Antisulfatase, Osteogenic, and Anticancer Activities of Steroid Sulfatase Inhibitor EO-33 in Mice.

Abstract

Steroid sulfatase (STS) is a key enzyme involved in the biosynthesis of estrogens from inactive sulfated steroids. After we reported EO-33 as a potent in vitro STS inhibitor without undesirable estrogenic activity and with osteogenic properties, we are now interested in validating EO-33's in vivo potential to inhibit STS, to prevent bone deterioration, and to reduce estrogen-dependent tumor growth. A scale-up synthesis was first elaborated to prepare the multigram quantity of EO-33 needed to perform in vivo studies. EO-33 blocked the uterine weight stimulated by estrone sulfate in ovariectomized mice by 69% and the STS activity in the liver by 81%. It also produced a selective estrogen receptor modulator effect as assessed by measuring the tibia weight and calcium content. Using a human breast cancer (MCF-7 xenograft) model in nude mice, EO-33 blocked 90% of tumor growth induced by estradiol sulfate, and no toxic effect was observed by assessing the body and liver weights.

• Authors: Donald Poirier, Jenny Roy, René Maltais, Diana Ayan
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 11 Pg. 5512-5521 (06 13 2019) ISSN: 1520-4804 [Electronic] United States
• PMID: 31062594 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Estrogens
• Sulfonic Acids
• sulfamic acid
• Steryl-Sulfatase

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Enzyme Inhibitors (chemistry, pharmacology)
• Estrogens (biosynthesis)
• Humans
• MCF-7 Cells
• Mice
• Osteogenesis (drug effects)
• Steryl-Sulfatase (antagonists & inhibitors)
• Sulfonic Acids (chemistry, pharmacology)
• Xenograft Model Antitumor Assays