Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Patent
1997-06-02
1999-04-06
Huff, Sheela
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
435 18, 435 29, 435183, 435975, C12Q 100
Patent
active
058916202
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to an assay.
In particular the present invention relates to an assay for use in determining the absence or presence of steroid sulphatase activity.
Steroid precursors, or pro-hormones, having a sulphate group in the 3-position of the steroid nucleus, referred to hereinafter simply as steroid sulphates, are known to play an important part as intermediates in steroid metabolism in the human body. Oestrone sulphate and dehydroepiandrosterone (DHA) sulphate, for example, are known to play an important role as intermediates in the production, in the body, of oestrogens such as oestrone, oestradiol and oestrogenic steroids such as androstenediol.
In particular, and by way of example, oestrone sulphate is known to represent one of the major circulating oestrogen precursors particularly in post-menopausal women and oestrone sulphatase activity in breast tumours is approximately a million fold greater than that of other enzymes involved in oestrogen formation (James et al., Steroids, 50, 269-279 (1987)).
In addition, oestrogens such as oestrone and oestradiol, particularly the over-production thereof, are strongly implicated in malignant conditions, such as breast cancer, see Breast Cancer, Treatment and Prognosis: Ed. R. A. Stoll, pp. 156-172, Blackwell Scientific Publications (1986), and the control of oestrogen production is the specific target of many anti-cancer therapies, both chemotherapy and surgical, e.g. oophorectomy and adrenalectomy.
So far as endocrine therapy is concerned, efforts have so far tended to concentrate on aromatase inhibitors, i.e. compounds which inhibit aromatase activity, which activity is involved in the conversion of androgens such as androstenedione and testosterone to oestrone and oestradiol respectively.
In WO 91/13083, WO 93/05063 and WO 93/05064 are reported methods, including compounds and compositions for use in those methods, for inhibiting or at least reducing steroid sulphatase activity.
In this regard, WO 91/13083 discloses a method of targeting a different point in the oestrogen metabolic pathway, or rather two different points, that is to say the conversion of DHA sulphate and oestrone sulphate to DHA and oestrone, respectively, by steroid sulphatase activity, and using 3-monoalkylthiophosphonate steroid esters as a steroid sulphatase inhibitor, more especially oestrone-3-monomethylthiophosphonate.
WO 93/05063 discloses novel compounds, including pharmaceutically acceptable salts thereof, having steroid sulphatase inhibitory activity. These compounds are the sulphonate and phosphonate esters of polycyclic alcohols, being polycyclic alcohols the sulphate of which is a substrate for enzymes having steroid sulphatase activity. In their broadest sense, the novel compounds have the formula shown as FORMULA I in FIG. 1--wherein: R is selected from H, alkyl, cycloalkyl, alkenyl and aryl; X is P or S; Y is --OH when X is P, and .dbd.O when X is S; and the group O-Polycycle represents the residue of a polycyclic alcohol, the sulphate of which is a substrate for enzymes having steroid sulphatase activity.
WO 93/05064 discloses novel compounds, including pharmaceutically acceptable salts thereof, having steroid sulphatase inhibitory activity, and in some cases with extremely high activity levels. These compounds are the sulphamic acid esters of polycyclic alcohols, being polycyclic alcohols the sulphate of which is a substrate for enzymes having steroid sulphatase (EC 3.1.6.2) activity, the N-alkyl and N-aryl derivatives of those sulphamic acid esters. In their broadest sense, the novel compounds of WO 93/05064 have the formula shown as FORMULA II in FIG. 2a--wherein: R.sub.1 and R.sub.2 are each independently selected from H, alkyl, cycloalkyl, alkenyl and aryl, or together represent alkylene optionally containing one or more hetero atoms or groups in the alkylene chain; and the group --O-- Polycycle represents the residue of a polycyclic alcohol, the sulphate of which is a substrate for enzymes having steroid sulphatase ac
REFERENCES:
British Journal of Dermatology, vol. 123, 1990, p. 547 XP000566526, M. Okano: "Commercial assay for steroid sulphatase activity . . . ".
J. Inherited Metabolic Disease, vol. 12, 1989, Dordrecht, pp. 273-280 XP000566527, O.P. Van Diggelen: "A Fluorometric assay of steroid sulphatase . . .".
Okano et al. British Journal of Dermatology vol. 113 p. 645, 1985.
Purohit Atul
Reed Michael J.
Huff Sheela
Imperial College of Science Technology and Medicine
Kowalski Thomas J.
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