penetration. Derivatives like P85 bypass this via β-cyclodextrin encapsulation, enhancing bioavailability .

Tamoxifen is a selective estrogen receptor modulator (SERM) primarily used in the treatment of estrogen receptor-positive breast cancer. Its biological activity extends beyond its role as an anti-cancer agent, revealing significant implications in various physiological processes and potential therapeutic applications. This article explores the multifaceted biological activities of this compound, including its mechanisms of action, off-target effects, and emerging applications in antimicrobial therapy.

Estrogen Receptor Modulation
this compound exerts its primary effects through competitive inhibition of estrogen at the estrogen receptor (ER), particularly in breast tissue. This antagonistic action reduces the proliferation of cancer cells that are responsive to estrogen. However, this compound also acts as an agonist in other tissues, such as the uterus and bone, which can lead to different biological responses.

Non-Estrogen Receptor Pathways
Recent studies have identified several estrogen receptor-independent mechanisms through which this compound exerts its effects:

• Oxidative Stress Induction : High concentrations of this compound induce oxidative stress by increasing reactive oxygen species (ROS) levels, leading to apoptosis in various cell types, including epithelial and non-epithelial cells . This mechanism is particularly relevant in ER-negative cancers and infections.
• Macrophage Activation : this compound enhances macrophage activity by activating pathways such as NRF2 and caspase-1, promoting inflammatory responses without inducing cell death. This results in increased phagocytosis and the production of neutrophil extracellular traps (NETs), which trap and kill pathogens .

Antimicrobial Activity

Emerging research has highlighted this compound's potential as an antimicrobial agent. Studies have demonstrated that this compound enhances the ability of neutrophils to migrate towards and engulf bacteria, suggesting its utility in treating infections:

• Effect on Neutrophils : In vitro studies showed that this compound-treated neutrophils produced more NETs and exhibited improved bacterial clearance capabilities . In vivo experiments indicated that mice treated with this compound displayed increased resilience against methicillin-resistant Staphylococcus aureus (MRSA) infections.
• Mechanistic Insights : The antimicrobial effects are thought to be mediated through alterations in lipid metabolism and immune modulation, enhancing the innate immune response against pathogens .

Table 1: Summary of this compound's Biological Activities

Research Findings

• Antimicrobial Efficacy : A study published in Frontiers in Pharmacology reported that this compound enhances macrophage function and promotes the M1 phenotype, leading to improved phagocytic activity against pathogens .
• Oxidative Stress Mechanism : Research indicates that this compound induces oxidative stress through undefined ER-independent pathways, contributing to its cytotoxic effects on various cell types .
• Clinical Trials for Repurposing : Ongoing clinical trials are exploring the efficacy of this compound for treating various infections, leveraging its immunomodulatory properties alongside its established cancer treatment profile .

Q. How is tamoxifen utilized in inducible Cre-loxP systems for tissue-specific gene knockout studies?

Basic Experimental Design
this compound is a critical tool in Cre-loxP systems for temporal and tissue-specific gene manipulation. Administered via intraperitoneal injection (0.22 mg/g body weight in mice), this compound activates cytosolic Cre-ERT2 recombinase, enabling floxed gene excision. Key considerations include:

• Dose Optimization : Multiple this compound doses (e.g., 3–5 consecutive days) improve recombination efficiency, as shown in olfactory epithelium regeneration studies .
• Leakiness Control : Pre-screen Cre lines for baseline recombination activity (e.g., HTT knockout models showed variable leakiness without this compound) .
• Timeline Validation : Align tissue collection with peak recombination (e.g., 3–9 months post-treatment in neurodegenerative models) .

Q. What methodological approaches are recommended for resolving contradictions in CYP2D6 genotype-phenotype associations with this compound efficacy?

Advanced Data Contradiction Analysis
Discrepancies in CYP2D6 studies arise from pharmacogenomic variability and clinical confounders. Mitigation strategies include:

• Comprehensive Genotyping : Interrogate all CYP2D6 alleles (*4, *10, 41) and copy number variations, as reduced-function alleles significantly lower endoxifen levels .
• Inhibitor Adjustment : Account for CYP2D6 inhibitors (e.g., paroxetine reduces endoxifen by 64% in wild-type patients) using LC-MS/MS metabolite monitoring .
• Cohort Stratification : Separate patients by menopausal status and adjuvant therapies (e.g., aromatase inhibitors confound this compound outcomes) .

Q. How should researchers design longitudinal studies to assess this compound's durable protective effects against breast cancer recurrence?

Long-Term Clinical Trial Methodology
The NSABP P-1 trial (1992–1999) established a framework:

• Risk Stratification : Use Gail’s model to enroll high-risk cohorts (e.g., 5-year risk ≥1.66%) .
• Endpoint Selection : Track invasive/noninvasive breast cancer incidence, endometrial cancer, and thromboembolic events over ≥5 years .
• Post-Treatment Follow-Up : Extend monitoring beyond drug discontinuation; 20-year data reveal persistent risk reduction .

Q. What analytical techniques are optimal for quantifying this compound and its active metabolites in human serum?

Basic Pharmacokinetic Methodology

• LC-MS/MS Assays : Quantify this compound, N-desmethylthis compound, and endoxifen with limits of detection ≤0.1 ng/mL. Validate using stable isotope-labeled internal standards .
• Statistical Normalization : Report median concentrations with interquartile ranges (IQR) to address skewed distributions in CYP2D6 variant carriers .
• Functional Correlates : Link metabolite levels to estrogen receptor (ER) antagonism via MCF7 cell proliferation assays .

Q. What experimental strategies can identify metabolic drivers of this compound resistance, such as NQO1 overexpression?

Advanced Resistance Mechanism Analysis

• CRISPR-Cas9 Screening : Knock out candidate genes (e.g., NQO1) in this compound-resistant cell lines to restore sensitivity .
• Mitochondrial Profiling : Measure oxidative phosphorylation (OXPHOS) flux via Seahorse assays; resistant cells exhibit elevated ATP production .
• Inhibitor Validation : Test dicoumarol (NQO1 inhibitor) in xenograft models to reverse resistance .

Q. How can principal component analysis (PCA) be applied to interpret transcriptomic changes in this compound-resistant breast cancer models?

Advanced Bioinformatics Workflow

• Data Preprocessing : Normalize cDNA array data (e.g., CLONTECH Atlas) to remove batch effects .
• Component Extraction : Identify PCA axes explaining variance (e.g., PC1 = overall expression, PC2 = estrogen-sensitive vs. resistant profiles) .
• Outlier Detection : Use 99% prediction regions to flag genes (e.g., erk-2, HSF-1) with differential expression, validated via Western blot .

Q. What safety protocols are essential when handling this compound in laboratory settings?

Basic Laboratory Compliance

• PPE Requirements : Lab coats, nitrile gloves, and ANSI-approved eye protection .
• Waste Management : Dispose this compound-contaminated materials as hazardous waste .
• Training : Document annual safety reviews for personnel handling this compound .

Q. How do co-administered CYP2D6 inhibitors like paroxetine affect this compound metabolite profiles, and how should this be addressed in clinical pharmacogenomic studies?

Advanced Drug Interaction Mitigation

• Metabolite Monitoring : Measure endoxifen pre-/post-SSRI coadministration; ≥50% reduction necessitates dose adjustment .
• Genotype-Guided Dosing : Avoid CYP2D6 inhibitors in CYP2D6 wild-type patients or switch to aromatase inhibitors .
• Adherence Tracking : Use pill counts or digital monitoring to exclude non-adherent subjects from analyses .