2-Methoxyestradiol disulfamate

2-Methoxyestradiol disulfamate
Clinical data
Other names	2-Methoxyestradiol disulfamate; 2-Methoxyestradiol 3,17β-disulfamate; 2-Methoxyestradiol-3,17β-O,O-bis(sulfamate); 3,17β-bis-Sulfamoyloxy-2-methoxyestra-1,3,5(10)-triene
Identifiers
	IUPAC name [(8R,9S,13S,14S,17S)-2-methoxy-13-methyl-3-sulfamoyloxy-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] sulfamate;
CAS Number	401600-86-0;
PubChem CID	9804302;
CompTox Dashboard (EPA)	DTXSID501336467 ;
Chemical and physical data
Formula	C19H28N2O7S2
Molar mass	460.56 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2OS(=O)(=O)N)CCC4=CC(=C(C=C34)OC)OS(=O)(=O)N;
	InChI InChI=1S/C19H28N2O7S2/c1-19-8-7-12-13(15(19)5-6-18(19)28-30(21,24)25)4-3-11-9-17(27-29(20,22)23)16(26-2)10-14(11)12/h9-10,12-13,15,18H,3-8H2,1-2H3,(H2,20,22,23)(H2,21,24,25)/t12-,13+,15-,18-,19-/m0/s1; Key:AQSNIXKAKUZPSI-SSTWWWIQSA-N;

2-Methoxyestradiol disulfamate (developmental code STX-140; also known as 2-methoxyestradiol 3,17β-O,O-bis(sulfamate)) is a synthetic, oral active anti-cancer medication which was previously under development for potential clinical use.^[1]^[2] It has improved potency, low metabolism, and good pharmacokinetic properties relative to 2-methoxyestradiol (2-MeO-E2).^[3] 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).

2-Methoxyestradiol disulfamate exhibits anti-angiogenic activity and induction of cell cycle arrest and apoptosis in human tumor xenografts, with clinical potential for hormone–independent tumors. Some of this activity stems from tubulin binding at the colchicine site and disruption of interphase microtubules. 2-Methoxyestradiol disulfamate is highly active in tumors that are resistant to chemotherapy.^[4]

In xenograft models of breast and prostate cancer complete cures were achieved after oral treatment with 2-methoxyestradiol disulfamate and drug-resistant tumors also shrank in size after oral treatment.^[2] Conventional treatments for hormone-independent cancers targeting tubulin are associated with side effects, such as neurotoxicity, and can only be given infrequently and intravenously. 2-Methoxyestradiol disulfamate is more effective on the same tumors, blocks metastatic spread without the peripheral neuropathy associated with current clinical anticancer drugs.^[5]

References

^ Leese MP, Leblond B, Smith A, Newman SP, Di Fiore A, De Simone G, et al. (December 2006). "2-substituted estradiol bis-sulfamates, multitargeted antitumor agents: synthesis, in vitro SAR, protein crystallography, and in vivo activity". Journal of Medicinal Chemistry. 49 (26): 7683–7696. doi:10.1021/jm060705x. PMID 17181151.
^ ^a ^b Thomas MP, Potter BV (September 2015). "Estrogen O-sulfamates and their analogues: Clinical steroid sulfatase inhibitors with broad potential". The Journal of Steroid Biochemistry and Molecular Biology. 153 (19): 160–169. doi:10.1016/j.jsbmb.2015.03.012. PMID 25843211. S2CID 24116740.
^ Thomas MP, Potter BV (October 2015). "Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women's Health". Journal of Medicinal Chemistry. 58 (19): 7634–7658. doi:10.1021/acs.jmedchem.5b00386. PMC 5159624. PMID 25992880.
^ Newman SP, Foster PA, Stengel C, Day JM, Ho YT, Judde JG, et al. (January 2008). "STX140 is efficacious in vitro and in vivo in taxane-resistant breast carcinoma cells". Clinical Cancer Research. 14 (2): 597–606. doi:10.1158/1078-0432.CCR-07-1717. PMID 18223236.
^ Meyer-Losic F, Newman SP, Day JM, Reed MJ, Kasprzyk PG, Purohit A, Foster PA (2013-12-06). Tan M (ed.). "STX140, but not paclitaxel, inhibits mammary tumour initiation and progression in C3(1)/SV40 T/t-antigen transgenic mice". PLOS ONE. 8 (12): e80305. Bibcode:2013PLoSO...880305M. doi:10.1371/journal.pone.0080305. PMC 3855596. PMID 24324595.

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[1] Leese MP, Leblond B, Smith A, Newman SP, Di Fiore A, De Simone G, et al. (December 2006). "2-substituted estradiol bis-sulfamates, multitargeted antitumor agents: synthesis, in vitro SAR, protein crystallography, and in vivo activity". Journal of Medicinal Chemistry. 49 (26): 7683–7696. doi:10.1021/jm060705x. PMID 17181151.

[:0-2] Thomas MP, Potter BV (September 2015). "Estrogen O-sulfamates and their analogues: Clinical steroid sulfatase inhibitors with broad potential". The Journal of Steroid Biochemistry and Molecular Biology. 153 (19): 160–169. doi:10.1016/j.jsbmb.2015.03.012. PMID 25843211. S2CID 24116740.

[3] Thomas MP, Potter BV (October 2015). "Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women's Health". Journal of Medicinal Chemistry. 58 (19): 7634–7658. doi:10.1021/acs.jmedchem.5b00386. PMC 5159624. PMID 25992880.

[4] Newman SP, Foster PA, Stengel C, Day JM, Ho YT, Judde JG, et al. (January 2008). "STX140 is efficacious in vitro and in vivo in taxane-resistant breast carcinoma cells". Clinical Cancer Research. 14 (2): 597–606. doi:10.1158/1078-0432.CCR-07-1717. PMID 18223236.

[5] Meyer-Losic F, Newman SP, Day JM, Reed MJ, Kasprzyk PG, Purohit A, Foster PA (2013-12-06). Tan M (ed.). "STX140, but not paclitaxel, inhibits mammary tumour initiation and progression in C3(1)/SV40 T/t-antigen transgenic mice". PLOS ONE. 8 (12): e80305. Bibcode:2013PLoSO...880305M. doi:10.1371/journal.pone.0080305. PMC 3855596. PMID 24324595.

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See also

References