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2-Methoxyestradiol

From Wikipedia, the free encyclopedia
Chemical compound

Not to be confused with2-Methoxyestriol.
Pharmaceutical compound
2-Methoxyestradiol
Clinical data
Trade namesPanzem
Other names2-ME2; 2-MeO-E2; 2-MeOE2; 2-Hydroxyestradiol 2-methyl ether; 2-Methoxyestra-1,3,5(10)-triene-3,17β-diol
Identifiers
  • (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
CAS Number
PubChemCID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.164.606Edit this at Wikidata
Chemical and physical data
FormulaC19H26O3
Molar mass302.414 g·mol−1
3D model (JSmol)
  • Oc1cc3c(cc1OC)[C@H]2CC[C@@]4([C@@H](O)CC[C@H]4[C@@H]2CC3)C
  • InChI=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 checkY
  • Key:CQOQDQWUFQDJMK-SSTWWWIQSA-N checkY
 ☒NcheckY (what is this?)  (verify)

2-Methoxyestradiol (2-ME2,2-MeO-E2) is anaturalmetabolite ofestradiol and2-hydroxyestradiol (2-OHE2). It is specifically the 2-methylether of 2-hydroxyestradiol. 2-Methoxyestradiol prevents the formation of newblood vessels thattumors need in order to grow (angiogenesis), hence it is anangiogenesis inhibitor.[1] It also acts as avasodilator[2] and inducesapoptosis in somecancercell lines.[3] 2-Methoxyestradiol is derived from estradiol, although it interacts poorly with theestrogen receptors (2,000-fold lower activational potency relative to estradiol).[4] However, it retains activity as a high-affinityagonist of theG protein-coupled estrogen receptor (GPER) (10 nM, relative to 3–6 nM for estradiol).[5][6] It can also be used to treatalveolar echinococcosis when combined withalbendazole.

Selected biological properties of endogenous estrogens in rats
EstrogenERTooltip Estrogen receptorRBATooltip relative binding affinity (%)Uterine weight (%)UterotrophyLHTooltip Luteinizing hormone levels (%)SHBGTooltip Sex hormone-binding globulinRBATooltip relative binding affinity (%)
Control–100–100–
Estradiol (E2)100506 ± 20+++12–19100
Estrone (E1)11 ± 8490 ± 22+++?20
Estriol (E3)10 ± 4468 ± 30+++8–183
Estetrol (E4)0.5 ± 0.2?Inactive?1
17α-Estradiol4.2 ± 0.8????
2-Hydroxyestradiol24 ± 7285 ± 8+b31–6128
2-Methoxyestradiol0.05 ± 0.04101Inactive?130
4-Hydroxyestradiol45 ± 12????
4-Methoxyestradiol1.3 ± 0.2260++?9
4-Fluoroestradiola180 ± 43?+++??
2-Hydroxyestrone1.9 ± 0.8130 ± 9Inactive110–1428
2-Methoxyestrone0.01 ± 0.00103 ± 7Inactive95–100120
4-Hydroxyestrone11 ± 4351++21–5035
4-Methoxyestrone0.13 ± 0.04338++65–9212
16α-Hydroxyestrone2.8 ± 1.0552 ± 42+++7–24<0.5
2-Hydroxyestriol0.9 ± 0.3302+b??
2-Methoxyestriol0.01 ± 0.00?Inactive?4
Notes: Values are mean ± SD or range.ERRBA =Relative binding affinity toestrogen receptors of ratuterinecytosol. Uterine weight = Percentage change in uterine wet weight ofovariectomized rats after 72 hours with continuous administration of 1 μg/hour viasubcutaneously implantedosmotic pumps.LH levels =Luteinizing hormone levels relative to baseline of ovariectomized rats after 24 to 72 hours of continuous administration via subcutaneous implant.Footnotes:a =Synthetic (i.e., notendogenous).b = Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours).Sources:[7][8][9][10][11][12][13][14][15]

Clinical development

[edit]

