(Z)-4-Hydroxytamoxifen

ER modulator, potent and selective CAS# 68047-06-3

(Z)-4-Hydroxytamoxifen

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Chemical structure

(Z)-4-Hydroxytamoxifen

3D structure

Chemical Properties of (Z)-4-Hydroxytamoxifen

Cas No. 68047-06-3 SDF Download SDF
PubChem ID 5284643 Appearance Powder
Formula C26H29NO2 M.Wt 387.51
Type of Compound N/A Storage Desiccate at -20°C
Synonyms 4-OH-TAM;4-Hydroxytamoxifen; Afimoxifene; Hydroxytamoxifen; Tamogel; 4-Monohydroxytamoxifen
Solubility DMSO : ≥ 28 mg/mL (72.26 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name 4-[(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-phenylbut-1-en-2-yl]phenol
SMILES CCC(=C(C1=CC=CC=C1)C2=CC=C(C=C2)OCCN(C)C)C3=CC=C(C=C3)O
Standard InChIKey DODQJNMQWMSYGS-QPLCGJKRSA-N
Standard InChI InChI=1S/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-
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of (Z)-4-Hydroxytamoxifen

DescriptionEstrogen receptor antagonist. Tamoxifen metabolite; exhibits greater potency than the parent compound. Chemotherapeutic agent. Also activates intein-linked inactive Cas9, reducing off-target CRISPR-mediated gene editing; system has ~25-fold higher specificity than wtCas9.

Protocol

Kinase Assay [1]
Cytosol (200 μL) is incubated for 30 min at 4°C with different concentrations of oestradiol, tamoxifen and (4-Hydroxytamoxifen) or dihydroxytamoxifen administered in 10 μL methanol. Control tubes are incubated with 10 μL methanol alone and non-specific binding is determined in a parallel incubation of cytosol (200 μL) with methanol (10 μL) containing DES (5 × 106 M). [2,4,6,7-3H]Oestradiol solution (50 μL) in TED buffer is added to each tube to give a final concentration of 2 × 10-9 M. Incubation is continued for 4 h (4°C) and then 400 μL of a suspension of dextran-coated charcoal (250 mg % Norit A, 2.5 mg % dextran) in TED buffer are added and allowed to stand for 20 min. Tubes are centrifuged at 800 g for 10 min (4°C) and 400 μL samples of the supernatant are added to 10 mL tritium scintillator (6 g butyl PBD, 135 mL toluene, 720 ml dioxan, 100 g naphthalene, 45 mL absolute methanol). Samples are counted for 10 min in a liquid scintillation spectrometer. Counting efficiency is determined by external standardization (35-36 %). Results are represented as a percentage of the specifically bound radioactivity (c.p.m.) in the control tubes[1].

Animal Administration [3]
Mice[3] Animals of each sex are divided into two groups: one group receives 4-Hydroxytamoxifen [6 μg/0.1 mL sesame oil/day, subcutaneously (s.c.) starting at 06.00 h] injections for three consecutive days, while the other group receives an equivalent amount of sesame oil injection for 3 days. Four hours following the third injection, each group is then subdivided into two groups: one receives four cumulative doses of methamphetamine hydrochloride (10 mg/kg, s.c.), and the other receives a comparable volume of saline at 2-h intervals. Bilateral gonadectomy is performed under pentobarbital anesthesia (50 mg/kg, intraperitoneally). Five weeks after surgery,gonadectomized mice of each sex are randomly divided into six groups. Five groups of each sex receive three daily injections ofvarious concentrations of 4-Hydroxytamoxifen (0, 1.5, 3.0, 6.0, and 12.0 μg/0.1 mL sesame oil/day). Four hours following the third injection, mice receive four doses of methamphetamine (MA, 10 mg/kg) at 2-h intervals. The remaining group of each sex receives sesame oil pretreatment for three consecutive days, followed by saline injections, and serves as the control group[3].

References:
[1]. Jordan VC, et al. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol. 1977 Nov;75(2):305-16. [2]. Davis KM, et al. Small molecule-triggered Cas9 protein with improved genome-editing specificity. Nat Chem Biol. 2015 May;11(5):316-8. [3]. Kuo YM, et al. 4-Hydroxytamoxifen attenuates methamphetamine-induced nigrostriatal dopaminergic toxicity in intact and gonadetomized mice. J Neurochem. 2003 Dec;87(6):1436-43.

(Z)-4-Hydroxytamoxifen Dilution Calculator

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Preparing Stock Solutions of (Z)-4-Hydroxytamoxifen

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.5806 mL 12.9029 mL 25.8058 mL 51.6116 mL 64.5145 mL
5 mM 0.5161 mL 2.5806 mL 5.1612 mL 10.3223 mL 12.9029 mL
10 mM 0.2581 mL 1.2903 mL 2.5806 mL 5.1612 mL 6.4514 mL
50 mM 0.0516 mL 0.2581 mL 0.5161 mL 1.0322 mL 1.2903 mL
100 mM 0.0258 mL 0.129 mL 0.2581 mL 0.5161 mL 0.6451 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on (Z)-4-Hydroxytamoxifen

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.

