2-Methoxyestradiol

Chemical compound vanc 6 2-Methoxyestriol changed changed 477213877 (8R,9S,13S,14S,17S)-2-Methoxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol 2-Methoxyestradiol.svg skin-invert-image 250px Panzem changed ?? 362-07-2 66414 correct drugbank correct chemspider 59788 correct FDA 6I2QW73SR5 correct EBI 28955 correct EBI 299613 2-ME2; 2-MeO-E2; 2-MeOE2; 2-Hydroxyestradiol 2-methyl ether; 2-Methoxyestra-1,3,5(10)-triene-3,17β-diol 19 26 3 Oc1c(OC)cc2[C@H]3CC[C@]4(C)[C@]5(CC[C@H]4[C@@H]3CCc2c1).O5 correct chemspider 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 correct chemspider CQOQDQWUFQDJMK-SSTWWWIQSA-N 2-Methoxyestradiol (2-ME2, 2-MeO-E2) is a natural metabolite of estradiol and 2-hydroxyestradiol (2-OHE2). It is specifically the 2-methyl ether of 2-hydroxyestradiol. 2-Methoxyestradiol prevents the formation of new blood vessels that tumors need in order to grow (angiogenesis), hence it is an angiogenesis inhibitor. Pribluda VS, Gubish ER, Lavallee TM, Treston A, Swartz GM, Green SJ 2-Methoxyestradiol: an endogenous antiangiogenic and antiproliferative drug candidate Cancer and Metastasis Reviews 19 1–2 173–179 2000 11191057 10.1023/a:1026543018478 20055299 It also acts as a vasodilator Koganti S, Snyder R, Thekkumkara T Pharmacologic effects of 2-methoxyestradiol on angiotensin type 1 receptor down-regulation in rat liver epithelial and aortic smooth muscle cells Gender Medicine 9 2 76–93 April 2012 22366193 3322289 10.1016/j.genm.2012.01.008 and induces apoptosis in some cancer cell lines. LaVallee TM, Zhan XH, Johnson MS, Herbstritt CJ, Swartz G, Williams MS, Hembrough WA, Green SJ, Pribluda VS 2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway Cancer Research 63 2 468–475 January 2003 12543804 http://cancerres.aacrjournals.org/content/63/2/468.long 2-Methoxyestradiol is derived from estradiol, although it interacts poorly with the estrogen receptors (2,000-fold lower activational potency relative to estradiol). Sibonga JD, Lotinun S, Evans GL, Pribluda VS, Green SJ, Turner RT Dose-response effects of 2-methoxyestradiol on estrogen target tissues in the ovariectomized rat Endocrinology 144 3 785–792 March 2003 12586754 10.1210/en.2002-220632 free However, it retains activity as a high-affinity agonist of the G protein-coupled estrogen receptor (GPER) (10 nM, relative to 3–6 nM for estradiol). Prossnitz ER, Arterburn JB International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators Pharmacological Reviews 67 3 505–540 July 2015 26023144 4485017 10.1124/pr.114.009712 Thekkumkara T, Snyder R, Karamyan VT Estrogen Receptors Competitive Binding Assay for the G-Protein-Coupled Receptor 30 (GPR30) or G-Protein-Coupled Estrogen Receptor (GPER) Methods in Molecular Biology 1366 11–7 2016 Springer 26585123 10.1007/978-1-4939-3127-9_2 978-1-4939-3126-2 It can also be used to treat alveolar echinococcosis when combined with albendazole. Clinical development 2-Methoxyestradiol was being developed as an experimental drug candidate with the tentative brand name Panzem. http://www.entremed.com/go.cfm?do=Page.View&ID=31 EntreMed's Statistics EntreMed, Inc. https://web.archive.org/web/20050504153826/http://www.entremed.com/go.cfm?do=Page.View&ID=31 May 4, 2005 It has undergone Phase 1 clinical trials against breast cancer. Tevaarwerk AJ, Holen KD, Alberti DB, Sidor C, Arnott J, Quon C, Wilding G, Liu G Phase I trial of 2-methoxyestradiol NanoCrystal dispersion in advanced solid malignancies Clinical Cancer Research 15 4 1460–1465 February 2009 19228747 2892631 10.1158/1078-0432.CCR-08-1599 A phase II trial of 18 advanced ovarian cancer patients reported encouraging results in October 2007.http://www.entremed.com/news/entremed-presents-results-for-panzem-ncd-phase-2-ovarian-cancer-study EntreMed Presents Results for Panzem NCD Phase 2 Ovarian Cancer Study dead https://web.archive.org/web/20120717045228/http://www.entremed.com/news/entremed-presents-results-for-panzem-ncd-phase-2-ovarian-cancer-study July 17, 2012 Preclinical models also suggest that 2-methoxyestradiol could also be effective against inflammatory diseases such as rheumatoid arthritis. Several studies have been conducted showing 2-methoxyestradiol is a microtubule inhibitor Lakhani NJ, Sarkar MA, Venitz J, Figg WD 2-Methoxyestradiol, a promising anticancer agent Pharmacotherapy 23 2 165–172 February 2003 12587805 10.1592/phco.23.2.165.32088 1541302 https://zenodo.org/record/1236347 and is inhibitory against prostate cancer in rodents. Sato F, Fukuhara H, Basilion JP Effects of hormone deprivation and 2-methoxyestradiol combination therapy on hormone-dependent prostate cancer in vivo Neoplasia 7 9 838–846 September 2005 16229806 1501932 10.1593/neo.05145 2015, all clinical development of 2-methoxyestradiol has been suspended or discontinued.http://adisinsight.springer.com/drugs/800008361 2-Methoxyestradiol - CASI Pharmaceuticals Adis Insight Springer Nature Switzerland AG 2 March 2017 This is significantly due to the very poor oral bioavailability of the molecule and also due to its extensive metabolism. Analogues have been developed in an attempt to overcome these problems. Potter BV SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects Journal of Molecular Endocrinology 61 2 T233–T252 August 2018 29618488 10.1530/JME-18-0045 free An example is 2-methoxyestradiol disulfamate (STX-140), the C3 and C17β disulfamate ester of 2-methoxyestradiol. 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 mg/day and by 4-fold at a dose of 1,200 mg/day. Sweeney C, Liu G, Yiannoutsos C, Kolesar J, Horvath D, Staab MJ, Fife K, Armstrong V, Treston A, Sidor C, Wilding G 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 Clinical Cancer Research 11 18 6625–6633 September 2005 16166441 10.1158/1078-0432.CCR-05-0440 free Conversely, it did not seem to suppress testosterone levels. 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. Wang SH, Myc A, Koenig RJ, Bretz JD, Arscott PL, Baker JR 2-Methoxyestradiol, an endogenous estrogen metabolite, induces thyroid cell apoptosis Molecular and Cellular Endocrinology 165 1-2 163–172 July 2000 10940494 10.1016/S0303-7207(00)00249-5 See also 2-Methoxyestriol 2-Methoxyestrone 4-Methoxyestradiol 4-Methoxyestrone MP-2001 References Category:Abandoned drugs Category:Angiogenesis inhibitors Category:Antineoplastic drugs Category:Estranes Category:Ethers Category:GPER agonists Category:Human metabolites Category:Lipid-lowering agents Category:Microtubule inhibitors Category:Mitotic inhibitors Category:Hydroxyarenes