68047-06-3

Basic information

• Product Name: 4-HYDROXYTAMOXIFEN
• Synonyms: trans-4-Hydroxytamoxifen, (Z)-4-(1-[4-(Dimethylaminoethoxy)phenyl]-2-phenyl-1-butenyl)phenol;(Z)-3,4-Diphenyl-4-[4-[2-(dimethylamino)ethoxy]phenyl]-3-buten-1-ol;2-[4-[(E)-1-(4-Hydroxyphenyl)-2-phenyl-1-butenyl]phenoxy]-N,N-dimethylethanamine;4-[(E)-1-[4-[2-(Dimethylamino)ethoxy]phenyl]-2-phenyl-1-butenyl]phenol;cis-4-Hydroxytamoxifen;N,N-Dimethyl-2-[4-[(E)-1-(4-hydroxyphenyl)-2-phenyl-1-butenyl]phenoxy]ethanamine;4-(1-(4-(dimethylaminoethoxy)phenyl)-2-phenyl-1-butenyl)phenol;(Z)-4-(1-[4-(Dimethylaminoethoxy)phenyl]-2-phenyl-1-butenyl)phenol
• CAS NO: 68047-06-3
• Molecular Formula: C₂₆H₂₉NO₂
• Molecular Weight: 387.51
• Product Categories: Drug Analogues;Intermediates & Fine Chemicals;Pharmaceuticals;Steroids;Aromatics;Metabolites & Impurities
• Mol File: 68047-06-3.mol

Chemical Properties

• Melting Point: 105-107°C
• Boiling Point: 513.45°C (rough estimate)
• Flash Point: 264.9°C
• Appearance: white/powder
• Density: 1.1005 (rough estimate)
• Vapor Pressure: 3.35E-11mmHg at 25°C
• Refractive Index: 1.6000 (estimate)
• Storage Temp.: 2-8°C
• Solubility: 95% ethanol: 20 mg/mL
• PKA: 10.35±0.15(Predicted)
• Stability: Stable. Store cool. Incompatible with strong oxidizing agents.
• CAS DataBase Reference: 4-HYDROXYTAMOXIFEN(CAS DataBase Reference)
• NIST Chemistry Reference: 4-HYDROXYTAMOXIFEN(68047-06-3)
• EPA Substance Registry System: 4-HYDROXYTAMOXIFEN(68047-06-3)

Safety Data

• Hazard Codes: Xn
• Statements: 20/21/22-63
• Safety Statements: 22-23-36
• WGK Germany: 3
• RTECS: SL1210000
• Hazardous Substances Data: 68047-06-3(Hazardous Substances Data)

Usage

Biological Activity

estrogen receptors (er) are members of the superfamily of ligand-modulated nuclear receptors that mediate the actions of steroid hormones, vitamin d, retinoids, and thyroid hormones. er is activated in vivo when bound by naturally occurring estrogens such as 17α-estradiol. in addition to regulating these physiological processes, estrogen also plays a central role in stimulating breast cancer growth. (z)-tamoxifen is a first generation selective er modulators that is currently approved by the fda and is widely used to treat estrogen-dependent breast cancers. its active metabolite, (z)-4-hydroxytamoxifen, is a potent estrogen receptor modulator.

Biochem/physiol Actions

Cell permeable: yes

in vitro

(z)-4-hydroxytamoxifen binds to er with 8-fold higher affinity than tamoxifen. it was found that only the z isomer has the required antiestrogenic activity; the (e)-4-hydroxytamoxifen has only about 5% of its affinity for the er [1].

in vivo

the antioestrogenic activities of (z)-4-hydroxytamoxifen and tamoxifen were determined after oral administration. (z)-4-hydroxytamoxifen was administered to groups of immature rats which also received s.c. injections of 0-2 μg oestradiol. both compounds produced a dose-related decrease in uterine wet weight when compared with the oestradiol-treated controls. at a dose of 1 μg/day, the antiuterotrophic effects of (z)-4-hydroxytamoxifen and tamoxifen were not significantly different but at 5μg/day, (z)-4-hydroxytamoxifen was more active (p < 0.01). (z)-4-hydroxytamoxifen therefore appears to retain its potent antioestrogenic activity after oral administration [2].

references

[1] donna d. yu and barry m. forman. simple and efficient production of (z)-4-hydroxytamoxifen, a potent estrogen receptor modulator. j. org. chem. 2003, 68, 9489-9491[2] jordan vc, collins mm, rowsby l, prestwich g. a monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. j endocrinol. 1977 nov;75(2):305-16.

