2-Methoxyestradiol

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2-Methoxyestradiol
2-Methoxyestradiol.svg
Clinical data
Trade names Panzem
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
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.164.606 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H26O3
Molar mass 302.414 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 Yes check.svgY
  • Key:CQOQDQWUFQDJMK-SSTWWWIQSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (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]

Contents

Selected biological properties of endogenous estrogens in rats
Estrogen ER Tooltip Estrogen receptor RBA Tooltip relative binding affinity (%) Uterine weight (%) Uterotrophy LH Tooltip Luteinizing hormone levels (%) SHBG Tooltip Sex hormone-binding globulin RBA Tooltip 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-Estradiol 4.2 ± 0.8 ? ? ? ?
2-Hydroxyestradiol 24 ± 7285 ± 8+b31–6128
2-Methoxyestradiol0.05 ± 0.04101Inactive ?130
4-Hydroxyestradiol 45 ± 12 ? ? ? ?
4-Methoxyestradiol 1.3 ± 0.2260++ ?9
4-Fluoroestradiol a180 ± 43 ?+++ ? ?
2-Hydroxyestrone 1.9 ± 0.8130 ± 9Inactive110–1428
2-Methoxyestrone 0.01 ± 0.00103 ± 7Inactive95–100120
4-Hydroxyestrone 11 ± 4351++21–5035
4-Methoxyestrone 0.13 ± 0.04338++65–9212
16α-Hydroxyestrone 2.8 ± 1.0552 ± 42+++7–24<0.5
2-Hydroxyestriol 0.9 ± 0.3302+b ? ?
2-Methoxyestriol 0.01 ± 0.00 ?Inactive ?4
Notes: Values are mean ± SD or range. ERRBA = 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

Related Research Articles

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<span class="mw-page-title-main">Estriol</span> Chemical compound

Estriol (E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estrone. Levels of estriol in women who are not pregnant are almost undetectable. However, during pregnancy, estriol is synthesized in very high quantities by the placenta and is the most produced estrogen in the body by far, although circulating levels of estriol are similar to those of other estrogens due to a relatively high rate of metabolism and excretion. Relative to estradiol, both estriol and estrone have far weaker activity as estrogens.

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<span class="mw-page-title-main">2-Hydroxyestrone</span> Chemical compound

2-Hydroxyestrone (2-OHE1), also known as estra-1,3,5(10)-trien-2,3-diol-17-one, is an endogenous, naturally occurring catechol estrogen and a major metabolite of estrone and estradiol. It is formed irreversibly from estrone in the liver and to a lesser extent in other tissues via 2-hydroxylation mediated by cytochrome P450 enzymes, mainly the CYP3A and CYP1A subfamilies. 2-OHE1 is the most abundant catechol estrogen in the body.

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<span class="mw-page-title-main">2-Methoxyestradiol disulfamate</span> Chemical compound

2-Methoxyestradiol disulfamate is a synthetic, oral active anti-cancer medication which was previously under development for potential clinical use. It has improved potency, low metabolism, and good pharmacokinetic properties relative to 2-methoxyestradiol (2-MeO-E2). It is also a potent inhibitor of steroid sulfatase, the enzyme that catalyzes the desulfation of steroids such as estrone sulfate and dehydroepiandrosterone sulfate (DHEA-S).

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): 173–179. 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. ↑ "EntreMed's Statistics". EntreMed, Inc. Archived from the original on May 4, 2005.
  8. ↑ 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.
  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): 165–172. doi:10.1592/phco.23.2.165.32088. PMID   12587805. S2CID   1541302.
  11. ↑ 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.
  12. ↑ "2-Methoxyestradiol - CASI Pharmaceuticals". Adis Insight. Springer Nature Switzerland AG. Retrieved 2 March 2017.
  13. 1 2 Potter 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.
  14. 1 2 Sweeney 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.
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