View source for 2-Methoxyestradiol

{{Short description|Chemical compound}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{distinguish|2-Methoxyestriol}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 477213877
| IUPAC_name = (8''R'',9''S'',13''S'',14''S'',17''S'')-2-Methoxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[''a'']phenanthrene-3,17-diol
| image = 2-Methoxyestradiol.svg
| width = 250px

<!--Clinical data-->
| tradename = Panzem
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category = 
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status = 
| routes_of_administration =

<!--Pharmacokinetic data-->
| bioavailability = 
| protein_bound = 
| metabolism = 
| elimination_half-life = 
| excretion =

<!--Identifiers-->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 362-07-2
| ATC_prefix = 
| ATC_suffix = 
| PubChem = 66414
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = 
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 59788
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 6I2QW73SR5
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 28955
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 299613
| synonyms = 2-ME2; 2-MeO-E2; 2-MeOE2; 2-Hydroxyestradiol 2-methyl ether; 2-Methoxyestra-1,3,5(10)-triene-3,17β-diol

<!--Chemical data-->
| C=19 | H=26 | O=3 
| SMILES = Oc1cc3c(cc1OC)[C@H]2CC[C@@]4([C@@H](O)CC[C@H]4[C@@H]2CC3)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C19H26O3/c1-19-8-7-12-13(15(19)5-6-18(19)21)4-3-11-9-16(20)17(22-2)10-14(11)12/h9-10,12-13,15,18,20-21H,3-8H2,1-2H3/t12-,13+,15-,18-,19-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = CQOQDQWUFQDJMK-SSTWWWIQSA-N
}}

'''2-Methoxyestradiol''' ('''2-ME2''', '''2-MeO-E2''') is a [[naturally occurring|natural]] [[metabolite]] of [[estradiol]] and [[2-hydroxyestradiol]] (2-OHE2). It is specifically the 2-[[methyl group|methyl]] [[ether]] of 2-hydroxyestradiol. 2-Methoxyestradiol prevents the formation of new [[blood vessel]]s that [[tumor]]s need in order to grow ([[angiogenesis]]), hence it is an [[angiogenesis inhibitor]].<ref>{{cite journal | vauthors = Pribluda VS, Gubish ER, Lavallee TM, Treston A, Swartz GM, Green SJ | title = 2-Methoxyestradiol: an endogenous antiangiogenic and antiproliferative drug candidate | journal = Cancer and Metastasis Reviews | volume = 19 | issue = 1–2 | pages = 173–179 | date = 2000 | pmid = 11191057 | doi = 10.1023/a:1026543018478 | s2cid = 20055299 }}</ref> It also acts as a [[vasodilator]]<ref>{{cite journal | vauthors = Koganti S, Snyder R, Thekkumkara T | title = Pharmacologic effects of 2-methoxyestradiol on angiotensin type 1 receptor down-regulation in rat liver epithelial and aortic smooth muscle cells | journal = Gender Medicine | volume = 9 | issue = 2 | pages = 76–93 | date = April 2012 | pmid = 22366193 | pmc = 3322289 | doi = 10.1016/j.genm.2012.01.008 }}</ref> and induces [[apoptosis]] in some [[cancer]] [[cell line]]s.<ref>{{cite journal | vauthors = LaVallee TM, Zhan XH, Johnson MS, Herbstritt CJ, Swartz G, Williams MS, Hembrough WA, Green SJ, Pribluda VS | title = 2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway | journal = Cancer Research | volume = 63 | issue = 2 | pages = 468–475 | date = January 2003 | pmid = 12543804 | url = http://cancerres.aacrjournals.org/content/63/2/468.long }}</ref> 2-Methoxyestradiol is derived from estradiol, although it interacts poorly with the [[estrogen receptor]]s (2,000-fold lower activational potency relative to estradiol).<ref>{{cite journal | vauthors = Sibonga JD, Lotinun S, Evans GL, Pribluda VS, Green SJ, Turner RT | title = Dose-response effects of 2-methoxyestradiol on estrogen target tissues in the ovariectomized rat | journal = Endocrinology | volume = 144 | issue = 3 | pages = 785–792 | date = March 2003 | pmid = 12586754 | doi = 10.1210/en.2002-220632 | doi-access = free }}</ref> However, it retains activity as a high-affinity [[agonist]] of the [[G protein-coupled estrogen receptor]] (GPER) (10&nbsp;nM, relative to 3–6&nbsp;nM for estradiol).<ref name="pmid26023144">{{cite journal | vauthors = Prossnitz ER, Arterburn JB | title = International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators | journal = Pharmacological Reviews | volume = 67 | issue = 3 | pages = 505–540 | date = July 2015 | pmid = 26023144 | pmc = 4485017 | doi = 10.1124/pr.114.009712 }}</ref><ref name="ThekkumkaraSnyder2016">{{cite book | vauthors = Thekkumkara T, Snyder R, Karamyan VT | title = Estrogen Receptors | chapter = Competitive Binding Assay for the G-Protein-Coupled Receptor 30 (GPR30) or G-Protein-Coupled Estrogen Receptor (GPER) | series = Methods in Molecular Biology | volume = 1366 | pages = 11–7 | year = 2016 | publisher = Springer | pmid = 26585123 | doi = 10.1007/978-1-4939-3127-9_2 | isbn = 978-1-4939-3126-2 }}</ref>

