Chemistry:Triphenylchloroethylene

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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]

SAR analogs

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]

Synthesis

The chemical synthesis has been described.[12][13] The Grignard reaction of benzylmagnesium bromide on benzophenone (or the action of phenylmagnesium bromide on desoxybenzoin or ethyl phenylacetate or chloroacetyl chloride etc.) give a carbinol which is dehydrated to the stilbene (i.e. triphenylethylene). Halogenation with chlorine in e.g. CCl4 solvent (c.f. TACE) then yields the product.

See also

Although the vinylic halogens has already been considered, it was discovered that Triphenylacrylonitrile [6304-33-2] also potently modulates the estrogen receptor.[14][15]

References

  1. ↑ Organic-chemical drugs and their synonyms: (an international survey). Wiley-VCH. 2001. pp. 1861–1862. ISBN 978-3-527-30247-5. https://books.google.com/books?id=zmpqAAAAMAAJ. "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. ↑ 2.0 2.1 2.2 "Halogen-substituted oestrogens related to triphenylethylene". The Journal of Endocrinology 5 (3): 170–173. July 1947. doi:10.1677/joe.0.0050170. PMID 20259249. 
  3. ↑ ""Gynosone" A New Synthetic Oestrogen". Proc R Soc Med 39 (11). Sep 1946. 
  4. ↑ "Genesis of Statins". Triumph of the Heart: The Story of Statins. Oxford University Press, USA. 3 April 2009. pp. 33–. ISBN 978-0-19-532357-3. https://books.google.com/books?id=-GPl1PA5EgMC&pg=PA33. 
  5. ↑ 5.0 5.1 5.2 "Synthetic estrogens and the relation between their structure and their activity". Chemical Reviews 37 (3): 481–598. December 1945. doi:10.1021/cr60118a004. PMID 21013428. 
  6. ↑ "Structure-Activity Relationships of Nonsteroidal Estrogens and Antiestrogens". Estrogen/antiestrogen Action and Breast Cancer Therapy. University of Wisconsin Press. 1986. pp. 23–. ISBN 978-0-299-10480-1. https://books.google.com/books?id=7WmLZfGXST0C&pg=PA23. 
  7. ↑ "Discovery and Pharmacology of Nonsteroidal Estrogens and Antiestrogens". Tamoxifen: Pioneering Medicine in Breast Cancer. Springer Science & Business Media. 23 July 2013. pp. 4–. ISBN 978-3-0348-0664-0. https://books.google.com/books?id=p-W5BAAAQBAJ&pg=PA4. 
  8. ↑ "Diethylstilbestrol: A Tragedy in Reproductive Endocrinology But a Pioneering Cancer Treatment". Estrogen Action, Selective Estrogen Receptor Modulators and Women's Health: Progress and Promise. World Scientific. 27 May 2013. pp. 42–. ISBN 978-1-84816-959-3. https://books.google.com/books?id=ZM26CgAAQBAJ&pg=PA42. 
  9. ↑ "The history of the hormonal treatment of cancer". The History of Oncology. Bohn Stafleu van Loghum. 13 July 2009. pp. 189–. ISBN 978-90-313-6143-4. https://books.google.com/books?id=53fmwacXu44C&pg=PA189. 
  10. ↑ "Adjunctions to Clomiphene Citrate". Contemporary Perspectives on Assisted Reproductive Technology. Elsevier India. 2006. pp. 18–. ISBN 978-81-8147-782-8. https://books.google.com/books?id=Zx-lRwGFU4gC&pg=PA18. 
  11. ↑ "Drugs used for ovarian stimulation: Clomiphene citrate, aromatase inhibitors, metformin, gonadotropins, gonadotropin-releasing hormone analogs and recombinant gonadotropins". Textbook of Assisted Reproductive Techniques Fourth Edition: Volume 2: Clinical Perspectives. CRC Press. 27 June 2012. pp. 51–. ISBN 978-1-84184-972-0. https://books.google.com/books?id=Ap1_AwAAQBAJ&pg=PA51. 
  12. ↑ "Preparation of Triphenylchloroethylene". Nature 148 (3741): 53–53. July 1941. doi:10.1038/148053a0. https://www.nature.com/articles/148053a0. 
  13. ↑ , GB518149 (1940 to HYMAN HENRY LIONEL LEVENE, Boots Pure Drug Co Ltd).
  14. ↑ "Multivariate analysis by the minimum spanning tree method of the structural determinants of diphenylethylenes and triphenylacrylonitriles implicated in estrogen receptor binding, protein kinase C activity, and MCF7 cell proliferation". Journal of Medicinal Chemistry 35 (3): 573–583. February 1992. doi:10.1021/jm00081a021. https://pubs.acs.org/doi/abs/10.1021/jm00081a021. Retrieved 14 January 2026. 
  15. ↑ "Effect of triphenylacrylonitrile derivatives on estradiol-receptor binding and on human breast cancer cell growth". Journal of Medicinal Chemistry 32 (9): 2092–2103. September 1989. doi:10.1021/jm00129a013. https://pubs.acs.org/doi/abs/10.1021/jm00129a013. 



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