Paroxypropione

Paroxypropione

Clinical data
Trade names	Frenantol, Frenormon, Hypophenon, Paroxon, Possipione, Profenone, others
Other names	Paraoxypropiophenone; H-365; NSC-2834; 4'-Hydroxypropiophenone; Ethyl p-hydroxyphenyl ketone; p-Propionylphenol; Paroxypropiophenone; Parahydroxypropiophenone; PHP
Drug class	Nonsteroidal estrogen; Antigonadotropin
ATC code	None
Legal status
Legal status	In general: ℞ (Prescription only)
Identifiers
IUPAC name 1-(4-hydroxyphenyl)-1-propanone
CAS Number	70-70-2
PubChem CID	6271
ChemSpider	6035
UNII	X9952001TG
CompTox Dashboard (EPA)	DTXSID8023426
ECHA InfoCard	100.000.676
Chemical and physical data
Formula	C9H10O2
Molar mass	150.177 g·mol−1
3D model (JSmol)	Interactive image
SMILES CCC(=O)c1ccc(cc1)O
InChI InChI=1S/C9H10O2/c1-2-9(11)7-3-5-8(10)6-4-7/h3-6,10H,2H2,1H3 Key:RARSHUDCJQSEFJ-UHFFFAOYSA-N

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. ^[1] The antigonadotropic properties of the drug were discovered in 1951 ^[3] 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 ^[4] 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]} This activity is presumably related to the microtubule-targeting agent (MTA) activity of paroxypropione, which binds to tubulin and favours its polymerization into microtubules. ^[19]

References

1. Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 662–. ISBN   978-1-4757-2085-3.
2. Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 796–. ISBN   978-3-88763-075-1.
3. Paulsen CA, Mortimore GE, Heller CG (August 1951). "The pituitary action and estrogenic effect of parahydroxy-propiophenone". The Journal of Clinical Endocrinology and Metabolism. 11 (8): 892–4. doi:10.1210/jcem-11-8-892. PMID   14861299.
4. Mombelli E (January 2012). "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. Bibcode:2012SQER...23...37M. doi:10.1080/1062936X.2011.623325. PMID   22014213. S2CID   19751228.
5. Buu-Hoi NP, Xuong ND, Lavit D (1953). "Fluorine-containing analogs of 4-hydroxypropiophenone". The Journal of Organic Chemistry. 18 (8): 910–915. doi:10.1021/jo50014a002. ISSN   0022-3263.
6. Chambers PL, Günzel P (12 March 2013). Mechanism of Toxic Action on Some Target Organs: Drugs and Other Substances. Springer Science & Business Media. pp. 276–. ISBN   978-3-642-67265-1.
7. Gottschlich R, Metzler M (January 1979). "High-pressure, reverse-phase partition chromatograhy separation of diethylstilbestrol metabolites and analogs". Analytical Biochemistry. 92 (1): 199–202. doi:10.1016/0003-2697(79)90645-6. PMID   426279.
8. Jones RE, Lopez KH (28 September 2013). Human Reproductive Biology. Academic Press. pp. 46–. ISBN   978-0-12-382185-0.
9. Pugazhendhi D, Pope GS, Darbre PD (2005). "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. doi:10.1002/jat.1066. PMID   16021681. S2CID   12342018.
10. De Vega R (1955). "Protein breakdown before and after operations. Influence of growth hormone and of inhibitors of the pituitary adrenal system". Cirug., Ginecol. Urol. 9: 289–326.
11. Bussolati C, de Carneri I, Castellino S, Marinoni V, Sperzani GL (July 1967). "Treatment of experimental and clinical schistosomiasis with hormonal inhibitors of ovulation" . The American Journal of Tropical Medicine and Hygiene. 16 (4): 497–9. doi:10.4269/ajtmh.1967.16.497. PMID   5006470.^{[ permanent dead link ]}
12. Scott CC, Kroc RL, Stasilli NR (June 1952). "Metabolic and toxicity studies on parahydroxypropiophenone". Endocrinology. 50 (6): 607–11. doi:10.1210/endo-50-6-607. PMID   12980070.
13. Murashige R, Hayashi Y, Ohmori S, Torii A, Aizu Y, Muto Y, Murai Y, Oda Y, Hashimoto M (2011). "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". Tetrahedron. 67 (3): 641–649. doi:10.1016/j.tet.2010.11.047. hdl: 2115/44794 .
14. William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1286, 1290. ISBN   978-0-8155-1856-3.
15. Szmant HH (1989). Organic Building Blocks of the Chemical Industry. John Wiley & Sons. pp. 532–. ISBN   978-0-471-85545-3.
16. Maconi G (June 1955). "[Hydroxypropiophenone in the therapy of metastases of carcinoma of the breast]" [Hydroxypropiophenone in the therapy of metastases of carcinoma of the breast]. Il Farmaco; Edizione Pratica (in Italian). 10 (6): 291–9. PMID   13241536.
17. Stoll BA (August 1956). "P-hydroxypropiophenone for advanced breast cancer: a preliminary report". The Medical Journal of Australia. 43 (5): 181–3. doi:10.5694/j.1326-5377.1956.tb56562.x. PMID   13358357. S2CID   22364847.
18. Grapulin G (June 1967). "[Experience with paraoxypropiophenone (Frenantol) in the treatment of dysplasias and metastasized carcinoma of the breast]" [Experience with paraoxypropiophenone (Frenantol) in the treatment of dysplasias and metastasized carcinoma of the breast]. Chirurgia Italiana (in Italian). 19 (3): 306–12. PMID   5188348.
19. Baksheeva VE, La Rocca R, Allegro D, Derviaux C, Pasquier E, Roche P, Morelli X, Devred F, Golovin AV, Tsvetkov PO (2015). "NanoDSF Screening for Anti-tubulin Agents Uncovers New Structure–Activity Insights". Journal of Medicinal Chemistry. doi:10.1021/acs.jmedchem.5c01008.

Further reading

• Gustavo RP (July 1958). "[Anti-gonadotropic action of possipione]" [Anti-gonadotropic action of possipione]. Quaderni di Clinica Ostetrica e Ginecologica (in Italian). 13 (7): 307–15. PMID   13579130.