2-Methoxyestradiol was beingdeveloped as an experimental drug candidate with the tentative brand name Panzem.[16] It has undergone Phase 1clinical trials againstbreast cancer.[17] A phase II trial of 18 advancedovarian cancer patients reported encouraging results in October 2007.[18]

Preclinical models also suggest that 2-methoxyestradiol could also be effective againstinflammatory diseases such asrheumatoid arthritis. Several studies have been conducted showing 2-methoxyestradiol is amicrotubule inhibitor[19] and is inhibitory againstprostate cancer in rodents.[20]

As of 2015[update], all clinical development of 2-methoxyestradiol has been suspended or discontinued.[21] This is significantly due to the very poororalbioavailability of the molecule and also due to its extensivemetabolism.Analogues have been developed in an attempt to overcome these problems.[22] An example is2-methoxyestradiol disulfamate (STX-140), the C3 and C17β disulfamateester of 2-methoxyestradiol.[22]

Clinical effects

[edit]

2-Methoxyestradiol was found to increasesex 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.[23] Conversely, it did not seem to suppresstestosterone levels.[23]

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 ofthyroid autoantibodies andautoimmunethyroid disease in women.[24]

See also

[edit]

References

[edit]
  1. ^Pribluda VS, Gubish ER, Lavallee TM, Treston A, Swartz GM, Green SJ (2000). "2-Methoxyestradiol: an endogenous antiangiogenic and antiproliferative drug candidate".Cancer and Metastasis Reviews.19 (1–2):173–179.doi:10.1023/a:1026543018478.PMID 11191057.S2CID 20055299.
  2. ^Koganti S, Snyder R, Thekkumkara T (April 2012)."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.doi:10.1016/j.genm.2012.01.008.PMC 3322289.PMID 22366193.
  3. ^LaVallee TM, Zhan XH, Johnson MS, Herbstritt CJ, Swartz G, Williams MS, et al. (January 2003)."2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway".Cancer Research.63 (2):468–475.PMID 12543804.
  4. ^Sibonga JD, Lotinun S, Evans GL, Pribluda VS, Green SJ, Turner RT (March 2003)."Dose-response effects of 2-methoxyestradiol on estrogen target tissues in the ovariectomized rat".Endocrinology.144 (3):785–792.doi:10.1210/en.2002-220632.PMID 12586754.
  5. ^Prossnitz ER, Arterburn JB (July 2015)."International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators".Pharmacological Reviews.67 (3):505–540.doi:10.1124/pr.114.009712.PMC 4485017.PMID 26023144.
  6. ^Thekkumkara T, Snyder R, Karamyan VT (2016). "Competitive Binding Assay for the G-Protein-Coupled Receptor 30 (GPR30) or G-Protein-Coupled Estrogen Receptor (GPER)".Estrogen Receptors. Methods in Molecular Biology. Vol. 1366. Springer. pp. 11–7.doi:10.1007/978-1-4939-3127-9_2.ISBN 978-1-4939-3126-2.PMID 26585123.
  7. ^Martucci C, Fishman J (March 1976). "Uterine estrogen receptor binding of catecholestrogens and of estetrol (1,3,5(10)-estratriene-3,15alpha,16alpha,17beta-tetrol)".Steroids.27 (3):325–333.doi:10.1016/0039-128x(76)90054-4.PMID 178074.S2CID 54412821.
  8. ^Martucci C, Fishman J (December 1977). "Direction of estradiol metabolism as a control of its hormonal action--uterotrophic activity of estradiol metabolites".Endocrinology.101 (6):1709–1715.doi:10.1210/endo-101-6-1709.PMID 590186.
  9. ^Fishman J, Martucci C (December 1978)."Differential biological activity of estradiol metabolites".Pediatrics.62 (6 Pt 2):1128–1133.doi:10.1542/peds.62.6.1128.PMID 724350.S2CID 29609115.