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].

Clinical trial: Up to now, (Z)-4-Hydroxytamoxifen is still in the preclinical development stage.

Reference:
[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.

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References on (Z)-4-Hydroxytamoxifen

Synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1butenyl]phenoxyacetic acid.[Pubmed:12076167]

J Org Chem. 2002 Jun 28;67(13):4608-11.

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.

Simple and efficient production of (Z)-4-hydroxytamoxifen, a potent estrogen receptor modulator.[Pubmed:14629178]

J Org Chem. 2003 Nov 28;68(24):9489-91.

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 and sulfatase inhibitory activities of (E)- and (Z)-4-hydroxytamoxifen sulfamates.[Pubmed:10021916]

Bioorg Med Chem Lett. 1999 Jan 18;9(2):141-4.

We report the development of (E)- and (Z)-4-Hydroxytamoxifen sulfamates as estrone sulfatase inhibitors, potential therapeutic agents for the treatment of breast cancer. Both compounds competitively inhibit estrone sulfatase isolated from rat liver with apparent Ki of 35.9 microM for (E)-4-hydroxytamoxifen sulfamate and an apparent Ki of > 500 microM for the (Z) isomer.

Small molecule-triggered Cas9 protein with improved genome-editing specificity.[Pubmed:25848930]

Nat Chem Biol. 2015 May;11(5):316-8.

Directly modulating the activity of genome-editing proteins has the potential to increase their specificity by reducing activity following target locus modification. We developed Cas9 nucleases that are activated by the presence of a cell-permeable small molecule by inserting an evolved 4-hydroxytamoxifen-responsive intein at specific positions in Cas9. In human cells, conditionally active Cas9s modify target genomic sites with up to 25-fold higher specificity than wild-type Cas9.

Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6.[Pubmed:15159443]

J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.

We performed comprehensive kinetic, inhibition, and correlation analyses in human liver microsomes and experiments in expressed human cytochromes P450 (P450s) to identify primary and secondary metabolic routes of tamoxifen (TAM) and the P450s catalyzing these reactions at therapeutically relevant concentrations. N-Desmethyl-TAM formation catalyzed by CYP3A4/5 was quantitatively the major primary metabolite of TAM; 4-hydroxy-TAM formation catalyzed by CYP2D6 (and other P450s) represents a minor route. Other minor primary metabolites include alpha -, 3-, and 4'-hydroxyTAM and one unidentified metabolite (M-I) and were primarily catalyzed by CYP3A4, CYP3A5, CYP2B6/2C19, and CYP3A4, respectively. TAM secondary metabolism was examined using N-desmethyl- and 4-hydroxy-TAM as intermediate substrates. N-Desmethyl-TAM was predominantly biotransformed to alpha-hydroxy N-desmethyl-, N-didesmethyl-, and 4-hydroxy N-desmethyl-TAM (endoxifen), whereas 4-hydroxy-TAM was converted to 3,4-dihydroxyTAM and endoxifen. Except for the biotransformation of N-desmethyl-TAM to endoxifen, which was exclusively catalyzed by CYP2D6, all other routes of N-desmethyl- and 4-hydroxy-TAM biotransformation were catalyzed predominantly by the CYP3A subfamily. TAM and its primary metabolites undergo extensive oxidation, principally by CYP3A and CYP2D6 to metabolites that exhibit a range of pharmacological effects. Variable activity of these P450s, brought about by genetic polymorphisms and drug interactions, may alter the balance of TAM effects in vivo.

A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity.[Pubmed:591813]

J Endocrinol. 1977 Nov;75(2):305-16.

The oestrogenic and antioestrogenic properties of tamoxifen and its monohydroxylated (monohydroxytamoxifen) and dihydroxylated (dihydroxytamoxifen) metabolites have been investigated in the immature rat. Whether administered orally or subcutaneously, monohydroxytamoxifen was more active than tamoxifen as an antioestrogen. Dihydroxytamoxifen was less active than tamoxifen as an antioestrogen, but this derivative alone was unable to induce a uterotrophic response. Both metabolites of tamoxifen were potent inhibitors of the binding of [3H]oestradiol to oestrogen receptors in vitro. It is possible that the metabolites play a supportive role in the antioestrogenic activity of tamoxifen. The potent activity of monohydroxytamoxifen in vivo and in vitro suggests that this compound could be an important new tool for the subcellular investigation of oestrogenic and antioestrogenic events.

Description

4-Hydroxytamoxifen is a selective estrogen receptor modulator (SERM).

Keywords:

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