Bicalutamide
Cat. No.:
B1683754
CAS No.:
90357-06-5
M. Wt:
430.4 g/mol
InChI Key:
LKJPYSCBVHEWIU-UHFFFAOYSA-N
Attention:
For research use only. Not for human or veterinary use.
Overview
Description
Bicalutamide is a nonsteroidal antiandrogen medication primarily used in the treatment of prostate cancer. It is known for its ability to block the action of androgens, which are male hormones that stimulate the growth of prostate cancer cells . This compound is often used in combination with other treatments such as gonadotropin-releasing hormone analogues or surgical removal of the testicles to manage metastatic prostate cancer .
Preparation Methods
Synthetic Routes and Reaction Conditions: The synthesis of Bicalutamide involves several key stepsThis oxidation is typically carried out using potassium permanganate in the presence of water or a mixture of water and a water-miscible solvent . The resulting product is this compound.
Industrial Production Methods: Industrial production of this compound follows similar synthetic routes but on a larger scale. The process is designed to be simple, convenient, safe, and cost-effective. The key steps involve the preparation of the sulfide compound, followed by its oxidation to form this compound .
Chemical Reactions Analysis
Types of Reactions: Bicalutamide undergoes several types of chemical reactions, including:
Substitution: this compound can undergo substitution reactions, particularly involving the cyano and trifluoromethyl groups on the phenyl ring.
Common Reagents and Conditions:
Oxidizing Agents: Potassium permanganate, peroxy acids such as m-chloroperbenzoic acid.
Solvents: Water, methanol, methylene chloride.
Major Products Formed: The major product formed from the oxidation reaction is this compound itself, which is a sulfone compound .
Scientific Research Applications
Prostate Cancer Treatment
- Early and Advanced Prostate Cancer : Bicalutamide is approved for the treatment of stage D2 metastatic prostate cancer when used alongside surgical or medical castration. It is also administered as monotherapy for stage C or D1 locally advanced prostate cancer at a dosage of 150 mg/day .
- Survival Benefits : A study indicated that patients receiving this compound had a 76.3% overall survival rate at 12 years compared to 71.3% in the placebo group, highlighting its effectiveness in prolonging survival .
Hormonal Therapy
- Transgender Care : this compound is used in hormone therapy for transgender women to block testosterone effects and manage symptoms associated with high testosterone levels in women .
- Puberty Blocker : It is also employed to prevent premature puberty in transgender girls and treat early puberty in boys .
Other Indications
- This compound has shown potential in treating skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women .
- Research suggests its utility in managing paraphilias and hypersexuality in men .
Efficacy
- This compound has demonstrated comparable efficacy to castration therapies while preserving sexual interest better than traditional methods .
- Studies have shown that it can effectively inhibit androgen-mediated cell adhesion in prostate cancer cells, potentially reducing metastasis risk .
Side Effects
- Common side effects include breast pain and gynecomastia, which are typical for antiandrogens. However, this compound has a more favorable tolerability profile compared to other antiandrogens like flutamide .
- Long-term follow-up studies have indicated that while side effects exist, they are generally manageable and do not outweigh the benefits of treatment .
Case Studies
Mechanism of Action
Bicalutamide works by competitively inhibiting the binding of androgens such as dihydrotestosterone and testosterone to androgen receptors. This inhibition prevents the stimulation of cell growth in prostate cancer . This compound binds to the androgen receptor without activating gene expression, leading to the regression of prostatic tumors . The molecular targets involved include the androgen receptors in prostate cancer cells .
Comparison with Similar Compounds
- Flutamide
- Nilutamide
- Enzalutamide
- Apalutamide
- Cyproterone Acetate
- Spironolactone
Comparison:
- First-Generation Nonsteroidal Antiandrogens: Compared to flutamide and nilutamide, Bicalutamide has improved potency, efficacy, tolerability, and safety . It has largely replaced these medications in clinical practice.
- Second-Generation Nonsteroidal Antiandrogens: Compared to enzalutamide and apalutamide, this compound has inferior potency and efficacy but similar tolerability and safety .
