Chemistry:Plomestane

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Plomestane (INN, USAN; former developmental code name MDL-18962; also known as propargylestrenedione, PED) is a steroidal, irreversible aromatase inhibitor which was under development by Marion Merrell Dow/Hoechst Marion Russell (now Hoechst AG) as an antineoplastic agent for the treatment of breast cancer.[1][2][3][4][5] It was found to be effective in preclinical studies and was also found to produce few adverse effects in human clinical trials, significantly reducing estrogen levels with a single administration.[5] However, development of the drug for clinical use was halted due to "technical issues" and it was never marketed.[6]

In addition to its activity as an aromatase inhibitor, plomestane has weak androgenic properties.[5]

Synthesis

The chemical synthesis was described:[7] Patent:[8]

Ketalization of Estr-5(10)-ene-3,17-dione [3962-66-1] (1) with two equivalents of ethylene glycol gives (2). Addition of NBS in water and hence hypobromous acid adds across the olefin to give (3). This rearranges to the oxirane in the presence of sodium methoxide base (4). The Gilman reagent was prepared from 1-(Trimethylsilyl)-1-propyne [6224-91-5] (6) and the reaction gave (7). Removal of the ketal protecting groups in acid, PC11784353 (8) and removal of the trimethyl silyl protecting group in base occurred with concomitant dehydration of the alcohol, completing the synthesis of plomestane (9).

See also

References

  1. ↑ Dictionary of Pharmacological Agents. CRC Press. 1997. p. 1635. ISBN 978-0-412-46630-4. https://books.google.com/books?id=A0THacd46ZsC&pg=PA1635. Retrieved 19 May 2012. 
  2. ↑ Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer. 1999. p. 227. ISBN 978-0-7514-0499-9. https://books.google.com/books?id=mqaOMOtk61IC&pg=PA227. Retrieved 20 May 2012. 
  3. ↑ "The irreversible inhibition of aromatase (oestrogen synthetase) by steroidal compounds". Current Pharmaceutical Design (Bentham Science Publishers) 1: 23–50 (45). June 1995. doi:10.2174/1381612801666220524190226. https://books.google.com/books?id=qq8uPl5YYuoC&pg=PA45. Retrieved 20 May 2012. 
  4. ↑ Exercise and Sport Nutrition. Exercise & Sport Nutrition. 2009. p. 350. ISBN 978-0-9742965-6-2. https://books.google.com/books?id=PW1ja6KxakC&pg=PA350. Retrieved 20 May 2012. 
  5. ↑ 5.0 5.1 5.2 "Aromatase inhibitors as potential cancer chemopreventives". Cancer Epidemiology, Biomarkers & Prevention 7 (1): 65–78. January 1998. PMID 9456245. http://cebp.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9456245. 
  6. ↑ Medicinal Chemistry of Anticancer Drugs. Elsevier. 4 June 2008. p. 69. ISBN 978-0-444-52824-7. https://books.google.com/books?id=GjhXyqB5iLcC&pg=PA69. Retrieved 20 May 2012. 
  7. ↑ "Interactions of thiol-containing androgens with human placental aromatase". Journal of Medicinal Chemistry 32 (1): 203–213. January 1989. doi:10.1021/jm00121a037. https://pubs.acs.org/doi/abs/10.1021/jm00121a037. 
  8. ↑ Cynthia L. Rand, U.S. Patent 5,516,922 (1996 to Aventis Pharmaceuticals Inc).





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