Paroxypropione Explained

Paroxypropione, also known as paraoxypropiophenone, is a synthetic nonsteroidal estrogen which has been used medically as an antigonadotropin in Spain and Italy but appears to no longer be marketed.^{[1] [2] [3] [4]} It was first synthesized in 1902. The antigonadotropic properties of the drug were discovered in 1951 and it entered clinical use shortly thereafter.^[5]

Pharmacology

Pharmacodynamics

Paroxypropione is closely related structurally to p-hydroxybenzoic acid and parabens such as methylparaben, and also bears a close resemblance to diethylstilbestrol (which, in fact, produces paroxypropione as an active metabolite)^{[6] [7]} and alkylphenols like nonylphenol, all of which are also estrogens.^{[8] [9]} The drug possesses relatively low affinity for the estrogen receptor and must be given at high dosages to achieve significant estrogenic and antigonadotropic effects, for instance, 0.8 to 1.6 g/day.^{[10] [11]} It possesses 0.1% of the estrogenic activity and less than 0.5% of the antigonadotropic potency of estrone.^[12]

Chemistry

Synthesis

The highest reported yield, approximately 96%, is from the between phenol and propionyl chloride.^[13] The mechanism is likely to involve initial esterification to give phenyl propionate, which then undergoes a Fries rearrangement.

Derivatives

Paroxypropione is a precursor in the chemical synthesis of diethylstilbestrol and dienestrol.^{[14] [15]}

Society and culture

Names

Brand names Frenantol, Frenormon, Hypophenon, Paroxon, Possipione, Profenone, numerous others; former developmental code name NSC-2834, also known as paroxypropiophenone (P.O.P.) or 4'-hydroxypropiophenone.

Research

Paroxypropione was studied and used in the treatment of breast cancer.^{[16] [17] [18]}

Further reading

• Gustavo RP . [Anti-gonadotropic action of possipione] . it . Quaderni di Clinica Ostetrica e Ginecologica . 13 . 7 . 307–15 . July 1958 . 13579130 . Anti-gonadotropic action of possipione .

Notes and References

1. Book: Elks J . The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. 14 November 2014. Springer. 978-1-4757-2085-3. 662–.
2. Book: Index Nominum 2000: International Drug Directory. January 2000. Taylor & Francis. 978-3-88763-075-1. 796–.
3. Paulsen CA, Mortimore GE, Heller CG . The pituitary action and estrogenic effect of parahydroxy-propiophenone . The Journal of Clinical Endocrinology and Metabolism . 11 . 8 . 892–4 . August 1951 . 14861299 . 10.1210/jcem-11-8-892 .
4. Mombelli E . Evaluation of the OECD (Q)SAR Application Toolbox for the profiling of estrogen receptor binding affinities . SAR and QSAR in Environmental Research . 23 . 1–2 . 37–57 . January 2012 . 22014213 . 10.1080/1062936X.2011.623325 . 2012SQER...23...37M . 19751228 .
5. Buu-Hoi NP, Xuong ND, Lavit D . Fluorine-containing analogs of 4-hydroxypropiophenone. The Journal of Organic Chemistry. 18. 8. 1953. 910–915. 0022-3263. 10.1021/jo50014a002.
6. Book: Chambers PL, Günzel P . Mechanism of Toxic Action on Some Target Organs: Drugs and Other Substances. 12 March 2013. Springer Science & Business Media. 978-3-642-67265-1. 276–.
7. Gottschlich R, Metzler M . High-pressure, reverse-phase partition chromatograhy separation of diethylstilbestrol metabolites and analogs . Analytical Biochemistry . 92 . 1 . 199–202 . January 1979 . 426279 . 10.1016/0003-2697(79)90645-6 .
8. Book: Jones RE, Lopez KH . Human Reproductive Biology. 28 September 2013. Academic Press. 978-0-12-382185-0. 46–.
9. Pugazhendhi D, Pope GS, Darbre PD . Oestrogenic activity of p-hydroxybenzoic acid (common metabolite of paraben esters) and methylparaben in human breast cancer cell lines . Journal of Applied Toxicology . 25 . 4 . 301–9 . 2005 . 16021681 . 10.1002/jat.1066 . 12342018 .
10. Protein breakdown before and after operations. Influence of growth hormone and of inhibitors of the pituitary adrenal system. . De Vega R . Cirug., Ginecol. Urol. . 1955 . 9 . 289–326 .
11. Bussolati C, de Carneri I, Castellino S, Marinoni V, Sperzani GL . Treatment of experimental and clinical schistosomiasis with hormonal inhibitors of ovulation . The American Journal of Tropical Medicine and Hygiene . 16 . 4 . 497–9 . July 1967 . 5006470 . 10.4269/ajtmh.1967.16.497 .
12. Scott CC, Kroc RL, Stasilli NR . Metabolic and toxicity studies on parahydroxypropiophenone . Endocrinology . 50 . 6 . 607–11 . June 1952 . 12980070 . 10.1210/endo-50-6-607 .
13. Murashige R, Hayashi Y, Ohmori S, Torii A, Aizu Y, Muto Y, Murai Y, Oda Y, Hashimoto M . Tetrahedron . 2011 . 67 . 3 . 641–649 . Comparisons of O-acylation and Friedel–Crafts acylation of phenols and acyl chlorides and Fries rearrangement of phenyl esters in trifluoromethanesulfonicacid: effective synthesis of optically active homotyrosines . 10.1016/j.tet.2010.11.047 . 2115/44794 . free .
14. Book: William Andrew Publishing. Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. 22 October 2013. Elsevier. 978-0-8155-1856-3. 1286, 1290.
15. Book: Szmant HH . Organic Building Blocks of the Chemical Industry. 1989. John Wiley & Sons. 978-0-471-85545-3. 532–.
16. Maconi G . [Hydroxypropiophenone in the therapy of metastases of carcinoma of the breast] . it . Il Farmaco; Edizione Pratica . 10 . 6 . 291–9 . June 1955 . 13241536 . Hydroxypropiophenone in the therapy of metastases of carcinoma of the breast .
17. Stoll BA . P-hydroxypropiophenone for advanced breast cancer: a preliminary report . The Medical Journal of Australia . 43 . 5 . 181–3 . August 1956 . 10.5694/j.1326-5377.1956.tb56562.x . 13358357 . 22364847 .
18. Grapulin G . [Experience with paraoxypropiophenone (Frenantol) in the treatment of dysplasias and metastasized carcinoma of the breast] . it . Chirurgia Italiana . 19 . 3 . 306–12 . June 1967 . 5188348 . Experience with paraoxypropiophenone (Frenantol) in the treatment of dysplasias and metastasized carcinoma of the breast .