- Steroidal Antiandrogens: Compared to cyproterone acetate and spironolactone, this compound has better selectivity in its action, superior efficacy as an antagonist of the androgen receptor, and better tolerability .
This compound’s unique properties, such as its selectivity and safety profile, make it a preferred choice in the treatment of prostate cancer .
Biological Activity
Bicalutamide is a nonsteroidal antiandrogen primarily used in the treatment of prostate cancer. Its biological activity is characterized by its ability to inhibit androgen receptors, thereby blocking the action of androgens like testosterone. This article provides a comprehensive overview of the biological activity of this compound, including its pharmacokinetics, mechanisms of action, clinical efficacy, and adverse effects.
Pharmacokinetics
This compound is administered orally, with a recommended dosage of 150 mg once daily for early nonmetastatic prostate cancer and 50 mg daily in combination with luteinizing hormone-releasing hormone analogues for advanced cases. Its pharmacokinetic profile reveals:
- Absorption : The (R)-enantiomer is absorbed slowly and saturably, while the (S)-enantiomer is more rapidly absorbed and cleared. Food intake does not significantly affect absorption.
- Elimination Half-life : Approximately one week, leading to a tenfold accumulation in plasma during daily administration.
- Metabolism : Primarily metabolized by cytochrome P450 enzymes, particularly CYP3A4. The (R)-enantiomer has potential inhibitory effects on CYP3A4 but does not show clinically relevant inhibition in vivo at standard doses .
This compound functions as a competitive antagonist at androgen receptors in target tissues such as the prostate. By binding to these receptors, it prevents androgens from exerting their biological effects, which is critical in managing androgen-dependent cancers.
Prostate Cancer Treatment
This compound has been extensively studied for its efficacy in treating prostate cancer. A notable study compared this compound monotherapy (50 mg/day) to castration. Results indicated that while this compound was associated with fewer adverse effects, it was inferior to castration regarding overall response rates and survival metrics:
- Time-to-Treatment Failure : Hazard ratio of 1.59 favoring castration.
- Prostate-Specific Antigen (PSA) Reduction : this compound showed a median fall of 86-88%, compared to 96-97% for castration .
Case Studies
- Phase II Trial in Breast Cancer : A multicenter trial assessed this compound's effectiveness in women with androgen receptor-positive metastatic breast cancer. The primary endpoint was the clinical benefit rate, which included complete responses and stable disease over six months. The results indicated potential benefits in this patient population, warranting further investigation .
- Weekly Administration Trial : A phase I-II trial evaluated the safety and activity of weekly this compound administration in men with elevated PSA levels. Results showed a significant reduction in PSA levels (50% reduction noted) and an improvement trend in high-grade prostatic intraepithelial neoplasia (HG-PIN) status among treated subjects .
Adverse Effects
While this compound is generally well-tolerated, it can lead to various side effects:
- Common Adverse Effects : Breast tenderness, gynecomastia, hot flushes, and liver enzyme alterations.
- Quality of Life Impact : Although some patients reported improved sexual functioning initially compared to those receiving castration, long-term studies indicate that higher doses may be needed to achieve comparable efficacy .
Comparative Efficacy Table
| Treatment Type | Objective Response Rate | Median Survival | PSA Reduction (%) |
|---|---|---|---|
| This compound (50 mg) | Lower than castration | Inferior | 86-88 |
| Castration | Higher | Superior | 96-97 |
Q & A
Basic Research Questions
Q. What experimental models are commonly used to investigate bicalutamide’s efficacy in androgen receptor (AR)-related pathologies, and how should researchers optimize dosing regimens?
- Methodological Guidance : Preclinical studies often employ knock-in (KI) mouse models, such as the AR113Q spinal and bulbar muscular atrophy (SBMA) model, to mimic human disease progression. This compound is administered subcutaneously (2 mg/kg twice weekly) in oil-based vehicles, with outcomes assessed via survival analysis (Kaplan-Meier curves) and motor behavior tests (rotarod, grip strength) . LC-MS is recommended for validating serum and tissue drug levels to ensure pharmacokinetic consistency .
Q. How can researchers design clinical trials to evaluate this compound’s impact on prostate cancer progression while minimizing bias?
