paroxypropione

{{Drugbox

| IUPAC_name = 1-(4-hydroxyphenyl)-1-propanone

| image = Paroxypropione.svg

| width = 225px

| tradename = Frenantol, Frenormon, Hypophenon, Paroxon, Possipione, Profenone, others

| pregnancy_AU =

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| legal_CA =

| legal_UK =

| legal_US =

| legal_status = Rx-only

| routes_of_administration =

| class = Nonsteroidal estrogen; Antigonadotropin

| bioavailability =

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| CAS_number = 70-70-2

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = X9952001TG

| ATC_prefix = None

| ATC_suffix =

| PubChem = 6271

| DrugBank =

| ChemSpiderID = 6035

| synonyms = Paraoxypropiophenone; H-365; NSC-2834; 4'-Hydroxypropiophenone; Ethyl p-hydroxyphenyl ketone; p-Propionylphenol; Paroxypropiophenone; Parahydroxypropiophenone; PHP

| C=9 | H=10 | O=2

| SMILES = CCC(=O)c1ccc(cc1)O

| StdInChI = 1S/C9H10O2/c1-2-9(11)7-3-5-8(10)6-4-7/h3-6,10H,2H2,1H3

| StdInChIKey = 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.{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA662|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=662–}}{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA796|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=796–}}{{cite journal | vauthors = Paulsen CA, Mortimore GE, Heller CG | title = The pituitary action and estrogenic effect of parahydroxy-propiophenone | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 11 | issue = 8 | pages = 892–4 | date = August 1951 | pmid = 14861299 | doi = 10.1210/jcem-11-8-892 }}{{cite journal | vauthors = Mombelli E | title = Evaluation of the OECD (Q)SAR Application Toolbox for the profiling of estrogen receptor binding affinities | journal = SAR and QSAR in Environmental Research | volume = 23 | issue = 1–2 | pages = 37–57 | date = January 2012 | pmid = 22014213 | doi = 10.1080/1062936X.2011.623325 | bibcode = 2012SQER...23...37M | s2cid = 19751228 }} It was first synthesized in 1902. The antigonadotropic properties of the drug were discovered in 1951 and it entered clinical use shortly thereafter.{{cite journal| vauthors = Buu-Hoi NP, Xuong ND, Lavit D |title=Fluorine-containing analogs of 4-hydroxypropiophenone|journal=The Journal of Organic Chemistry|volume=18|issue=8|year=1953|pages=910–915|issn=0022-3263|doi=10.1021/jo50014a002}}

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){{cite book| vauthors = Chambers PL, Günzel P |title=Mechanism of Toxic Action on Some Target Organs: Drugs and Other Substances|url=https://books.google.com/books?id=zUH1CAAAQBAJ&pg=PA276|date=12 March 2013|publisher=Springer Science & Business Media|isbn=978-3-642-67265-1|pages=276–}}{{cite journal | vauthors = Gottschlich R, Metzler M | title = High-pressure, reverse-phase partition chromatograhy separation of diethylstilbestrol metabolites and analogs | journal = Analytical Biochemistry | volume = 92 | issue = 1 | pages = 199–202 | date = January 1979 | pmid = 426279 | doi = 10.1016/0003-2697(79)90645-6 }} and alkylphenols like nonylphenol, all of which are also estrogens.{{cite book| vauthors = Jones RE, Lopez KH |title=Human Reproductive Biology|url=https://books.google.com/books?id=M4kEdSnS-pkC&pg=PA46|date=28 September 2013|publisher=Academic Press|isbn=978-0-12-382185-0|pages=46–}}{{cite journal | vauthors = Pugazhendhi D, Pope GS, Darbre PD | title = Oestrogenic activity of p-hydroxybenzoic acid (common metabolite of paraben esters) and methylparaben in human breast cancer cell lines | journal = Journal of Applied Toxicology | volume = 25 | issue = 4 | pages = 301–9 | year = 2005 | pmid = 16021681 | doi = 10.1002/jat.1066 | s2cid = 12342018 }} 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.{{cite journal | title = Protein breakdown before and after operations. Influence of growth hormone and of inhibitors of the pituitary adrenal system. | vauthors = De Vega R | journal = Cirug., Ginecol. Urol. | year = 1955 | volume = 9 | pages = 289–326 | url = http://www.cabdirect.org/abstracts/19561404674.html}}{{cite journal | vauthors = Bussolati C, de Carneri I, Castellino S, Marinoni V, Sperzani GL | title = Treatment of experimental and clinical schistosomiasis with hormonal inhibitors of ovulation | journal = The American Journal of Tropical Medicine and Hygiene | volume = 16 | issue = 4 | pages = 497–9 | date = July 1967 | pmid = 5006470 | doi = 10.4269/ajtmh.1967.16.497 | url = http://www.ajtmh.org/content/16/4/497.extract }}{{Dead link|date=March 2023 |bot=InternetArchiveBot |fix-attempted=yes }} It possesses 0.1% of the estrogenic activity and less than 0.5% of the antigonadotropic potency of estrone.{{cite journal | vauthors = Scott CC, Kroc RL, Stasilli NR | title = Metabolic and toxicity studies on parahydroxypropiophenone | journal = Endocrinology | volume = 50 | issue = 6 | pages = 607–11 | date = June 1952 | pmid = 12980070 | doi = 10.1210/endo-50-6-607 }}

Chemistry

=Synthesis=

The highest reported yield, approximately 96%, is from the between phenol and propionyl chloride.{{cite journal | vauthors = Murashige R, Hayashi Y, Ohmori S, Torii A, Aizu Y, Muto Y, Murai Y, Oda Y, Hashimoto M |journal= Tetrahedron |year= 2011 |volume= 67 |issue= 3 |pages= 641–649 |title= 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 |doi= 10.1016/j.tet.2010.11.047 |hdl= 2115/44794 |hdl-access= free }} 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.{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1286|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=1286, 1290}}{{cite book| vauthors = Szmant HH |title=Organic Building Blocks of the Chemical Industry|url=https://books.google.com/books?id=a2XNyj1WtkMC&pg=PA532|year=1989|publisher=John Wiley & Sons|isbn=978-0-471-85545-3|pages=532–}}

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.{{cite journal | vauthors = Maconi G | title = [Hydroxypropiophenone in the therapy of metastases of carcinoma of the breast] | language = it | journal = Il Farmaco; Edizione Pratica | volume = 10 | issue = 6 | pages = 291–9 | date = June 1955 | pmid = 13241536 | trans-title = Hydroxypropiophenone in the therapy of metastases of carcinoma of the breast }}{{cite journal | vauthors = Stoll BA | title = P-hydroxypropiophenone for advanced breast cancer: a preliminary report | journal = The Medical Journal of Australia | volume = 43 | issue = 5 | pages = 181–3 | date = August 1956 | doi = 10.5694/j.1326-5377.1956.tb56562.x | pmid = 13358357 | s2cid = 22364847 }}{{cite journal | vauthors = Grapulin G | title = [Experience with paraoxypropiophenone (Frenantol) in the treatment of dysplasias and metastasized carcinoma of the breast] | language = it | journal = Chirurgia Italiana | volume = 19 | issue = 3 | pages = 306–12 | date = June 1967 | pmid = 5188348 | trans-title = Experience with paraoxypropiophenone (Frenantol) in the treatment of dysplasias and metastasized carcinoma of the breast }}