Estrone sulfamates: potent inhibitors of estrone sulfatase with therapeutic potential

Howarth, Nicola M.; Purohit, Atul; Reed, Michael J.; Potter, Barry V. L.

doi:10.1021/jm00028a002

Cited by 214 publications

(148 citation statements)

References 6 publications

(11 reference statements)

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“…Potent inhibitors such as 17a-t-butylbenzyl-E 2 , 20 estrone sulfamate (EMATE) 10,11 and 17a-t-butylbenzyl-EMATE 22 were also used as reference compounds. The experimental conditions for measuring IC 50 were the same as in the screening assay, except that a range of inhibitor concentrations was used and two substrates studied; [ 3 H]-labeled E 1 S (100 mM) and […”

Section: Ic 50 Valuesmentioning

confidence: 99%

3β-Sulfamate Derivatives of C19 and C21 Steroids Bearing a t -Butylbenzyl or a Benzyl Group: Synthesis and Evaluation as Non-estrogenic and Non-androgenic Steroid Sulfatase Inhibitors

Ciobanu

Boivin

Luu‐The

et al. 2003

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of C19 and C21 steroids bearing one or two inhibiting groups (3b-sulfamate and 17a-or 20(S)-tbutylbenzyl or benzyl) were synthesized and tested for inhibition of steroid sulfatase activity. When only a sulfamate group was added to dehydroepiandrosterone, androst-5-ene-3b,17b-diol, pregnenolone and 20-hydroxy-pregnenolone, no significant inhibition of steroid sulfatase occurred at concentrations of 0.3 and 3 mM. With only a t-butylbenzyl or a benzyl group, a stronger steroid sulfatase inhibition was obtained in the androst-5-ene than in the pregn-5-ene series. Comparative results from the screening tests and the IC 50 values have shown that the effect of a sulfamate moiety as a second inhibiting group can be combined to the t-butylbenzyl or benzyl effect in the C19 and C21 steroid series. The 3b-sulfamoyloxy-17a-t-butylbenzyl-5-androsten-17b-ol (10) was thus found to be the most active compound with IC 50 values of 46 6 8 and 14 6 1 nM; respectively for the transformations of E 1 S to E 1 and DHEAS to DHEA. The IC 50 values of compound 10 are similar to that of 17a-t-butylbenzyl-estradiol, which was previously reported by our group as a good steroid sulfatase reversible inhibitor, but remains higher than that of the potent inactivators estrone-3-O-sulfamate (EMATE) and 17a-t-butylbenzyl-EMATE. However, contrary to these two latter inhibitors, compound 10 did not induce any proliferative effect on estrogensensitive ZR-75-1 cells nor on androgen-sensitive Shionogi cells at concentrations tested, suggesting that this steroid sulfatase inhibitor is non estrogenic and non androgenic.

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Section: Ic 50 Valuesmentioning

confidence: 99%

3β-Sulfamate Derivatives of C19 and C21 Steroids Bearing a t -Butylbenzyl or a Benzyl Group: Synthesis and Evaluation as Non-estrogenic and Non-androgenic Steroid Sulfatase Inhibitors

Ciobanu

Boivin

Luu‐The

et al. 2003

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…11,12 Unexpectedly, EMATE proved to be a potent estrogen on oral application in the rat. 13 This is thought to result from its absorption into red blood cells after ingestion thus protecting it from inactivation during transit through the liver.…”

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confidence: 99%

Inhibition of in vitro angiogenesis by 2‐methoxy‐ and 2‐ethyl‐estrogen sulfamates