- Methodological Guidance : Use the PICOT framework to structure trials:
- P opulation: Patients with locally advanced or metastatic prostate cancer (e.g., T1b-T4, M0).
- I ntervention: this compound 150 mg/day + standard care (radical prostatectomy, radiotherapy).
- C omparison: Placebo + standard care.
- O utcome: Progression-free survival (PFS), overall survival (OS).
- T ime: Median 5.4-year follow-up.
Stratify subgroups (e.g., localized vs. locally advanced disease) to address outcome discrepancies, as this compound benefits locally advanced patients but may harm those with localized disease .
Q. What analytical methods ensure reliable quantification of this compound in pharmaceutical formulations and biological samples?
- Methodological Guidance :
- Pharmaceutical purity : Use reverse-phase HPLC with UV detection (λ = 270 nm), validated per ICH guidelines. Ensure mobile phases include diluted phosphoric acid and acetonitrile for optimal resolution of related substances (e.g., isomers, degradation products) .
- Biological samples : LC-MS/MS for serum and tissue quantification, with calibration curves adjusted for matrix effects .
Advanced Research Questions
Q. How do AR variants (e.g., AR-V7) influence resistance to this compound, and what combinatorial strategies can overcome this?
- Methodological Guidance :
- Mechanistic studies : Use this compound-resistant cell lines (e.g., prostate cancer models) to quantify AR-V7 expression via qPCR/Western blot.
- Combinatorial therapy : Co-administer niclosamide (AR-V7 inhibitor) with this compound. Validate synergy using proliferation assays (Ki67 staining) and apoptosis markers (PARP cleavage) .
- Statistical analysis : Compare hazard ratios (HRs) for PFS between monotherapy and combination arms using Cox regression .
Q. What molecular pathways underlie this compound’s neuroprotective effects in SBMA, and how can autophagy modulation enhance therapeutic outcomes?
- Methodological Guidance :
- Autophagy analysis : Measure autophagic flux via LC3-II/p62 Western blot in skeletal muscle. This compound restores basal HSPB8 levels, resolving ARpolyQ aggregation. Combine with trehalose (autophagy inducer) to amplify efficacy .
- Mitochondrial markers : Quantify mtDNA copy number and OXPHOS enzyme accumulation to assess metabolic recovery .
Q. How should researchers resolve contradictions in survival outcomes from large-scale clinical trials (e.g., Early Prostate Cancer Program)?
- Methodological Guidance :
- Subgroup analysis : Stratify data by disease stage (localized vs. locally advanced). Use two-way ANOVA with Tukey’s post-hoc test to identify treatment effects within subgroups .
- Bias mitigation : Adjust for confounding variables (e.g., baseline PSA, Gleason score) using multivariate regression. Report HRs with 95% confidence intervals .
Q. What biomarkers predict this compound’s clinical benefit in AR-negative breast cancer, and how can they be validated?
- Methodological Guidance :
- Retrospective biomarker screening : Analyze archived tumor samples for AR splice variants or immune checkpoint markers (e.g., PD-L1) via immunohistochemistry.
- Validation cohort : Use a prospective trial design with pre-specified endpoints (e.g., 6-month clinical benefit rate). Apply log-rank tests to compare PFS between biomarker-positive and -negative cohorts .
