Triphenylchloroethylene

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Triphenylchloroethylene
Triphenylchloroethylene.png
Clinical data
Trade names Gynosone, Oestrogyl
Other namesTPCE; Triphenylchlorethylene; Chlorotriphenylethylene; Phenylstilbene chloride
Drug class Nonsteroidal estrogen
Identifiers
  • (1-chloro-2,2-diphenylethenyl)benzene
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C20H15Cl
Molar mass 290.79 g·mol−1
3D model (JSmol)
  • C1=CC=C(C=C1)C(=C(C2=CC=CC=C2)Cl)C3=CC=CC=C3
  • InChI=1S/C20H15Cl/c21-20(18-14-8-3-9-15-18)19(16-10-4-1-5-11-16)17-12-6-2-7-13-17/h1-15H
  • Key:QEQFTTCZLHLKFX-UHFFFAOYSA-N

Triphenylchloroethylene (TPCE; brand names Gynosone, Oestrogyl), or triphenylchlorethylene, also known as chlorotriphenylethylene or as phenylstilbene chloride, is a synthetic nonsteroidal estrogen of the triphenylethylene group that was marketed in the 1940s for the treatment of menopausal symptoms, vaginal atrophy, lactation suppression, and all other estrogen-indicated conditions. [1] [2] [3]

The estrogenic effects of triphenylethylene, the parent compound of triphenylchloroethylene, were discovered in 1937. [4] Triphenylchloroethylene was first reported in 1938 and was found to have 20 to 100 times the estrogenic activity of the relatively weak triphenylethylene, a potentiation of effect that was afforded by its halogen substituent. [2] [5] The drug has a relatively long duration of action when administered via subcutaneous injection but a duration similar to that of diethylstilbestrol or estradiol benzoate when administered orally. [2] [6] [7] Along with diethylstilbestrol and triphenylmethylethylene, triphenylchloroethylene was studied in 1944 by Sir Alexander Haddow for the treatment of breast cancer and was found to be significantly effective, and this is historically notable in that it was the first time that high-dose estrogens were found to be effective in the treatment of breast cancer. [8] [9]

Chlorotrianisene, or tri-p-anisylchloroethylene (TACE), is a potent marketed estrogen and a derivative of triphenylchloroethylene in which each of the three phenyl rings has been substituted with a 4-methoxy group. [5] [10] Estrobin, or DBE, is a related, never-marketed estrogen in which there is a bromine in place of the chlorine and two of the three phenyl rings have ethoxy groups. [5] Broparestrol, or BDPE is a marketed selective estrogen receptor modulator (SERM) that has a bromine in place of the chlorine of triphenylchloroethylene and a 4-ethyl group on one of the phenyl rings. The SERM clomifene is also a derivative of triphenylchloroethylene. [11]

See also

Related Research Articles

Clomifene Infertility treatment for women

Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a course of treatment that usually lasts for 5 days.

Selective estrogen receptor modulator

Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.

Tamoxifen Medication

Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.

Chlorotrianisene

Chlorotrianisene (CTA), also known as tri-p-anisylchloroethylene (TACE) and sold under the brand name Tace among others, is a nonsteroidal estrogen related to diethylstilbestrol (DES) which was previously used in the treatment of menopausal symptoms and estrogen deficiency in women and prostate cancer in men, among other indications, but has since been discontinued and is now no longer available. It is taken by mouth.

Afimoxifene

Afimoxifene is a selective estrogen receptor modulator (SERM) of the triphenylethylene group and an active metabolite of tamoxifen. The drug is under development under the tentative brand name TamoGel as a topical gel for the treatment of hyperplasia of the breast. It has completed a phase II clinical trial for cyclical mastalgia, but further studies are required before afimoxifene can be approved for this indication and marketed.

Nafoxidine

Nafoxidine or nafoxidine hydrochloride (USAN) is a nonsteroidal selective estrogen receptor modulator (SERM) or partial antiestrogen of the triphenylethylene group that was developed for the treatment of advanced breast cancer by Upjohn in the 1970s but was never marketed. It was developed at around the same time as tamoxifen and clomifene, which are also triphenylethylene derivatives. The drug was originally synthesized by the fertility control program at Upjohn as a postcoital contraceptive, but was subsequently repurposed for the treatment of breast cancer. Nafoxidine was assessed in clinical trials in the treatment of breast cancer and was found to be effective. However, it produced side effects including ichthyosis, partial hair loss, and phototoxicity of the skin in almost all patients, and this resulted in the discontinuation of its development.

Idoxifene Pharmaceutical compound

Idoxifene, also known as pyrrolidino-4-iodotamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group which was under development for the treatment of breast cancer and postmenopausal osteoporosis but was never marketed. It reached phase III clinical trials for postmenopausal osteoporosis and phase II clinical trials for breast cancer before development was discontinued in 1999 due to insufficient effectiveness in both cases.