Newman

Leese

Purohit

et al. 2004

Intl Journal of Cancer

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Sulfamoylation of 2-methoxyestrone (2-MeOE1) was shown previously to enhance its potency as an anti-proliferative agent against breast cancer cells. We have examined the ability of a series of 2-methoxyestradiol (2-MeOE2) and 2-ethylestradiol (2-EtE2) sulfamates to inhibit angiogenesis in vitro. 2-MeOE2 bis-sulfamate and 2-EtE2 sulfamate were potent inhibitors of human umbilical vein endothelial cell (HUVEC) proliferation with IC 50 values of 0.05 M and 0.01 M, respectively. A novel co-culture system, in which endothelial cells were cultured in a matrix of human dermal fibroblasts, was also used to assess the anti-angiogenic potential of these drugs. In this system endothelial cells proliferate and migrate through the culture matrix to form tubule structures. Key words: angiogenesis; breast cancer; estrogens; estrogen sulfamates; microtubulesEstrogens can be metabolised via either a 2-hydroxylase or 16␣-hydroxylase pathway and there is a growing awareness that the route of estrogen metabolism may influence the development of breast tumors. 2-Hydroxyestrogens and their 2-methoxy derivatives are non-estrogenic whereas 16␣-hydroxy metabolites are estrogenic due, in part, to their ability to form adducts with proteins. 1,2 Research carried out by Bradlow and others 3,4 has indicated that although the 2-hydroxylase pathway is associated with a reduced risk of breast cancer, increased formation of 16␣-hydroxy metabolites may increase breast cancer risk. It was suggested recently that the major derivative of 2-hydroxyestrogens, 2-methoxyestradiol (2-MeOE2, Fig. 1) may in fact be the endogenous estrogen metabolite that inhibits breast carcinogenesis. 5 2-MeOE2 is currently undergoing Phase I/II trials as a novel agent for breast cancer therapy. 6 Its selection for development as an anti-cancer agent was based on its ability to inhibit the proliferation of a wide range of cancer cells including estrogen receptor positive (ERϩ) and negative (ERϪ) breast cancer cells. 7,8 In vivo oral administration of 2-MeOE2 inhibited the growth of Meth-A sarcoma, B16 melanoma and human MDA-MB-435 breast carcinomas. 8,9 Relatively high doses of 2-MeOE2 (75-100 mg/kg/day) were administered to produce the reductions in tumor growth. In addition to its anti-proliferation effects 2-MeOE2 was also identified as the active ingredient of urine extracts that was able to inhibit angiogenesis. 9 Using brain-derived capillary endothelial cells 2-MeOE2 was found to be a specific inhibitor of the proliferation of these cells being 90ϫ more potent than 2-methoxyestrone (2-MeOE1) and 250ϫ more potent than estradiol. Several subsequent investigations have confirmed the potency of 2-MeOE2 as an inhibitor of endothelial cell growth and angiogenesis in vitro and in vivo. 8,10 The mechanism(s) by which 2-MeOE2 inhibits endothelial cell growth and angiogenesis remains to be elucidated.The estrogen sulfamate, estrone-3-O-sulfamate (EMATE) was initially identified as a potent steroid sulfatase inhibitor. 11,12 Unexpectedly, EMATE proved to be a potent estroge...

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“…As an alternative approach to modification of either the steroid nucleus or the C2 position of 2-MeOE2, the C3/C17 hydroxy groups were sulphamoylated to give 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (2-MeOE2bisMATE, Figures 1, 2) (Howarth et al, 1994;Purohit et al, 1995a, b;Raobaikady et al, 2003;Newman et al, 2004;Leese et al, 2006). In addition, a C17 analogue of 2-MeOE2bisMATE, cyanomethyl derivative (2-methoxy-3-O-sulphamoyl-17b-cyanomethyloestra-1,3,5(10)-triene,17-Cym-2-MeOE2-MATE, Figures 1, 3) was also synthesised (Utsumi et al, 2005).…”

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In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

et al. 2007

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Drugs that inhibit growth of tumours and their blood supply could have considerable therapeutic potential. 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate (2-MeOE2bisMATE) has been shown to inhibit the proliferation of MCF-7 (ER+) breast cancer cells and angiogenesis in vitro. 2-MeOE2bisMATE and its analogue, 17-Cym-2-MeOE2MATE, were investigated for their ability to inhibit in vivo angiogenesis and tumour growth. The mouse Matrigel plug assay for angiogenesis was used to investigate the effect of compounds on neovascularisation and was quantified using a FITC-dextran injection technique. Nude mice bearing tumours derived from MCF-7 cells were used to assess efficacy on tumour growth. Tumour sections were stained for VEGFR-2 and Ki67 to assess tumour angiogenesis and cell proliferation respectively. Matrigel plugs supplemented with basic fibroblast growth factor resulted in increased neovascularisation over 7 days. Oral administration of 2-MeOE2bisMATE for 7 days at 10 or 50 mg kg À1 significantly reduced neovascularisation to or below control levels respectively. 17-Cym-2-MeOE2MATE at 20 mg kg À1 was equally effective. 2-MeOE2bisMATE, dosed daily for 21 days, caused a 52% reduction in tumour growth at 5 mg kg À1 and 38% regression at 20 mg kg À1 . 17-Cym-2-MeOE2MATE (20 mg kg À1 ) reduced tumour growth by 92%. Immunohistochemistry revealed a reduction in angiogenesis and proliferation. Matrigel plug and tumour imaging after FITC-dextran injection indicated that 2-MeOE2bisMATE caused a marked disruption of vasculature. These sulphamoylated oestrogen derivatives have been shown to be potent inhibitors of angiogenesis in vivo. This, together with their ability to inhibit tumour growth, indicates the potential of this new class of drugs for further development for cancer therapy.

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Estrone sulfamates: potent inhibitors of estrone sulfatase with therapeutic potential

Cited by 214 publications

References 6 publications

3β-Sulfamate Derivatives of C19 and C21 Steroids Bearing a t -Butylbenzyl or a Benzyl Group: Synthesis and Evaluation as Non-estrogenic and Non-androgenic Steroid Sulfatase Inhibitors

3β-Sulfamate Derivatives of C19 and C21 Steroids Bearing a t -Butylbenzyl or a Benzyl Group: Synthesis and Evaluation as Non-estrogenic and Non-androgenic Steroid Sulfatase Inhibitors

Inhibition of in vitro angiogenesis by 2‐methoxy‐ and 2‐ethyl‐estrogen sulfamates

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

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