Q. Methodological Best Practices
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Experimental Design :
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Data Analysis :
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Analytical Validation :
Properties
IUPAC Name |
N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)sulfonyl-2-hydroxy-2-methylpropanamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C18H14F4N2O4S/c1-17(26,10-29(27,28)14-6-3-12(19)4-7-14)16(25)24-13-5-2-11(9-23)15(8-13)18(20,21)22/h2-8,26H,10H2,1H3,(H,24,25) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
LKJPYSCBVHEWIU-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC(CS(=O)(=O)C1=CC=C(C=C1)F)(C(=O)NC2=CC(=C(C=C2)C#N)C(F)(F)F)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C18H14F4N2O4S |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID2022678 |
Source
|
| Record name | Bicalutamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID2022678 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
430.4 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Bicalutamide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015260 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
Slightly soluble in chloroform and absolute ethanol; sparingly soluble in methanol; soluble in acetone and tetrahydrofuan, Practically insoluble in water at 37 °C (5 mg/1000 mL), 9.28e-03 g/L |
Source
|
| Record name | Bicalutamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01128 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | BICALUTAMIDE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7655 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Bicalutamide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015260 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Mechanism of Action |
Bicalutamide competes with androgen for the binding of androgen receptors, consequently blocking the action of androgens of adrenal and testicular origin which stimulate the growth of normal and malignant prostatic tissue., Bicalutamide is a nonsteroidal antiandrogen that is structurally and pharmacologically related to flutamide and nilutamide. Bicalutamide inhibits the action of androgens by competitively blocking nuclear androgen receptors in target tissues such as the prostate, seminal vesicles, and adrenal cortex; blockade of androgen receptors in the hormone-sensitive tumor cells may result in growth arrest or transient tumor regression through inhibition of androgen-dependent DNA and protein synthesis. Bicalutamide is a selective antiandrogen with no androgenic or progestational activity in various animal models. The relative binding affinity of bicalutamide at the androgen receptor is more than that of nilutamide and approximately 4 times that of hydroxyflutamide, the active metabolite of flutamide., Common pharmacologic therapies for prostate cancer (ie, gonadotropin-releasing hormone [GnRH] analogs, nonsteroidal antiandrogens) when used as monotherapy initially result in increased serum testosterone concentrations, which may limit the effects of the drugs. Androgen receptors in the hypothalamus are blocked by bicalutamide, which disrupts the inhibitory feedback of testosterone on luteinizing hormone (LH) release, resulting in a temporary increase in secretion of LH; the increase in LH stimulates an increase in the production of testosterone. As GnRH analogs have potent GnRH agonist properties, testicular steroidogenesis continues during the first few weeks after initiating therapy. However, the combination of orchiectomy or GnRH analog therapy to suppress testicular androgen production and an antiandrogen to block response of remaining adrenal androgens provides maximal androgen blockade. Concomitant administration of antiandrogens such as bicalutamide in patients initiating therapy with a GnRH analog can inhibit initial androgenic stimulation and potential exacerbation of symptoms (e.g., bone pain, urinary obstruction, liver pain, impending spinal cord compression) that may occur during the first month of GnRH analog therapy., Bicalutamide was developed from a series of nonsteroidal compounds related to flutamide that showed a range of pharmacologic activity from full androgen agonist to pure antiandrogen, including progestational and antiprogestational properties. Bicalutamide is a pure antiandrogen that binds to rat, dog, and human prostate; the affinity compared with the natural ligand 5 alpha-dihydrotestosterone is low, but bicalutamide has an affinity for the rat androgen receptor approximately four times higher than hydroxyflutamide, the active metabolite of flutamide. Bicalutamide also binds to androgen receptors found in the LNCaP human prostate tumor and the Shionogi S115 mouse mammary tumor cell line, as well as androgen receptors transfected into CV-1 and HeLa cells. In all cases, bicalutamide behaves as a pure antiandrogen and inhibits gene expression and cell growth stimulated by androgen. Studies with the LNCaP cell line are particularly interesting, as these cells contain a mutated androgen receptor (codon 868, Thr-->Ala), which behaves idiosyncratically with other antiandrogens (cyproterone acetate and flutamide): both these antiandrogens act as agonists in this cell line and stimulate proliferation. Studies in vivo show that