Compounds for the treatment of oestrogen-dependent illnesses

Abstract

Compounds that interfere with the enzymes involved in oestrogen biosynthesis are useful in the treatment of oestrogen-dependent breast cancers. Oestrone sulphatase is the critical enzyme in the biosynthesis of oestradiol in breast cancer cells and high levels of this enzyme, as well as its substrate oestradiol sulphate, were detected in the cancerous, but not normal, tissues. This enzyme is inhibited by sulphamates, which act as transition state analogues in the steroid sulphate hydrolysis. Duquesne University of the Holy Ghost discloses in this patent a series of sulphamates also possessing a moiety that assures affinity for the oestrogen receptor, so that these derivatives possess a dual mechanism of action: inhibition of oestradiol biosynthesis (due to inhibition of oestrone sulphatase enzymatic activity) and binding to the oestrogen receptor, thus impeding the access of the hormone to its cellular site of action. The disclosed compounds were synthesised by simple procedures, for instance, the reaction of (Z)-4-hydroxytamoxifen with sulphamoyl chloride, and were assayed in vitro and ex vivo for the inhibition of liver microsome sulphatase and MDA-MB-231 breast cancer cell sulphatase, respectively. The compound (Z)-4-hydroxytamoxifen represents an interesting lead for the development of novel types of anticancer drugs.

• breast cancer
• oestrogen-dependent tumours
• oestrone sulphatase
• sulphamate
• sulphonamide
• tamoxifen