Toremifene (NSC 613680; NK 622; FC 1157a) is an orally bioavailable and second-generation SERM (selective estrogen receptor modulator) used in the treatment of advanced breast cancer. Toremifene citrate acts by antagonizing the actions of estrogen in the body. Toremifene (7.5 mM) causes approximately 60% of the cells to exhibit morphologic characteristics typical of cells undergoing programmed death, or apoptosis in human breast cancer cells. Toremifene (5-10 mM) results in elevated levels of TRPM-2 and TGF beta 1 mRNAs in in vitro or in vivo grown tumor cells.
Physicochemical Properties
| Molecular Formula | C26H28CLNO |
| Molecular Weight | 405.97 |
| Exact Mass | 405.185 |
| CAS # | 89778-26-7 |
| Related CAS # | Toremifene citrate;89778-27-8;Toremifene-d6;Toremifene-d6 hydrochloride |
| PubChem CID | 3005573 |
| Appearance | White to light yellow solid powder |
| Density | 1.1±0.1 g/cm3 |
| Boiling Point | 535.1±50.0 °C at 760 mmHg |
| Melting Point | 108-110°C |
| Flash Point | 277.4±30.1 °C |
| Vapour Pressure | 0.0±1.4 mmHg at 25°C |
| Index of Refraction | 1.588 |
| LogP | 7.82 |
| Hydrogen Bond Donor Count | 0 |
| Hydrogen Bond Acceptor Count | 2 |
| Rotatable Bond Count | 9 |
| Heavy Atom Count | 29 |
| Complexity | 483 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | CN(C)CCOC1=CC=C(C=C1)/C(=C(/CCCl)\C2=CC=CC=C2)/C3=CC=CC=C3 |
| InChi Key | XFCLJVABOIYOMF-QPLCGJKRSA-N |
| InChi Code | InChI=1S/C26H28ClNO/c1-28(2)19-20-29-24-15-13-23(14-16-24)26(22-11-7-4-8-12-22)25(17-18-27)21-9-5-3-6-10-21/h3-16H,17-20H2,1-2H3/b26-25- |
| Chemical Name | Ethanamine, 2-(4-((1Z)-4-chloro-1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl- |
| Synonyms | GTx 006 Z-Toremifene Acapodene Farestone |
| 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 | Toremifene is a selective estrogen receptor modulator (SERM) of the second generation being developed to stop osteoporosis and other side effects of ADT-induced prostate cancer [1]. The proliferation of Ac-1 cells is inhibited in vitro by tamoxifen, toremifene, and atamestane, with IC50 values of 1.8±1.3μM, 1±0.3μM, and 60.4±17.2μM, respectively. The combination of toremifene and atamestane is more effective than either drug alone, according to in vitro research [3]. |
| ln Vivo | After that, the impact of this combination was investigated in vivo utilizing Ac-1 xenografts developed in female SCID mice with ovariectomies. Toremifene (1000 μg/day), atamestane (1000 μg/day), tamoxifen (100 μg/day), or a combination of toremifene and atamestane were injected into mice. The findings of this investigation indicate that toremifene plus atamestane is as effective as either drug alone, although it might not be any more so than either drug alone. There are no further benefits associated with tamoxifen usage [3]. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Well absorbed Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency. 580 L 5 L/h Metabolism / Metabolites Hepatic. Mainly by CYP3A4 to N-demethyltoremifene, which exhibits antiestrogenic effects but has weak antitumor potency in vivo. Toremifene has known human metabolites that include N-desmethyltoremifene. Biological Half-Life 5 days |
| Toxicity/Toxicokinetics |
Hepatotoxicity Toremifene has been associated with mild-to-moderate serum ALT or AST elevations in 5% to 19% of patients, but these abnormalities are usually transient and not associated with symptoms or jaundice. Elevations above 5 times the ULN are uncommon ( Likelihood score: D (possible cause of clinically apparent liver injury). Protein Binding Toremifen is primarily bound to albumin (92%), 2% bound to α1-acid glycoprotein, and 6% bound to β1-globulin in the serum. |
| References |
