2-Methoxyestradiol

Not to be confused with 2-Methoxyestriol.

2-Methoxyestradiol

Clinical data
Trade names	Panzem
Other names	2-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	362-07-2  N
PubChem CID	66414
ChemSpider	59788  Y
UNII	6I2QW73SR5
ChEBI	CHEBI:28955  Y
ChEMBL	ChEMBL299613  Y
CompTox Dashboard (EPA)	DTXSID3040938
ECHA InfoCard	100.164.606
Chemical and physical data
Formula	C19H26O3
Molar mass	302.414 g·mol−1
3D model (JSmol)	Interactive image
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 Y Key:CQOQDQWUFQDJMK-SSTWWWIQSA-N Y
NY  (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]}

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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)	100	506 ± 20	+++	12–19	100
Estrone (E1)	11 ± 8	490 ± 22	+++	?	20
Estriol (E3)	10 ± 4	468 ± 30	+++	8–18	3
Estetrol (E4)	0.5 ± 0.2	?	Inactive	?	1
17α-Estradiol	4.2 ± 0.8	?	?	?	?
2-Hydroxyestradiol	24 ± 7	285 ± 8	+b	31–61	28
2-Methoxyestradiol	0.05 ± 0.04	101	Inactive	?	130
4-Hydroxyestradiol	45 ± 12	?	?	?	?
4-Methoxyestradiol	1.3 ± 0.2	260	++	?	9
4-Fluoroestradiol a	180 ± 43	?	+++	?	?
2-Hydroxyestrone	1.9 ± 0.8	130 ± 9	Inactive	110–142	8
2-Methoxyestrone	0.01 ± 0.00	103 ± 7	Inactive	95–100	120
4-Hydroxyestrone	11 ± 4	351	++	21–50	35
4-Methoxyestrone	0.13 ± 0.04	338	++	65–92	12
16α-Hydroxyestrone	2.8 ± 1.0	552 ± 42	+++	7–24	<0.5
2-Hydroxyestriol	0.9 ± 0.3	302	+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 ^[update] , 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]

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. ^[15]

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): 173–179. 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. 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. 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.
15. 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.