bicalutamide is a potent antiandrogen in the rat. In immature, castrated male rats treated daily with testosterone propionate, bicalutamide produces a profound inhibition of accessory sex organ (ventral prostate and seminal vesicles) growth at oral doses as low as 0.25 mg/kg; it is more active in this test than flutamide or cyproterone acetate. In mature male rats, daily oral doses of bicalutamide produce a dose-related reduction in weights of the ventral prostate glands and seminal vesicles: in this test, bicalutamide is around five times as potent as flutamide. In contrast to flutamide, which produces dose-related, marked increases in serum luteinizing hormone (LH) and testosterone as a consequence of the central inhibition of the negative feedback effects of androgens on the hypothalamic-pituitary-tests axis, bicalutamide has little effect on serum LH and testosterone; i.e., it is peripherally selective. The peripheral selectivity of bicalutamide in the rat is not due to differences between the prostate versus hypothalamic or pituitary receptors, as bicalutamide reverses the suppressive effect of testosterone on luteinizing hormone-releasing hormone (LHRH) secretion from hypothalamic slices in vitro and is as effective as flutamide at sensitizing the pituitary gland to secrete LH in response to administered LHRH. The peripheral selectivity of bicalutamide has now been shown to be due to poor penetration across the blood-brain barrier: tissue distribution studies with [3H]bicalutamide show that although it is concentrated in the organs of metabolism and secretion as well as in the prostate, the pituitary glands, and the seminal vesicles, levels in the hypothalamus and the central nervous system (CNS) are much lower than in blood. Indeed, it is probable that levels found in the CNS reflect levels of blood contamination. In dogs, bicalutamide has exquisite potency and causes dose-related atrophy of the prostate gland and epididymides; with an oral ED50 of 0.1 mg/kg, it is around 50 times as potent as flutamide in this species and also more potent than the steroidal antiandrogen WIN49596 and the 5 alpha-reductase inhibitor MK-906. Even at substantial multiples of the active dose (up to 100 mg/kg orally), bicalutamide failed to increase serum testosterone, so it is also peripherally selective in the dog., Although widely accepted as an androgen receptor antagonist, the mechanism by which it induces apoptosis remains unclear. Defining exact pathways by which bicalutamide induces its apoptotic effects would help to advance its clinical applications. /Investigators/ aimed to examine the apoptotic effects of bicalutamide at 24 hr and comment on the role of the caspases and calpains in mediating bicalutamide-induced apoptosis in androgen-dependent and androgen-independent cells. PWR-1E, PC-3 and DU-145 cells were treated with bicalutamide and assessed for apoptosis by flow cytometry at 24 hr. DU-145 cells were used to compare differences between two different metastatic receptor-negative cells and to verify apoptotic induction at 48 hr. To delineate a specific pathway of action for bicalutamide, PC-3 and PWR-1E cells were pretreated with specific inhibitors of caspase-dependent (zVAD-FMK) and caspase-independent pathways (calpain 2 inhibitor). Bicalutamide induced apoptosis in androgen-dependent PWR-1E cells via a caspase-dependent and calpain-independent mechanism. In androgen-independent PC-3 cells, bicalutamide also induced apoptosis by mechanisms that were partially inhibited by pan-caspase inhibition but were partially calpain dependent. Understanding into how bicalutamide exerts its effects in androgen-independent cells will yield further insights into the treatment of hormone-refractory disease. |
Source
|
| Record name | Bicalutamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01128 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
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| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7655 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Color/Form |
Crystals from 1:1 (v/v) mix of ethyl acetate and petroleum ether, Fine white to off-white powder | |
CAS No. |
90357-06-5 |
Source
|
| Record name | Bicalutamide | |
| Source | CAS Common Chemistry | |
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| Record name | Bicalutamide [USAN:USP:INN:BAN] | |
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| Record name | Bicalutamide | |
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| URL | https://www.drugbank.ca/drugs/DB01128 | |
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| Record name | bicalutamide | |
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| Record name | Bicalutamide | |
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| Record name | Propanamide, N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl | |
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| Record name | BICALUTAMIDE | |
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| Record name | Bicalutamide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015260 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
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Melting Point |
191-193 °C, 191 - 193 °C |
Source
