Related Experiment Videos
Recent advances in the development of steroid sulphatase inhibitors
Abstract:
Inhibition of steroid sulphatase is now an important target for the development of new drugs for the treatment of women with endocrine-dependent breast tumours. The first potent sulphatase inhibitor identified, oestrone-3-O-sulphamate (EMATE) proved. unexpectedly, to be oestrogenic. A number of strategies have therefore been adopted to design and synthesize a non-oestrogenic inhibitor. For this, a number of modifications have been made to the A and D rings of the oestrone nucleus. 2 Methoxyoestrone-3-O-sulphamate, while having similar in vitro and in vivo sulphatase inhibitory potency to that of EMATE, was devoid of oestrogenic activity when tested at 2 mg/kg in an ovariectomised rat uterine weight gain assay. 17-Deoxyoestrone-3-O-sulphamate was also a potent steroid sulphatase inhibitor and while it was devoid of oestrogenic activity when tested at 0.1 mg/kg, did stimulate uterine growth at 1.0 mg/kg. As an alternative approach to the use of steroid-based inhibitors a number of single ring, bicyclic non-fused ring, and two fused ring sulphamate analogues were designed, synthesized and tested for their ability to inhibit steroid sulphatase activity. In general, although the single ring and bicyclic non-fused ring sulphamate analogues could inhibit sulphatase activity, they were considerably less potent than EMATE. The mono- and bis-sulphamate derivatives of 5,7-dihydroxyisoflavone were relatively potent, inhibiting in vivo steroid sulphatase activity by 62 and 81% respectively at a single oral dose of 10 mg/kg. A study of the structure-activity relationship of a series of coumarin-based sulphamates has led to the development of a number of potent non-steroidal inhibitors, one of which has a similar potency to that of EMATE. The identification of potent steroid- and non-steroid-based sulphatase inhibitors will enable the therapeutic value of this therapy to be examined in the near future.
Insights
Researchers developed non-oestrogenic steroid sulphatase inhibitors for breast cancer treatment. Modifications to oestrone and new non-steroidal compounds show promise, advancing potential therapies for endocrine-dependent tumors.
Area of Science:
- Endocrinology and pharmacology
- Medicinal chemistry
- Oncology
Background:
- Steroid sulphatase inhibition is a key strategy for treating hormone-dependent breast cancers.
- The initial inhibitor, oestrone-3-O-sulphamate (EMATE), exhibited undesirable oestrogenic activity.
- Developing non-oestrogenic inhibitors is crucial for safer and more effective therapies.
Purpose of the Study:
- To design and synthesize novel non-oestrogenic inhibitors of steroid sulphatase.
- To evaluate the efficacy and oestrogenicity of modified steroid-based and novel non-steroidal sulphamate analogues.
- To identify potent inhibitors for potential clinical application in breast cancer treatment.
Main Methods:
- Chemical synthesis of modified oestrone derivatives (e.g., 2-methoxyoestrone-3-O-sulphamate, 17-deoxyoestrone-3-O-sulphamate).
- Design and synthesis of various sulphamate analogues (single ring, bicyclic, fused ring, isoflavone, and coumarin derivatives).
- In vitro and in vivo assays to assess sulphatase inhibitory potency and oestrogenic activity (e.g., rat uterine weight gain assay).
Main Results:
- 2-Methoxyoestrone-3-O-sulphamate showed potent sulphatase inhibition without oestrogenic activity.
- 17-Deoxyoestrone-3-O-sulphamate was a potent inhibitor but showed oestrogenic effects at higher doses.
- Isoflavone and coumarin-based sulphamates demonstrated significant in vivo sulphatase inhibition, with some non-steroidal compounds matching EMATE's potency.
Conclusions:
- Steroid and non-steroidal sulphatase inhibitors can be designed to lack oestrogenic activity.
- Modified oestrone derivatives and novel non-steroidal compounds offer promising therapeutic candidates.
- Further investigation into these potent inhibitors could lead to new treatments for endocrine-dependent breast tumours.