近年来，我们实验室首次发现了一组全新的内源性非极性雌激素代谢产物，它们是雌激素二聚体（NEDs）。本研究项目旨在确定这类 NEDs 的化学结构，完成它们的化学合成，并研究它们的抗雌激素和抗乳腺癌的活性。我们的工作假说是：有些NEDs是具有抗雌激素活性的内源性雌激素代谢衍生物。 在本研究项目中，我们有以下三个大目标：.• 目标1. 结构鉴定和化学合成：1A. 鉴定 NEDs 的化学结构，特别是那些具有抗雌激素活性的NEDs的化学结构。 1B. 用化学合成方法合成足够量的具有抗雌激素的NEDs。.• 目标2. 生物活性的研究：2A. 用体外模型来研究NEDs的抗雌激素活性。 2B. 用动物实验模型来研究NEDs的抗乳腺癌活性，并比较它们与雌激素受体调控药Tamoxifen和Fulvestrant的抗乳腺癌活性。.• 目标3. 人体研究：检测人体尿液中的 NEDs 水平，并形成生理周期图谱。

In recent years, our laboratory has discovered a group of nonpolar estrogen dimer (NED) derivatives that are formed by human cytochrome P450 enzymes during the NADPH-dependent oxidative metabolism of 17β-estradiol or estrone. The objective of this grant application is to characterize the structures of this group of NEDs and to determine their anticancer efficacy in estrogen-sensitive mammary cancer in animal tumor models. Our hypothesis is that some of the estrogen dimer metabolites identified in our in vitro metabolism studies are also formed in the human body and they can serve as endogenous antiestrogens. We will pursue the following three Aims: ..AIM 1. STRUCTURAL IDENTIFICATION AND CHEMICAL SYNTHESIS: 1A. Determine the structures of the anti-estrogenic NEDs formed in vitro by human cytochrome P450 enzymes. 1B. Chemically synthesize the anti-estrogenic NEDs in adequate quantities...AIM 2. BIOACTIVITY STUDIES：2A. Determine the biological functions of the NEDs using in vitro bioassays. 2B. Evaluate the selected NEDs for their efficacy in inhibiting estrogen-inducible cell growth as well as tumorigenesis in animal models, and compare the biological activity of the NEDs with tamoxifen and fulvestrant, two FDA-approved selective estrogen receptor modulators...AIM 3. HUMAN STUDIES：Determine the daily urinary levels of the anti-estrogenic HEDs as well as their monthly patterns for a complete normal menstrual cycle.