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Chemical compound
2-Methoxyestradiol
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
(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
Formula C 19 H 26 O 3
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
Y Key:CQOQDQWUFQDJMK-SSTWWWIQSA-N
Y
N Y
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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]
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 di
sulfamate
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
References
^ 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 .
^ 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 .
^ 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 .
^ 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 .
^ 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 .
^ 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 .
^
"EntreMed's Statistics" . EntreMed, Inc . Archived from
the original on May 4, 2005.
^ 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 .
^
"EntreMed Presents Results for Panzem NCD Phase 2 Ovarian Cancer Study" . Archived from
the original on July 17, 2012.
^ 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 .
^ 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 .
^
"2-Methoxyestradiol - CASI Pharmaceuticals" . Adis Insight . Springer Nature Switzerland AG. Retrieved 2 March 2017 .
^
a
b 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 .
^
a
b 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 .
ER Tooltip Estrogen receptor
Agonists
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3-Methyl-19-methyleneandrosta-3,5-dien-17β-ol
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11β-Chloromethylestradiol
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