{{Selected biological properties of endogenous estrogens in rats}}

==Clinical development==
2-Methoxyestradiol was being [[drug development|developed]] as an experimental drug candidate with the tentative brand name Panzem.<ref>{{cite web | url = http://www.entremed.com/go.cfm?do=Page.View&ID=31 | title = EntreMed's Statistics | work = EntreMed, Inc. | archive-url = https://web.archive.org/web/20050504153826/http://www.entremed.com/go.cfm?do=Page.View&ID=31 | archive-date=May 4, 2005 }}</ref> It has undergone Phase 1 [[clinical trials]] against [[breast cancer]].<ref>{{cite journal | vauthors = Tevaarwerk AJ, Holen KD, Alberti DB, Sidor C, Arnott J, Quon C, Wilding G, Liu G | title = Phase I trial of 2-methoxyestradiol NanoCrystal dispersion in advanced solid malignancies | journal = Clinical Cancer Research | volume = 15 | issue = 4 | pages = 1460–1465 | date = February 2009 | pmid = 19228747 | pmc = 2892631 | doi = 10.1158/1078-0432.CCR-08-1599 }}</ref> A phase II trial of 18 advanced [[ovarian cancer]] patients reported encouraging results in October 2007.<ref>{{cite web|url=http://www.entremed.com/news/entremed-presents-results-for-panzem-ncd-phase-2-ovarian-cancer-study |title=EntreMed Presents Results for Panzem NCD Phase 2 Ovarian Cancer Study |url-status=dead |archive-url=https://web.archive.org/web/20120717045228/http://www.entremed.com/news/entremed-presents-results-for-panzem-ncd-phase-2-ovarian-cancer-study |archive-date=July 17, 2012 }}</ref>

Preclinical models also suggest that 2-methoxyestradiol could also be effective against [[inflammatory disease]]s such as [[rheumatoid arthritis]]. Several studies have been conducted showing 2-methoxyestradiol is a [[microtubule inhibitor]]<ref>{{cite journal | vauthors = Lakhani NJ, Sarkar MA, Venitz J, Figg WD | title = 2-Methoxyestradiol, a promising anticancer agent | journal = Pharmacotherapy | volume = 23 | issue = 2 | pages = 165–172 | date = February 2003 | pmid = 12587805 | doi = 10.1592/phco.23.2.165.32088 | s2cid = 1541302 | url = https://zenodo.org/record/1236347 }}</ref> and is inhibitory against [[prostate cancer]] in rodents.<ref>{{cite journal | vauthors = Sato F, Fukuhara H, Basilion JP | title = Effects of hormone deprivation and 2-methoxyestradiol combination therapy on hormone-dependent prostate cancer in vivo | journal = Neoplasia | volume = 7 | issue = 9 | pages = 838–846 | date = September 2005 | pmid = 16229806 | pmc = 1501932 | doi = 10.1593/neo.05145 }}</ref>

