Inactivation of Steroid Sulfatase by an Active Site-Directed Inhibitor, Estrone-3-O-Sulfamate

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

doi:10.1021/bi00036a025

Cited by 162 publications

(132 citation statements)

References 20 publications

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“…However, recent finding indicated that the third ring appears to be predominately in the boat conformation rather than previously proposed chair conformation based on temperature factors (B-factors) and electron density map results [79]. With the advent of this new finding regarding the conformation of the 7-membered ring on compound 30 it can now be explained that its higher potency (IC 50 value of 8 nM and K i value of 40 nM) than EMATE (IC 50 = 25 nM and K i = 670 nM) is attributed to the tendency to mimic the steroidal CD-ring; perhaps, better hydrophobic interactions due to favorable binding to the active site of the enzyme are in play [61,85,86].…”

Section: Sulfatase Inhibitormentioning

confidence: 99%

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

Musa

Cooperwood²,

Khan³

2008

CMC

479

190

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The coumarin (benzopyran-2-one, or chromen-2-one) ring system, present in natural products (such as the anticoagulant warfarin) that display interesting pharmacological properties, has intrigued chemists and medicinal chemists for decades to explore the natural coumarins or synthetic analogs for their applicability as drugs. Many molecules based on the coumarin ring system have been synthesized utilizing innovative synthetic techniques. The diversity oriented synthetic routes have led to interesting derivatives including the furanocoumarins, pyranocoumarins, and coumarin sulfamates (COUMATES), which have been found to be useful in photochemotherapy, antitumor and anti-HIV therapy, and as stimulants for central nervous system, antibacterials, anti-inflammatory, anti-coagulants, and dyes. Of particular interest in breast cancer chemotherapy, some coumarins and their active metabolite 7-hydroxycoumarin analogs have shown sulfatase and aromatase inhibitory activities. Coumarin based selective estrogen receptor modulators (SERMs) and coumarin-estrogen conjugates have also been described as potential antibreast cancer agents. Since breast cancer is the second leading cause of death in American women behind lung cancer, there is a strong impetus to identify potential new drug treatments for breast cancer. Therefore, the objective of this review is to focus on important coumarin analogs with antibreast cancer activities, highlight their mechanisms of action and structure-activity relationships on selected receptors in breast tissues, and the different methods that have been applied in the construction of these pharmacologically important coumarin analogs.

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Section: Sulfatase Inhibitormentioning

confidence: 99%

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

Musa

Cooperwood²,

Khan³

2008

CMC

479

190

View full text Add to dashboard Cite

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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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“…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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Inactivation of Steroid Sulfatase by an Active Site-Directed Inhibitor, Estrone-3-O-Sulfamate

Cited by 162 publications

References 20 publications

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

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

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