Nonsteroidal estrogen Class of drugs

A nonsteroidal estrogen is an estrogen with a nonsteroidal chemical structure. The most well-known example is the stilbestrol estrogen diethylstilbestrol (DES). Although nonsteroidal estrogens formerly had an important place in medicine, they have gradually fallen out of favor following the discovery of toxicities associated with high-dose DES starting in the early 1970s, and are now almost never used. On the other hand, virtually all selective estrogen receptor modulators (SERMs) are nonsteroidal, with triphenylethylenes like tamoxifen and clomifene having been derived from DES, and these drugs remain widely used in medicine for the treatment of breast cancer among other indications. In addition to pharmaceutical drugs, many xenoestrogens, including phytoestrogens, mycoestrogens, and synthetic endocrine disruptors like bisphenol A, are nonsteroidal substances with estrogenic activity.

Broparestrol

Broparestrol (INN), also known as α-bromo-α,β-diphenyl-β-p-ethylphenylethylene (BDPE), is a synthetic, nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that has been used in Europe as a dermatological agent and for the treatment of breast cancer. The drug is described as slightly estrogenic and potently antiestrogenic, and inhibits mammary gland development and suppresses prolactin levels in animals. It is structurally related to clomifene and diethylstilbestrol. Broparestrol is a mixture of E- and Z- isomers, both of which are active and are similarly antiestrogenic but, unlike broparestrol, were never marketed.

Triphenylethylene

Triphenylethylene (TPE) is a simple aromatic hydrocarbon that possesses weak estrogenic activity. Its estrogenic effects were discovered in 1937. TPE was derived from structural modification of the more potent estrogen diethylstilbestrol, which is a member of the stilbestrol group of nonsteroidal estrogens.

Estrobin

Estrobin, also known as α,α-di(p-ethoxyphenyl)-β-phenylbromoethylene and commonly abbreviated as DBE, is a synthetic, nonsteroidal estrogen of the triphenylethylene group that was never marketed. Chlorotrianisene, and subsequently clomifene and tamoxifen, were derived from it. Estrobin, similarly to other triphenylethylenes, is very lipophilic and hence very long-lasting in its duration of action. Similarly to chlorotrianisene, estrobin behaves a prodrug to a much more potent estrogen in the body.

Ethamoxytriphetol

Ethamoxytriphetol is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed. MER-25 was first reported in 1958, and was the first antiestrogen to be discovered. It has been described as "essentially devoid of estrogenic activity" and as having "very low estrogenic activity in all species tested". However, some estrogenic effects in the uterus have been observed, so it is not a pure antiestrogen but is, instead, technically a selective estrogen receptor modulator (SERM). For all intents and purposes, it is a nearly pure antiestrogen, however.

Bisdehydrodoisynolic acid

Bisdehydrodoisynolic acid (BDDA), as the (Z)-isomer ( -BDDA), is a synthetic, nonsteroidal estrogen related to doisynolic acid that was never marketed. It is one of the most potent estrogens known, although it has more recently been characterized as a selective estrogen receptor modulator (SERM). BDDA and other doisynolic acid derivatives display relatively low affinity accompanied by disproportionately high estrogenic potency in vivo, which was eventually determined to be due to transformation into metabolites with greater estrogenic activity. The drug was discovered in 1947 as a degradation product of the reaction of equilenin or dihydroequilenin with potassium hydroxide. It is the seco-analogue of equilenin, while doisynolic acid is the seco-analogue of estrone. These compounds, along with diethylstilbestrol, can be considered to be open-ring analogues of estradiol. The methyl ether of BDDA, doisynoestrol, is also an estrogen, and in contrast to BDDA, has been marketed.

Triphenylbromoethylene

Triphenylbromoethylene, also known as bromotriphenylethylene or as phenylstilbene bromide, is a synthetic nonsteroidal estrogen of the triphenylethylene group that was marketed in the 1940s similarly to the closely related estrogen triphenylchloroethylene.

Triphenylmethylethylene

Triphenylmethylethylene, also known as methyltriphenylethylene or as triphenylpropene, is a synthetic nonsteroidal estrogen of the triphenylethylene group that is related to triphenylchloroethylene and was never marketed. Along with diethylstilbestrol and triphenylchoroethylene, triphenylmethylethylene was studied in 1944 by Sir Alexander Haddow for the treatment of breast cancer, and this is historically notable in that it was the first time that high-dose estrogens were found to be effective in the treatment of breast cancer. However, while diethylstilbestrol and triphenylchloroethylene were found to be significantly effective, triphenylmethylethylene was less effective and showed a favorable response in only 1 of 4 treated cases.

