2-Methoxyestradiol

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
IUPAC name
  • (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
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.164.606
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Chemical and physical data
FormulaC19H26O3
Molar mass302.414 g·mol−1
3D model (JSmol)
SMILES
  • Oc1cc3c(cc1OC)[C@H]2CC[C@@]4([C@@H](O)CC[C@H]4[C@@H]2CC3)C
InChI
  • 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 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.[1] It also acts as a vasodilator[2] and induces apoptosis in some cancer cell lines.[3] 2-Methoxyestradiol is derived from estradiol, although it interacts poorly with the estrogen receptors (2,000-fold lower activational potency relative to estradiol).[4] 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).[5][6]

Selected biological properties of endogenous estrogens in rats
EstrogenER RBA (%)Uterine weight (%)UterotrophyLH levels (%)SHBG RBA (%)
Control–100–100–
Estradiol100506 ± 20+++12–19100
Estrone11 ± 8490 ± 22+++ ?20
Estriol10 ± 4468 ± 30+++8–183
Estetrol0.5 ± 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. ER RBA = Relative binding affinity to estrogen receptors of rat uterine cytosol. Uterine weight = Percentage change in uterine wet weight of ovariectomized rats after 72 hours with continuous administration of 1 μg/hour via subcutaneously implanted osmotic 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., not endogenous). b = Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours). Sources: See template.

Clinical development

2-Methoxyestradiol was being developed as an experimental drug candidate with the tentative brand name Panzem.[7] It has undergone Phase 1 clinical trials against breast cancer.[8] A phase II trial of 18 advanced ovarian cancer patients reported encouraging results in October 2007.[9]

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[10] and is inhibitory against prostate cancer in rodents.[11]

As of 2015, all clinical development of 2-methoxyestradiol has been suspended or discontinued.[12] 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.[13] An example is 2-methoxyestradiol disulfamate (STX-140), the C3 and C17β disulfamate ester of 2-methoxyestradiol.[13]

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.[14] Conversely, it did not seem to suppress testosterone levels.[14]

See also

  • 2-Methoxyestriol
  • 2-Methoxyestrone
  • 4-Methoxyestradiol
  • 4-Methoxyestrone
  • MP-2001

References

  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): 173–9. doi:10.1023/a:1026543018478. PMID 11191057. S2CID 20055299.
  2. ↑ Koganti, Sivaramakrishna; Snyder, Russell; Thekkumkara, Thomas (April 2012). "Pharmacological 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. ISSN 1550-8579. PMC 3322289. PMID 22366193.
  3. ↑ LaVallee TM, Zhan XH, Johnson MS, Herbstritt CJ, Swartz G, Williams MS, Hembrough WA, Green SJ, Pribluda VS (January 2003). "2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway". Cancer Research. 63 (2): 468–75. 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): 785–92. 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". Pharmacol. Rev. 67 (3): 505–40. 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. pp. 11–7. doi:10.1007/978-1-4939-3127-9_2. ISBN 978-1-4939-3126-2. PMID 26585123.
  7. ↑ EntreMed's Product Information Site Archived May 4, 2005, at the Wayback Machine
  8. ↑ Tevaarwerk, Amye J.; Holen, Kyle D.; Alberti, Dona B.; Sidor, Carolyn; Arnott, Jamie; Quon, Check; Wilding, George; Liu, Glenn (2009-02-15). "Phase I Trial of 2-Methoxyestradiol (2ME2, Panzem®) NanoCrystal® Dispersion (NCD®) in Advanced Solid Malignancies". Clinical Cancer Research. 15 (4): 1460–1465. doi:10.1158/1078-0432.CCR-08-1599. ISSN 1078-0432. PMC 2892631. PMID 19228747.
  9. ↑ "EntreMed Presents Results for Panzem® NCD Phase 2 Ovarian Cancer Study". Archived from the original on July 17, 2012.
  10. ↑ Lakhani NJ, Sarkar MA, Venitz J, Figg WD (February 2003). "2-Methoxyestradiol, a promising anticancer agent". Pharmacotherapy. 23 (2): 165–72. doi:10.1592/phco.23.2.165.32088. PMID 12587805. S2CID 1541302.
  11. ↑ Sato, Fuminori; Fukuhara, Hiroshi; Basilion, James P. (2005-09-01). "Effects of Hormone Deprivation, 2-Methoxyestradiol Combination Therapy on Hormone-Dependent Prostate Cancer In Vivo". Neoplasia. 7 (9): 838–846. doi:10.1593/neo.05145. ISSN 1476-5586. PMC 1501932. PMID 16229806.
  12. ↑ "2-Methoxyestradiol - CASI Pharmaceuticals". Adis Insight. Retrieved 2 March 2017.
  13. 1 2 Potter, B V L (2018). "SULFATION PATHWAYS: Steroid Sulphatase Inhibition by Aryl Sulphamates: Clinical Progress, Mechanism and Future Prospects". J. Mol. Endocrinol. 61 (2): T233–T252. doi:10.1530/JME-18-0045. PMID 29618488.
  14. 1 2 Sweeney C, Liu G, Yiannoutsos C, Kolesar J, Horvath D, Staab MJ, Fife K, Armstrong V, Treston A, Sidor C, Wilding G (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". Clin Cancer Res. 11 (18): 6625–33. doi:10.1158/1078-0432.CCR-05-0440. PMID 16166441.
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