Benzestrol

Last updated
Benzestrol
Benzestrol.png
Clinical data
Trade names Chemestrogen, Ocestrol, Octestrol, Octoestrol, Octofollin
Drug class Nonsteroidal estrogen
Identifiers
  • 4,4'-(3-ethylhexane-2,4-diyl)diphenol
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C20H26O2
Molar mass 298.426 g·mol−1
3D model (JSmol)
  • CCC(C1=CC=C(C=C1)O)C(CC)C(C)C2=CC=C(C=C2)O
  • InChI=InChI=1S/C20H26O2/c1-4-19(14(3)15-6-10-17(21)11-7-15)20(5-2)16-8-12-18(22)13-9-16/h6-14,19-22H,4-5H2,1-3H3
  • Key:DUTFBSAKKUNBAL-UHFFFAOYSA-N

Benzestrol (INN Tooltip International Nonproprietary Name, BAN Tooltip British Approved Name) (brand names Chemestrogen, Ocestrol, Octestrol, Octoestrol, Octofollin) is a synthetic nonsteroidal estrogen of the stilbestrol group which was formerly used medically but has since been discontinued. [1] [2] [3] The stilbestrol estrogens, the best-known of which is diethylstilbestrol (DES) were used extensively in the mid-1900s and were finally banned by the FDA due to them causing tumors in the children of women who used them. [4]

Contents

Medical uses

Benzestrol and other stilbestrol were used as synthetic estrogens in order to prevent premature births. [4] Based on the idea that premature births happened because the mother did not produce enough estrogen on her own, doctors prescribed benzestrol to mothers in order to increase their estrogen levels.

Studies have been done in the past on normal, mature and castrate female rats. Benzestrol produced the same type of estrus in the castrate rat when injected at 0.8 to 1.0 micrograms as when the rat was injected with 2.0 to 2.5 micrograms of estrone. [5] This is significant because less benzestrol could be used to produce the same effect as estrone in increasing estrogen production. It has been used in the past as a nonsteroidal estrogen antagonist.

Pharmacology

Pharmacodynamics

Benzestrol is described as a very potent estrogen. [6] It is reported to have about 130% of the relative binding affinity of estradiol for the estrogen receptors. [7]

Chemistry

Benzestrol is usually grouped with the stilbestrol estrogens. However, benzestrol is technically not a stilbestrol derivative because its central chain is elongated by one carbon. In any case, it is a very close analogue of the stilbestrol estrogens. [8]

A recent article discusses the isomer stereochemistry. [9]

Synthesis

The chemical synthesis has been discussed: [10] [11] [12] Improved: [13] Patents: [14] [15] [16] [17] Book notes (page 103): [18]

Benzestrolsynthesis.svg

A Claisen-Schmidt condensation between anisaldehyde [123-11-5] (1) and p-methoxybutyrophenone [4160-51-4] (2) gives the substituted chalcone [90-92-6] [71526-40-4] (3). Soft addition (Michael reaction) of ethylmagnesium bromide to the conjugate system gives introduces a second ethyl group into the molecule to yield 2-Ethyl-1,3-bis(4-methoxyphenyl)pentan-1-one, PC71777307 (4). {Although this reaction was performed with a Grignard reagent, addition of Copper(I) chloride catalyst or Gilman reagent is the modern take to mitigate the "hard" addition side reaction to the ketone. For example, this is needed to know for phenyltropane and nocaine chemistry}. For the next step, addition of methylmagnesium bromide to the remaining carbonyl gave the carbinol (5). Dehydration of the alcohol and reduction of the olefin gives Benzestrol Dimethyl Ether [131-87-3] (6). Cleavage of both the ethers then completes the synthesis of Benzestrol (7).