Miproxifene

Miproxifene (INN) is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was never marketed. It is a derivative of afimoxifene (4-hydroxytamoxifen) in which an additional 4-isopropyl group is present in the β-phenyl ring. The drug has been found to be 3- to 10-fold more potent than tamoxifen in inhibiting breast cancer cell growth in in vitro models. Miproxifene is the active metabolite of miproxifene phosphate (TAT-59), a phosphate ester and prodrug of miproxifene that was developed to improve its water solubility. Miproxifene phosphate was under development for the treatment of breast cancer and reached phase III clinical trials for this indication but development was discontinued.

Miproxifene phosphate

Miproxifene phosphate is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was under development in Japan for the treatment of breast cancer but was abandoned and never marketed. It reached phase III clinical trials for this indication before development was discontinued. The drug is a phosphate ester and prodrug of miproxifene (DP-TAT-59) with improved water solubility that was better suited for clinical development. Miproxifene has been found to be 3- to 10-fold as potent as tamoxifen in inhibiting breast cancer cell growth in in vitro models. It is a derivative of afimoxifene (4-hydroxytamoxifen) in which an additional 4-isopropyl group is present in the β-phenyl ring.

Zindoxifene

Zindoxifene is a nonsteroidal selective estrogen receptor modulator (SERM) that was under development in the 1980s and early 1990s for the treatment of breast cancer but was not marketed. It showed estrogenic-like activity in preclinical studies and failed to demonstrate effectiveness as a treatment for breast cancer in clinical trials. Zindoxifene was the lead compound of the distinct 2-phenylindole class of SERMs, and the marketed SERM bazedoxifene was derived from the major active metabolite of zindoxifene, D-15414. Zindoxifene was first described in 1984.

Panomifene

Panomifene is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group related to tamoxifen that was under development as an antineoplastic agent by Egis Pharmaceuticals and IVAX Drug Research Institute in the 1990s for the treatment of breast cancer, but it was never marketed. It reached phase II clinical trials before development was terminated. The drug was described in 1981.

Nitromifene

Nitromifene is a nonsteroidal selective estrogen receptor modulator (SERM) related to triphenylethylenes like tamoxifen that was never marketed. It is a mixture of (E)- and (Z)-isomers that possess similar antiestrogenic activity. The drug was described in 1966. Along with tamoxifen, nafoxidine, and clomifene, it was one of the earliest SERMs.

References

  1. ↑ Martin Negwer; Hans-Georg Scharnow (2001). Organic-chemical drugs and their synonyms: (an international survey). Wiley-VCH. pp. 1861–1862. ISBN   978-3-527-30247-5. C20H15Cl 18084-97-4 Chlorotriphenylethene = Triphenylchloroethylene = Phenylstilbene chloride = 1,1',1"-(1-Chloro-1-ethenyl-2-ylidene)tris[benzene] (•) S Gynosone, Oestrogyl, Phenylstilbene chloride U Synthetic estrogen
  2. 1 2 3 EMMENS CW (1947). "Halogen-substituted oestrogens related to triphenylethylene". J. Endocrinol. 5 (3): 170–3. doi:10.1677/joe.0.0050170. PMID   20259249.
  3. ↑ "Advertisement" (PDF). Proc R Soc Med. 39 (11). Sep 1946. PMC   2181944 .
  4. ↑ Jie Jack Li (3 April 2009). Triumph of the Heart: The Story of Statins. Oxford University Press, USA. pp. 33–. ISBN   978-0-19-532357-3.
  5. 1 2 3 SOLMSSEN UV (1945). "Synthetic estrogens and the relation between their structure and their activity". Chem. Rev. 37 (3): 481–598. doi:10.1021/cr60118a004. PMID   21013428.
  6. ↑ Virgil Craig Jordan (1986). Estrogen/antiestrogen Action and Breast Cancer Therapy. Univ of Wisconsin Press. pp. 23–. ISBN   978-0-299-10480-1.
  7. ↑ Philipp Y. Maximov; Russell E. McDaniel; V. Craig Jordan (23 July 2013). Tamoxifen: Pioneering Medicine in Breast Cancer. Springer Science & Business Media. pp. 4–. ISBN   978-3-0348-0664-0.
  8. ↑ V Craig Jordan (27 May 2013). Estrogen Action, Selective Estrogen Receptor Modulators and Women's Health: Progress and Promise. World Scientific. pp. 42–. ISBN   978-1-84816-959-3.
  9. ↑ D. J. Th. Wagener (13 July 2009). The History of Oncology. Bohn Stafleu van Loghum. pp. 189–. ISBN   978-90-313-6143-4.
  10. ↑ Gautam Allahbadia (2006). Contemporary Perspectives on Assisted Reproductive Technology. Elsevier India. pp. 18–. ISBN   978-81-8147-782-8.
  11. ↑ David K. Gardner; Ariel Weissman; Colin M Howles; Zeev Shoham (27 June 2012). Textbook of Assisted Reproductive Techniques Fourth Edition: Volume 2: Clinical Perspectives. CRC Press. pp. 51–. ISBN   978-1-84184-972-0.


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