[1]. Matthew R Smith, Selective Estrogen Receptor Modulators to Prevent Treatment-Related Osteoporosis.Rev Urol. 2005; 7(Suppl 3): S30-S35. [2]. Screening and Reverse-Engineering of Estrogen Receptor Ligands as Potent Pan-Filovirus Inhibitors. J Med Chem. 2020 Sep 4. [3]. Gauri J Sabnis, Luciana Macedo, Olga Goloubeva, Toremifene - Atamestane; Alone or In Combination: Predictions from the Preclinical Intratumoral Aromatase Model. J Steroid Biochem Mol Biol. 2008 January; 108(1-2): 1-7. [4]. Taneja SS, Morton R, Barnette G, Prostate cancer diagnosis among men with isolated high-grade intraepithelial neoplasia enrolled onto a 3-year prospective phase III clinical trial of oral toremifene. J Clin Oncol. 2013 Feb 10;31(5):523-9. |
| Additional Infomation |
Toremifene is a tertiary amine, an organochlorine compound and an aromatic ether. It has a role as an antineoplastic agent, an estrogen antagonist, an estrogen receptor modulator and a bone density conservation agent. It derives from a hydride of a stilbene. Toremifene is a selective estrogen receptor modulator (SERM) and a nonsteroidal antiestrogen used to treat estrogen receptor positive breast cancer. Like [tamoxifen], toremifene is part of the first-generation triphenylethylene derivative chemical class of SERMs. Toremifene possesses tissue-specific actions: it has estrogenic (agonist) activity on the cardiovascular system and on bone tissue and it has weak estrogenic effects on uterine tissue, however, it also has antiestrogenic (estrogen-antagonist) activity on breast tissue. Toremifene is an Estrogen Agonist/Antagonist. The mechanism of action of toremifene is as a Selective Estrogen Receptor Modulator. Toremifene is a nonsteroidal antiestrogen that is used in the treatment of estrogen receptor positive breast cancer. Long term toremifene therapy has been associated with development of fatty liver, steatohepatitis, cirrhosis, and rare instances of clinically apparent acute liver injury. Toremifene is a nonsteroidal triphenylethylene antiestrogen. Chemically related to tamoxifen, toremifene is a selective estrogen receptor modulator (SERM). This agent binds competitively to estrogen receptors, thereby interfering with estrogen activity. Toremifene also has intrinsic estrogenic properties, which are manifested according to tissue type or species. (NCI04) A first generation selective estrogen receptor modulator (SERM). Like TAMOXIFEN, it is an estrogen agonist for bone tissue and cholesterol metabolism but is antagonistic on mammary and uterine tissue. See also: Toremifene Citrate (has salt form). Drug Indication For the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or receptor-unknown tumors. Toremifene is currently under investigation as a preventative agent for prostate cancer in men with high-grade prostatic intraepithelial neoplasia and no evidence of prostate cancer. First line hormone treatment of hormone-dependent metastatic breast cancer in postmenopausal patients. Fareston is not recommended for patients with estrogen receptor negative tumours. Mechanism of Action Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, in other words, its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Toremifene may also inhibit tumor growth through other mechanisms, such as induction of apoptosis, regulation of oncogene expression, and growth factors. Pharmacodynamics Toremifene is an antineoplastic hormonal agent primarily used in the treatment of advanced breast cancer. Toremifene is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Toremifene inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, Toremifene appears to exert its antitumor effects by binding the estrogen receptors. In cytosols derived from human breast adenocarcinomas, Toremifene competes with estradiol for estrogen receptor protein. |
Solubility Data
| Solubility (In Vitro) | May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4632 mL | 12.3162 mL | 24.6324 mL | |
| 5 mM | 0.4926 mL | 2.4632 mL | 4.9265 mL | |
| 10 mM | 0.2463 mL | 1.2316 mL | 2.4632 mL |