Estrogen receptors. Chlorotrianisene is a synthetic non-steroidal estrogen and an estrogen receptor modulator (agonist/antagonist). It exhibits little or no binding to the uterine estrogen receptor in vitro, but demonstrates potent estrogenic activity in vivo, indicating that it is a prodrug (pro-estrogen/pro-antiestrogen).

Initial evidence of the potential for ER activation as a growth-stimulating mechanism is provided by comparing the intracellular estrogen receptor (ER) affinity of chlortrianisene with the comparable rat uterine cytosolic ER affinity. With a 500 nM Ki and an EC50 of 28 nM, chlorotrianisene stimulates cell proliferation in MCF-7 cells in a concentration-dependent manner[1].
Chlorotrianisene exerts its effects through estrogen receptor modulation. In vivo, it is converted to its active form and binds to estrogen receptors, producing estrogenic effects. The compound demonstrates potent estrogenic activity in vivo despite little or no binding to the uterine estrogen receptor in vitro, indicating that it is a prodrug. It has been used for the treatment of menopause, ovarian deficiencies, and prostate cancer.

Rat liver microsomes and NADPH were incubated with chlortrianisene to produce reaction intermediates that covalently bound to the protein. The uterine estrogen receptor may be rendered inactive by intermediates (ER). Under conditions that resulted in intermediates, the ER binding capacity for [3H]estradiol (E2) was significantly reduced when chlorotrianisene was incubated with rat liver microsomes and NADPH in the presence of a rat uterus [3].
In vivo, chlorotrianisene prevents mammary tumor formation induced by DMBA in rats at 5 mg/animal (s.c.). It also prevents bone loss and uterine atrophy in ovariectomized rats. The compound demonstrates potent estrogenic activity in vivo and has been used for the treatment of menopause symptoms, ovarian deficiencies, and prostate cancer.

In vitro receptor binding assays for chlorotrianisene involve measuring its affinity for estrogen receptors using radioligand binding techniques. Uterine estrogen receptors are incubated with radiolabeled estradiol and increasing concentrations of chlorotrianisene. Bound and free ligand are separated by filtration, and radioactivity is measured. Chlorotrianisene exhibits little or no binding to the uterine estrogen receptor in vitro.

In vitro cellular assays for chlorotrianisene involve treating estrogen-responsive cell lines with the compound and measuring estrogen receptor-mediated gene expression or cell proliferation. Cells are treated with various concentrations of chlorotrianisene, and the expression of estrogen-responsive genes is measured by qPCR or reporter assays. The compound's estrogenic or anti-estrogenic activity is assessed.

In vivo animal studies for chlorotrianisene typically involve administration to rodent models. In rats, chlorotrianisene (5 mg/animal, s.c.) prevents mammary tumor formation induced by DMBA. It also prevents bone loss and uterine atrophy in ovariectated rats. These studies demonstrate the compound's estrogenic activity and potential therapeutic applications.

Absorption, Distribution and Excretion
Absorption is rapid after oral administration. …Long-acting… Its application is not widespread due to accumulation in adipose tissue. …Indicates that the drug is converted to a more active form in the liver. …It is stored in fat and slowly released from there to exert a sustained effect. …Estrogenic activity can still be detected in adipose tissue up to one month after discontinuation. Metabolism/Metabolites Primarily metabolized in the liver, but the kidneys, gonads, and muscle tissue may also be involved to some extent. The metabolic pathway of synthetic estrogen is not fully elucidated. The O-demethylation reaction rate reaches its maximum at a concentration of 0.4 mmol NADPH. Although NADH alone cannot catalyze this reaction, it has a synergistic effect in the presence of equimolar concentrations of NADPH. The extract of the incubation mixture contains one major metabolite (mono-O-demethylation) and one minor metabolite (bis-O-demethylation).
Pharmacokinetic studies of chlorotrianisene show that the compound is orally bioavailable and highly lipophilic. It exhibits little or no binding to the uterine estrogen receptor in vitro but demonstrates potent estrogenic activity in vivo, indicating that it is a prodrug. The compound has a molecular weight of 380.86 and a molecular formula of C23H21ClO3.