History

Benzestrol is a drug in the stilbestrol family of estrogens. These drugs were first produced in the late 1930s. Benzestrol itself was reported in 1946. [1] In 1953, experiments began on benzestrol and other stilbestrols to see if they actually helped stop premature births. This study in 1953 found that benzestrol did not in fact help stop premature births. [4] A study in 1971 found that benzestrol was the cause of a rare vaginal cancer in girls and women whose mothers had been on benzestrol while pregnant. [4]

See also

References

  1. 1 2 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 133–. ISBN   978-1-4757-2085-3.
  2. ↑ Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 47–. ISBN   978-94-011-4439-1.
  3. ↑ "Benzestrol". Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 106–. ISBN   978-3-88763-075-1.
  4. 1 2 3 4 "DES History". U.S. Centers for Disease Control and Prevention. Archived from the original on 15 June 2019. Retrieved 17 December 2012.
  5. ↑ Stebbins RB, Blanchard EW (1945). "The Effects of a New Synthetic Estrogen, Benzestrol Upon the Hematopoietic System in the Rat". Endocrinology. 36 (5): 305. doi:10.1210/endo-36-5-305.
  6. ↑ Agarwal OP (2006). "Sex hormones". Natural Products. Krishna Prakashan Media. pp. 288–. ISBN   978-81-87224-85-3.
  7. ↑ Fink BE, Mortensen DS, Stauffer SR, Aron ZD, Katzenellenbogen JA (April 1999). "Novel structural templates for estrogen-receptor ligands and prospects for combinatorial synthesis of estrogens". Chemistry & Biology. 6 (4): 205–219. doi: 10.1016/S1074-5521(99)80037-4 . PMID   10099132.
  8. ↑ Sevringhaus EL (1944). "Therapy of the Patient in the Menopause: Endocrine Methods". The Journal of Clinical Endocrinology & Metabolism. 4 (12): 597–604. doi:10.1210/jcem-4-12-597. ISSN   0021-972X.
  9. ↑ Hou, Y., Nwachukwu, J. C., Carlson, K., Kim, S. H., Angle, S., Jacobsen, E. N., Woods, T., Mateus, S. L., Fanning, S. W., Ziegler, Y., Katzenellenbogen, B. S., Nettles, K. W., Katzenellenbogen, J. A. (8 August 2025). "Benzestrol Isomer Stereochemistry Determines the Distinct Estrogenic Activities and Conformations of the Eight Isomers When Bound to Estrogen Receptor α". ACS Pharmacology & Translational Science. 8 (8): 2526–2535. doi:10.1021/acsptsci.5c00117.
  10. ↑ Stuart, Alfred H. (1946). "Synthetic Estrogenic Compounds. III. Trialkyl Derivatives of 1,3-Di-(p-hydroxyphenyl)-propane. Benzestrol". Journal of the American Chemical Society 68 (5): 729–733. doi:10.1021/ja01209a001.
  11. ↑ Shukis, A. J.; Ritter, John J. (1950). "A New Synthesis of Benzestrol1". Journal of the American Chemical Society. 72 (4): 1488–1489. doi:10.1021/ja01160a017.
  12. ↑ Dodds, E. C.; Huang, R. L.; Lawson, W.; Robinson, R. (1953). "Synthetic Oestrogenic Compounds Related to Stilbene and Diphenylethane. III". Proceedings of the Royal Society B: Biological Sciences. 140 (901): 470–497. doi:10.1098/rspb.1953.0003.
  13. ↑ Kiprianov, Kutsenko, Zh. Prikl. Khim. 31, 665 (1958).
  14. ↑ Ralph C Tallman & Alfred H Stuart, U.S. patent 2,400,033 (1946 to Schieffelin and Co).
  15. ↑ Ralph C Tallman & Alfred H Stuart, U.S. patent 2,400,034 (1946 to Schieffelin and Co).
  16. ↑ Ralph C Tallman & Alfred H Stuart, U.S. patent 2,455,535 (1948 to Schieffelin and Co).
  17. ↑ Ralph C Tallman & Alfred H Stuart, U.S. patent 2,486,580 (1949 to Schieffelin and Co).
  18. ↑ Lednicer, D., Mitscher, L. A. (1977). The organic chemistry of drug synthesis. 1. Wiley. ISBN   9780471521419.
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