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| Record name | Bicalutamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01128 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
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| Record name | BICALUTAMIDE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7655 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Bicalutamide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015260 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Synthesis routes and methods I
Procedure details
180 mg of the chiral epoxide of example 17 was dissolved in a mixture of 12 ml chloroform and 12 ml of water. 133 mg of sodium-p-fluorobenzenesulfinate and 107 mg of tetrabutylammonium bromide were added. The reaction mixture was heated till reflux and kept at reflux, while stirring vigorously. The reaction was monitored with HPLC. After 4 days at reflux, the starting epoxide was completely converted. The mixture was cooled to room temperature. 10 ml of chloroform was added. The organic layer was washed with 3×20 ml of water, dried (Na2SO4), filtrated and evaporated to dryness. Residue: 226 mg (brown oil). Purification of the residue by column chromatography (Merck silica gel 60; eluens: heptane/ethyl acetate=1/1) afforded R-enantiomer of bicalutamide as a white/yellow solid material. Purified yield: 122 mg (43%). HPLC: 96.3% purity. HPLC (chiral column): 94.7% e.e. 1H and 13C NMR in agreement with R-bicalutamide
Name
sodium p-fluorobenzenesulfinate
Quantity
133 mg
Type
reactant
Reaction Step Two
[Compound]
Name
epoxide
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Three
Synthesis routes and methods II
Procedure details
0.500 g of the epoxyamide (5A) was dissolved in a mixture of 40 ml of chloroform and 40 ml of water and 371 mg of sodium p-fluorobenzenesulfinate was added. Subsequently, 298 mg of tetrabutylammonium bromide was added. The reaction mixture was heated till reflux, while stirring vigorously. The reaction was monitored with HPLC. After 96 hours of reflux, the reaction mixture was cooled to room temperature. 20 ml of chloroform was added and the organic layer was washed with 3×50 ml of water, dried (Na2SO4) and evaporated to dryness. Yield: 860 mg. Purification of the crude product by column chromatography (Merck silica gel 60; eluent: heptane/ethyl acetate=1/1) afforded bicalutamide as white solid. Isolated yield: 380 mg (48%). 1H-NMR: confirmed the structure.
Name
sodium p-fluorobenzenesulfinate
Quantity
371 mg
Type
reactant
Reaction Step One
Name
Synthesis routes and methods III
Procedure details
4′-Cyano-3-(4-fluorophenylthio)-2-hydroxy-2-methyl-3′-trifluoromethylpropionanilide (12.20 g, 30.6 mmol) and ethyl acetate (20 ml) were successively charged in a 200 ml four-neck flask, and the mixture was stirred under ice-cooling (2° C.–7° C.). A solution of mono-perphthalic acid in ethyl acetate (166.58 g, net 22.31 g, 122.5 mmol) was dropwise added at not higher than 10° C., and the mixture was stirred for 1 hr. A 20% KOH solution (117.5 g) was dropwise added thereto and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate (30 ml). The combined organic layer was washed with a solution of sodium pyrosulfite (3.0 g) dissolved in deionized water (30 ml), dried over magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (66 ml) was added to the residue and the mixture was heated to 60° C. n-Heptane (40 ml) was added dropwise at a temperature of 60° C.–65° C. over 40 min. After the completion of the dropwise addition, the mixture was allowed to cool to room temperature (about 20° C.–25° C.) and filtrated to give 4′-cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3′-trifluoromethylpropionanilide (12.24 g, yield 91.2%). Purity 99.97%.
Quantity
12.2 g
Type
reactant
Reaction Step One
Synthesis routes and methods IV
Procedure details
Quantity
Extracted from reaction SMILES
Type
reactant
Reaction Step One
Quantity
Extracted from reaction SMILES
Type
reactant
Reaction Step One
Synthesis routes and methods V
Procedure details
To a solution of 2 g (2.51 mmol) of N-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenyl-thio]-2-hydroxy-2-methyl-propionamide in 10 ml of acetonitrile, 20 ml of methanol and 0.6 ml of water 0.38 g (2.75 mmol) of potassium carbonate was added. The mixture was cooled to 5° C. and 10 ml of 30% aqueous hydrogen peroxide solution was added dropwise. The mixture was stirred at 25° C. overnight, then diluted with 100 ml of water and extracted twice with 100 ml of dichloromethane. The organic layer was washed with 50 ml of brine, dried over sodium sulfate and concentrated under diminished pressure. The residue was recrystallized from a 1:4 mixture of ethyl acetate/petroleum ether, which has a boiling range of 40–70° C. The yield was 1.53 g (70.83%).
Quantity
2 g
Type
reactant
Reaction Step One
Retrosynthesis Analysis
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| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
Reactant of Route 1
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Bicalutamide
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Bicalutamide
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Bicalutamide
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Reactant of Route 5
Bicalutamide
Reactant of Route 6
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