Protein Binding
50-80%
Preclinical toxicity studies of chlorotrianisene have established its safety profile for therapeutic use. The compound has been used clinically for the treatment of menopause, ovarian deficiencies, and prostate cancer. It is an approved pharmaceutical agent. The compound should be used under medical supervision due to its hormonal activity.

[1]. Estrogenic tamoxifen derivatives: categorization of intrinsic estrogenicity in MCF-7 cells. J Steroid Biochem Mol Biol. 1997 Nov-Dec;63(4-6):203-9.

[2]. Large-scale prediction and testing of drug activity on side-effect targets. Nature. 2012 Jun 10;486(7403):361-7.

[3]. Inactivation of the uterine estrogen receptor binding of estradiol during P-450 catalyzed metabolism of chlorotrianisene (TACE). Speculation that TACE antiestrogenic activity involves covalent binding to the estrogen receptor. FEBS Lett.

Chlorotrianisene may be carcinogenic, depending on state or federal labeling requirements. It appears as small white crystals or a white powder. It softens at 226 °F (107 °C). It is odorless. (NTP, 1992) Chlorotrianisene is a chlorinated olefin. It is an estrogen receptor modulator, antitumor drug, and isoestrone. It is derived from the hydride of stilbene. Chlorotrianisene is a highly bioavailable, lipophilic synthetic triphenylene oxide (TPE) derivative and a selective estrogen receptor modulator (SERM). It primarily exhibits estrogenic activity but also possesses antiestrogenic activity. After administration, Chlorotrianisene binds to the estrogen receptor (ER) and, depending on the target cell, activates or inhibits ER activity. This modulates the expression of ER-responsive genes in a tissue-specific manner. The drug may increase bone density, improve lipid profiles, and alleviate vasomotor symptoms. Trichlorophenylethylamine inhibits the pituitary gland's secretion of gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) through a negative feedback mechanism. It is a potent synthetic nonsteroidal estrogen. Indications: It is used to treat menopausal symptoms, ovarian insufficiency (including female hypogonadism and certain types of infertility), and in rare cases, prostate cancer. Trichlorophenylethylamine can also be used to prevent postpartum breast engorgement. Mechanism of Action: Trichlorophenylethylamine binds to estrogen receptors on various cells expressing estrogen receptors. Target cells include those in the female reproductive tract, mammary glands, hypothalamus, and pituitary gland. Estrogen increases the synthesis of sex hormone-binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins in the liver and inhibits the secretion of follicle-stimulating hormone (FSH) from the anterior pituitary gland.
Chlorotrianisene (TACE) is a synthetic non-steroidal estrogen and selective estrogen receptor modulator that was used for the treatment of menopause symptoms, ovarian deficiencies, and prostate cancer. It is a highly lipophilic triphenylethylene derivative. The compound exhibits little or no binding to the uterine estrogen receptor in vitro but demonstrates potent estrogenic activity in vivo as a prodrug. In animal models, it prevents DMBA-induced mammary tumor formation and bone loss.

C23H21CLO3

380.86

380.118

569-57-3

Chlorotrianisene-d9;1276197-26-2

11289

Off-white to light yellow solid powder

1.168g/cm3

514.2ºC at 760mmHg

114-116ºC

164.1ºC

1.591

5.867

0

3

6

27

442

0

BFPSDSIWYFKGBC-UHFFFAOYSA-N InChi Code

InChI=1S/C23H21ClO3/c1-25-19-10-4-16(5-11-19)22(17-6-12-20(26-2)13-7-17)23(24)18-8-14-21(27-3)15-9-18/h4-15H,1-3H3

1-[1-chloro-2,2-bis(4-methoxyphenyl)ethenyl]-4-methoxybenzene

Chlorotrianisene Chlortrianisestrol Chlortrianizen Chlorotrianisine Chlorestrolo Chlorotrianizen Khlortrianizen Clorestrolo Clorotrisin Hormonisene Anisene Metace Rianil Tace

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~262.56 mM)

Solubility in Formulation 1: 2.5 mg/mL (6.56 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.56 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)