Development of Dual Acting Inhibitors for Breast Cancer
Abstract
To design dual acting inhibitors that can block the enzyme estrone sulfatase and act as antiestiogens. Scope: The design and synthesis of 30 dual inhibit&s are proposed. The inhibitors contain 4 different structural core. The synthesized inhibitors will be tested on their ability to inhibit the enzyme estrone sulfatase and also their abilities to inhibit the growth of breast cancer cells stimulated by estrone sulfate. In addition, selected inhibitors will be tested in vivo using NMU-induced mammary tumors in rats. Major findings: More than 83 % (25 out of 30) of the proposed inhibitors have been synthesized. The inhibitors have been tested for their ability to inhibit estrone sulfatase activity of rat liver microsomes at 20 %M concentrations and in the presence of 20 %M of substrate estrone sulfate. All the inhibitors tested so far are more potent than our lead compound Tamoxifen sulfamate. Raloxifene sulfamate (inhibitor 30) is still the most potent compound among the 25 inhibitors we have synthesized. It inhibits more than 95% of the sulfatase activity at 20 %M concentration. It is by far the most potent dual inhibitor we have ever obtained. We have selected inhibitor 30 as one of the compounds for in vivo study using NMU-induced mammary tumors in rats. We have synthesized 4 grams of the compound needed for the study.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2003
- Accession Number
- ADA421903
Entities
People
- Pui K. Li
Organizations
- Ohio State University