InChI:InChI=1/C26H29NO2/c1-4-25(20-10-14-23(28)15-11-20)26(21-8-6-5-7-9-21)22-12-16-24(17-13-22)29-19-18-27(2)3/h5-17,28H,4,18-19H2,1-3H3/b26-25-

Upstream product

• 96212-84-9 (E)-1-bromo-2-phenyl-1-(trimethylsilyl)-1-butene 
• 10540-29-1 tamoxifen 
• 91221-46-4 1,1-bis(4-hydroxyphenyl)-2-phenyl-1-butene 
• 107-99-3 2-(dimethylamino)ethyl chloride 
• 611-99-4 4,4'-Dihydroxybenzophenone 
• 93-55-0 1-phenyl-propan-1-one 
• 75-03-6 ethyl iodide 
• 93790-54-6 [2-(4-iodophenoxy)ethyl]dimethylamine 
• 2633-75-2 ethylzinc chloride 
• 124-40-3 dimethyl amine 
• 147323-02-2 E/Z-1-[4-(2-bromoethoxy)phenyl]-1-(4-hydroxyphenyl)-2-phenylbutene 
• 106-41-2 4-bromo-phenol 
• 36603-49-3 4-(tetrahydropyran-2'-yloxy)-1-bromobenzene 
• 126402-32-2 1-(trimethylsilyl)-1-(4-<(2-tetrahydropyranyl)oxy>phenyl)-2-phenyl-1-butene 

Downstream Products

• 1454890-28-8 4-((E)-1-(4-(2-(dimethylamino)ethoxy)phenyl)-2-phenylbut-1-enyl)phenyl 10-((Z)-2-((4-methoxy-1H,1'H-2,2'-bipyrrol-5-yl)methylene)-3,5-dimethyl-2H-pyrrol-4-yl)-10-oxodecanoate 
• 1454890-27-7 4-((E)-1-(4-(2-(dimethylamino)ethoxy)phenyl)-2-phenylbut-1-en-1-yl)phenyl 4-(-2-((4-methoxy-1H,1'H-[2,2'-bipyrrol]-5-yl)methylene)-3,5-dimethyl-2H-pyrrol-4-yl)-4-oxobutanoate 
• 174592-47-3 trans 4-hydroxytamoxifen 
• 76117-70-9 (E)-4-{1-[4-(2-dimethylaminoethoxy)phenyl]-2-phenylbut-1-enyl}phenyl acetate 
• 199541-66-7 4-hydroxytamoxifen quinone methide 

Relevant articles and documents

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method development for screening of potential tamoxifen-drug/herb interaction via in vitro cytochrome P450 inhibition assay

Screening for potential drug-drug interaction (DDI) or herb-drug interaction (HDI) using in vitro cytochrome P450 inhibition (IVCI) assays requires robust analytical methods with high sensitivity and reproducibility. Utilization of liquid chromatography-mass spectrometry (LC-MS) for analyte quantification is often hampered by the presence of non-volatile IVCI sample buffer constituents that often results in ion suppression. In this study, to enable screening of drug interactions involving tamoxifen (TAM) metabolism using IVCI-LC-MS/MS, a liquid–liquid extraction (LLE) method was developed and optimized for sample clean-up. Utilization of chloroform as extraction solvent and adjustment of sample pH to 11 was found to result in satisfactory recovery (>70%) and low ion suppression (A LC-MS/MS method was subsequently developed and validated for simultaneous quantification of major TAM metabolites, such as N-desmethyltamoxifen (NDT), endoxifen (EDF) and 4-hydroxytamoxifen (HTF) to enable IVCI sample analysis. Satisfactory separation of E-/Z-isomers of endoxifen with peak resolution (Rs) of 1.9 was achieved. Accuracy and precision of the method was verified within the linear range of 0–50 ng/mL for NDT, 0–25 ng/mL for HTF and 0–25 ng/mL for EDF (E/Z isomers). Inhibitory potency (IC50, Ki and mode of inhibition) of known CYP inhibitors and Strobilanthes crispus extract was then evaluated using the validated method. In summary, the results demonstrated applicability of the developed LLE and validated LC-MS/MS method for in vitro screening of DDI and HDI involving TAM metabolism.

New approach based on immunochemical techniques for monitoring of selective estrogen receptor modulators (SERMs) in human urine

Antiestrogenic compounds such as tamoxifen, toremifen and chlomifen are used illegally by athletes to minimize physical impacts such as gynecomastia resulting from the secondary effects of anabolic androgenic steroids, used to increase athletic efficiency unlawfully. The use of these compounds is banned by the World Anti-Doping Agency (WADA) and controls are made through analytical methodologies such as HPLC–MS/MS, which do not fulfil the sample throughput requirements. Moreover, compounds such as tamoxifen are also used to treat hormone receptor-positive breast cancer (ER +).Therapeutic drug monitoring (TDM) of tamoxifen may also be clinically useful for guiding treatment decisions. An accurate determination of these drugs requires a solid phase extraction of patient serum followed by HPLC–MS/MS. In the context of an unmet need of high-throughput screening (HTS) and quantitative methods for antiestrogenic substances we have approached the development of antibodies and an immunochemical assay for the determination of these antiestrogenic compounds. The strategy applied has taken into consideration that these drugs are metabolized and excreted in urine as the corresponding 4-hydroxylated compounds. A microplate-based ELISA procedure has been developed for the analysis of these metabolites in urine with a LOD of 0.15, 0.16 and 0.63 μg/L for 4OH-tamoxifen, 4OH-toremifen and 4OH-clomifen, respectively, much lower than the MRPL established by WADA (20 μg/L).