  10. ^Martucci CP, Fishman J (December 1979). "Impact of continuously administered catechol estrogens on uterine growth and luteinizing hormone secretion".Endocrinology.105 (6):1288–1292.doi:10.1210/endo-105-6-1288.PMID 499073.
  11. ^Fishman J, Martucci CP (1980). "New Concepts of Estrogenic Activity: the Role of Metabolites in the Expression of Hormone Action". In Pasetto N, Paoletti R, Ambrus JL (eds.).The Menopause and Postmenopause. pp. 43–52.doi:10.1007/978-94-011-7230-1_5.ISBN 978-94-011-7232-5.
  12. ^Fishman J, Martucci C (September 1980). "Biological properties of 16 alpha-hydroxyestrone: implications in estrogen physiology and pathophysiology".The Journal of Clinical Endocrinology and Metabolism.51 (3):611–615.doi:10.1210/jcem-51-3-611.PMID 7190977.
  13. ^Martucci CP (July 1983). "The role of 2-methoxyestrone in estrogen action".Journal of Steroid Biochemistry.19 (1B):635–638.doi:10.1016/0022-4731(83)90229-7.PMID 6310247.
  14. ^Fishman J, Martucci C (1980). "Dissociation of biological activities in metabolites of estradiol". In McLachlan JA (ed.).Estrogens in the Environment: Proceedings of the Symposium on Estrogens in the Environment, Raleigh, North Carolina, U.S.A., September 10-12, 1979. Elsevier. pp. 131–145.ISBN 9780444003720.
  15. ^Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration".Climacteric. 8 Suppl 1:3–63.doi:10.1080/13697130500148875.PMID 16112947.S2CID 24616324.
  16. ^"EntreMed's Statistics".EntreMed, Inc. Archived fromthe original on May 4, 2005.
  17. ^Tevaarwerk AJ, Holen KD, Alberti DB, Sidor C, Arnott J, Quon C, et al. (February 2009)."Phase I trial of 2-methoxyestradiol NanoCrystal dispersion in advanced solid malignancies".Clinical Cancer Research.15 (4):1460–1465.doi:10.1158/1078-0432.CCR-08-1599.PMC 2892631.PMID 19228747.
  18. ^"EntreMed Presents Results for Panzem NCD Phase 2 Ovarian Cancer Study". Archived fromthe original on July 17, 2012.
  19. ^Lakhani NJ, Sarkar MA, Venitz J, Figg WD (February 2003)."2-Methoxyestradiol, a promising anticancer agent".Pharmacotherapy.23 (2):165–172.doi:10.1592/phco.23.2.165.32088.PMID 12587805.S2CID 1541302.
  20. ^Sato F, Fukuhara H, Basilion JP (September 2005)."Effects of hormone deprivation and 2-methoxyestradiol combination therapy on hormone-dependent prostate cancer in vivo".Neoplasia.7 (9):838–846.doi:10.1593/neo.05145.PMC 1501932.PMID 16229806.
  21. ^"2-Methoxyestradiol - CASI Pharmaceuticals".Adis Insight. Springer Nature Switzerland AG. Retrieved2 March 2017.
  22. ^abPotter BV (August 2018)."SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects".Journal of Molecular Endocrinology.61 (2):T233 –T252.doi:10.1530/JME-18-0045.PMID 29618488.
  23. ^abSweeney C, Liu G, Yiannoutsos C, Kolesar J, Horvath D, Staab MJ, et al. (September 2005)."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.doi:10.1158/1078-0432.CCR-05-0440.PMID 16166441.
  24. ^Wang SH, Myc A, Koenig RJ, Bretz JD, Arscott PL, Baker JR (July 2000). "2-Methoxyestradiol, an endogenous estrogen metabolite, induces thyroid cell apoptosis".Molecular and Cellular Endocrinology.165 (1–2):163–172.doi:10.1016/S0303-7207(00)00249-5.PMID 10940494.
Endogenous
Exogenous
See also
ERTooltip Estrogen receptor
Agonists
Mixed
(SERMsTooltip Selective estrogen receptor modulators)
Antagonists
GPERTooltip G protein-coupled estrogen receptor
Agonists
Antagonists
Unknown
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