{{As of|2015}}, all clinical development of 2-methoxyestradiol has been suspended or discontinued.<ref>{{cite web|url=http://adisinsight.springer.com/drugs/800008361|title=2-Methoxyestradiol - CASI Pharmaceuticals|work=Adis Insight | publisher = Springer Nature Switzerland AG |access-date=2 March 2017}}</ref> This is significantly due to the very poor [[oral administration|oral]] [[bioavailability]] of the molecule and also due to its extensive [[metabolism]]. [[Structural analog|Analogue]]s have been developed in an attempt to overcome these problems.<ref name="pmid29618488">{{cite journal | vauthors = Potter BV | title = SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects | journal = Journal of Molecular Endocrinology | volume = 61 | issue = 2 | pages = T233–T252 | date = August 2018 | pmid = 29618488 | doi = 10.1530/JME-18-0045 | doi-access = free }}</ref> An example is [[2-methoxyestradiol disulfamate]] (STX-140), the C3 and C17β di[[sulfamate]] [[ester]] of 2-methoxyestradiol.<ref name="pmid29618488" />

==Clinical effects==
2-Methoxyestradiol was found to increase [[sex hormone-binding globulin]] (SHBG) levels in men by 2.5-fold at a dose of 400&nbsp;mg/day and by 4-fold at a dose of 1,200&nbsp;mg/day.<ref name="pmid16166441">{{cite journal | vauthors = Sweeney C, Liu G, Yiannoutsos C, Kolesar J, Horvath D, Staab MJ, Fife K, Armstrong V, Treston A, Sidor C, Wilding G | title = A phase II multicenter, randomized, double-blind, safety trial assessing the pharmacokinetics, pharmacodynamics, and efficacy of oral 2-methoxyestradiol capsules in hormone-refractory prostate cancer | journal = Clinical Cancer Research | volume = 11 | issue = 18 | pages = 6625–6633 | date = September 2005 | pmid = 16166441 | doi = 10.1158/1078-0432.CCR-05-0440 | doi-access = free }}</ref> Conversely, it did not seem to suppress [[testosterone]] levels.<ref name="pmid16166441" />

A study in 2000 indicated that 2-Methoxyestradiol induces G2/M cycle arrest, [[apoptosis]] and the disruption of thyroid follicles. This process results in the release of thyroid antigens that may play a role in high incidence of [[thyroid autoantibodies]] and [[autoimmune]] [[thyroid disease]] in women.<ref>{{cite journal | vauthors = Wang SH, Myc A, Koenig RJ, Bretz JD, Arscott PL, Baker JR | title = 2-Methoxyestradiol, an endogenous estrogen metabolite, induces thyroid cell apoptosis | journal = Molecular and Cellular Endocrinology | volume = 165 | issue = 1-2 | pages = 163–172 | date = July 2000 | pmid = 10940494 | doi = 10.1016/S0303-7207(00)00249-5 }}</ref>

== See also ==
* [[2-Methoxyestriol]]
* [[2-Methoxyestrone]]
* [[4-Methoxyestradiol]]
* [[4-Methoxyestrone]]
* [[MP-2001]]

== References ==
{{Reflist}}

{{Antiangiogenics}}
{{Estrogen receptor modulators}}

{{DEFAULTSORT:Methoxyestradiol, 2-}}
[[Category:Abandoned drugs]]
[[Category:Angiogenesis inhibitors]]
[[Category:Antineoplastic drugs]]
[[Category:Estranes]]
[[Category:Ethers]]
[[Category:GPER agonists]]
[[Category:Human metabolites]]
[[Category:Hypolipidemic agents]]
[[Category:Microtubule inhibitors]]
[[Category:Mitotic inhibitors]]
[[Category:Hydroxyarenes]]