Chlorotrianisene is a long-acting, orally bioactive non-steroidal synthetic estrogen that was used for the treatment of menopause, deficiencies in ovary function, and prostate cancer.
Physicochemical Properties
| Molecular Formula | C23H21CLO3 |
| Molecular Weight | 380.86 |
| Exact Mass | 380.118 |
| CAS # | 569-57-3 |
| Related CAS # | Chlorotrianisene-d9;1276197-26-2 |
| PubChem CID | 11289 |
| Appearance | Off-white to light yellow solid powder |
| Density | 1.168g/cm3 |
| Boiling Point | 514.2ºC at 760mmHg |
| Melting Point | 114-116ºC |
| Flash Point | 164.1ºC |
| Index of Refraction | 1.591 |
| LogP | 5.867 |
| Hydrogen Bond Donor Count | 0 |
| Hydrogen Bond Acceptor Count | 3 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 27 |
| Complexity | 442 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | BFPSDSIWYFKGBC-UHFFFAOYSA-N InChi Code |
| 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 |
| Chemical Name | 1-[1-chloro-2,2-bis(4-methoxyphenyl)ethenyl]-4-methoxybenzene |
| Synonyms | Chlorotrianisene Chlortrianisestrol Chlortrianizen Chlorotrianisine Chlorestrolo Chlorotrianizen Khlortrianizen Clorestrolo Clorotrisin Hormonisene Anisene Metace Rianil Tace |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | 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]. |
| ln Vivo | 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]. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Absorption following oral administration is rapid. ...LONG-ACTING...BECAUSE OF SEQUESTRATION IN ADIPOSE TISSUE &, THEREFORE, IS NOT WIDELY USED. ...SUGGESTS THAT DRUG IS CONVERTED IN LIVER TO MORE ACTIVE FORM. ... IT IS STORED IN FAT, FROM WHICH IT IS SLOWLY RELEASED TO GIVE SUSTAINED ACTION. ESTROGENIC ACTIVITY HAS BEEN FOUND IN ADIPOSE TISSUE UP TO MONTH AFTER CESSATION OF THERAPY. Metabolism / Metabolites Metabolized principally in the liver, although the kidneys, gonads, and muscle tissues may be involved to some extent. The metabolic fate of the synthetic estrogens has not been fully elucidated. RATE OF O-DEMETHYLATION WAS MAXIMAL AT 0.4 MMOLAR NADPH. ALTHOUGH NADH DID NOT CATALYZE REACTION ALONE, IT HAD SYNERGISTIC EFFECT IN PRESENCE OF EQUIMOLAR AMT OF NADPH. EXTRACTS FROM INCUBATION MIXT CONTAINED 1 MAJOR (MONO-O-DEMETHYLATED) & A MINOR (BIS-O-DEMETHYLATED) METAB. |
| Toxicity/Toxicokinetics |
Protein Binding 50-80% |
| References |
[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. |
| Additional Infomation |
Chlorotrianisene can cause cancer according to state or federal government labeling requirements. Small white crystals or white powder. Softens at 226 °F. Odorless. (NTP, 1992) Chlorotrianisene is a chloroalkene. It has a role as an estrogen receptor modulator, an antineoplastic agent and a xenoestrogen. It derives from a hydride of a stilbene. Chlorotrianisene is an orally bioavailable, highly lipophilic, synthetic triphenylethylene (TPE) derivative and selective estrogen receptor modulator (SERM), with predominantly estrogenic but also antiestrogenic activities. Upon administration, chlorotrianisene binds to estrogen receptors (ER) and, depending on the responsive target cells, either activates or blocks ER activity. This modulates the expression of ER-responsive genes in a tissue-specific manner. This agent may increase bone mineral density, modify the lipid profile and ameliorate vasomotor symptoms. Chlorotrianisene inhibits the pituitary secretion of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) through a negative feedback mechanism. A powerful synthetic, non-steroidal estrogen. Drug Indication Used to treat symptoms of menopause, deficiencies in ovary function (including underdevelopment of female sexual characteristics and some types of infertility), and in rare cases, prostate cancer. Chlorotrianisene may also be used to prevent breast engorgement following childbirth. Mechanism of Action Chlorotrianisene binds to the estrogen receptor on various estrogen receptor bearing cells. Target cells include cells in the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~262.56 mM) |
| Solubility (In Vivo) |
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. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6256 mL | 13.1282 mL | 26.2564 mL | |
| 5 mM | 0.5251 mL | 2.6256 mL | 5.2513 mL | |
| 10 mM | 0.2626 mL | 1.3128 mL | 2.6256 mL |