2-Methoxyestradiol

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

Estrogen	ER RBA (%)	Uterine weight (%)	Uterotrophy	LH levels (%)	SHBG RBA (%)
Control	–	100	–	100	–
Estradiol	100	506 ± 20	+++	12–19	100
Estrone	11 ± 8	490 ± 22	+++	?	20
Estriol	10 ± 4	468 ± 30	+++	8–18	3
Estetrol	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. 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.

2-Methoxyestradiol

Clinical data
Other names	2-ME2; 2-MeO-E2; 2-MeOE2; 2-Hydroxyestradiol 2-methyl ether; 2-Methoxyestra-1,3,5(10)-triene-3,17β-diol; Panzem
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)

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]

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 Metastasis Reviews. 19 (1–2): 173–9. doi:10.1023/a:1026543018478. PMID 11191057.
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)". Methods in Molecular Biology. 1366: 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.
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. 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.