Methods for Determining the Oncogenic Condition of Cell, Uses Thereof, and Methods for Treating Cancer

The invention relates to methods for detecting the oncogenic condition of cells, including step where the amount of the OCDO compound in said cells is measured, and to the uses thereof. The invention further relates to OCDO inhibitors for use in methods for treating cancer.

Photochemical Activation of Tertiary Amines for Applications in Studying Cell Physiology

Representative tertiary amines were linked to the 8-cyano-7-hydroxyquinolinyl (CyHQ) photoremovable protecting group (PPG) to create photoactivatable forms suitable for use in studying cell physiology. The photoactivation of tamoxifen and 4-hydroxytamoxifen, which can be used to activate Cre recombinase and CRISPR-Cas9 gene editing, demonstrated that highly efficient release of bioactive molecules could be achieved through one- and two-photon excitation (1PE and 2PE). CyHQ-protected anilines underwent a photoaza-Claisen rearrangement instead of releasing amines. Time-resolved spectroscopic studies revealed that photorelease of the tertiary amines was extremely fast, occurring from a singlet excited state of CyHQ on the 70 ps time scale.

Biomimetic oxidation of aromatic xenobiotics: Synthesis of the phenolic metabolites from the anti-HIV drug efavirenz

We report the oxidation of the first line anti-HIV drug efavirenz (EFV), mediated by a bio-inspired nonheme Fe-complex. Depending upon the experimental conditions this system can be tuned either to yield the major EFV metabolite, 8-hydroxy-EFV, in enantiomerically pure form or to mimic cytochrome P450 (CYP) activity, yielding 8-hydroxy-EFV and 7-hydroxy-EFV, the two phenolic EFV metabolites reported to be formed in vivo. The successful oxidation of the anti-estrogen tamoxifen and the equine estrogen equilin into their CYP-mediated metabolites supports the general application of bio-inspired nonheme Fe-complexes in mirroring CYP activity.

METHODS FOR DETERMINING THE ONCOGENIC CONDITION OF CELL, USES THEREOF, AND METHODS FOR TREATING CANCER

The invention relates to methods for detecting the oncogenic condition of cells, including step where the amount of the OCDO compound in said cells is measured, and to the uses thereof. The invention further relates to OCDO inhibitors for use in methods for treating cancer

Synthesis of tetrasubstituted alkenes by stereo- and regioselective stannyllithiation of diarylacetylenes

Addition of trimethylstannyllithium to a diarylacetylene takes place exclusively in an anti-fashion to produce a lithio vinylstannane intermediate. The regioselectivity of the addition is controlled by the steric and electronic property of the acetylene and reaches up to >99:1. The two newly formed C-metal bonds can be sequentially and stereospecifically transformed into two new C-C bonds as illustrated by stereoselective synthesis of 4-hydroxytamoxifen and its regioisomer. A tetraarylethene bearing different aryl groups can be synthesized similarly and cyclized to a substituted dibenzo[g,p]chrysene derivative via a palladium-catalyzed arylation reaction.

TARGETED DRUG-FORMALDEHYDE CONJUGATES AND METHODS OF MAKING AND USING THE SAME

The invention provides a prodrug platform technology for improving the therapeutic value of a variety of parent drug compounds by altering and improving drug characteristics such as aqueous solubility, hydrolytic stability, therapeutic index, toxicity profile, pharmacokinetics and selectivity while allowing the potential for synthetic elaboration. The prodrug platform is particularly well suited for targeting therapeutic drugs, including anti-tumor drugs and antibiotics, to specific receptors on target cells (e.g., cancer cells and bacteria). The platform is a technology for providing an improved, preactivated form of a therapeutic drug, and for optionally targeting such drug to target cells or biological molecules. The invention is broadly applicable to many different therapeutic drugs, as well as to a variety of diseases and conditions, including a variety of forms of cancer and bacterial infections.

Simple and Efficient Production of (Z)-4-Hydroxytamoxifen, a Potent Estrogen Receptor Modulator

A McMurry coupling reaction and selective crystallization were used to develop a simple and efficient two-step synthesis of (Z)-4-hydroxytamoxifen (2a). This compound is an active metabolite of tamoxifen, a selective estrogen receptor (ER) modulator widely used to treat breast cancer. The synthesis employed 1,1-bis(4-hydroxyphenyl)-2-phenylbut-1-ene (1) as a useful building block.

Synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1-butenyl]phenoxyacetic acid

The synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1-butenyl]phenoxyacetic acid was accomplished using a McMurry reaction as the key step. The perfluorotolyl derivatives of the McMurry products enabled the separation of the minor undesirable geometrical isomer. The methodology proceeds without E,Z isomerization, employs a very mild final debenzylation step compatible with a large array of functional groups, and can be applied to the generation of a variety of 4-hydroxytamoxifen analogues.