RESOLUTION & ANTITUMOR TESTING OF CHIRAL ANTIESTROGENS

本研究的目的是准备和评估一个新的班级， 非甾体抗雌激素上级目前用于 乳腺癌的治疗 目前，没有抗雌激素药物可用 其缺乏雌激素（促子宫）活性。 所示数据 该提案表明先导化合物AnalogII缺乏 在小鼠子宫中的促子宫活性，这与在小鼠子宫中的其他抗雌激素不同。 存在 已发现类似物II同样有效或更有效。 比他莫昔芬（一种临床上使用的抗雌激素药物， 活性）在治疗已建立的肿瘤和预防 7，12-二甲基苯并蒽（DMBA）诱发大鼠肿瘤发生的实验研究 乳腺肿瘤模型 基于类似物II和空间位阻的这些发现， 在现有的抗雌激素的特点，一类新的抗雌激素是 提出了 因此，这些新的类似物，当制备时， 制备，将在测定系统中检查其雌激素， 抗雌激素和对体内促性腺激素分泌及受体的影响 体外结合活性。 所有化合物将在一个 MCF-7人乳腺癌细胞系以评估抗肿瘤活性。 活性 这类新的抗雌激素药物中的成员， 在人类中的活动将显着改善治疗 乳腺癌患者的雌激素依赖性肿瘤。 还有那些 具有非常少副作用的化合物将可用于治疗 在预防女性雌激素依赖性肿瘤的发生方面， 高风险类别。

The purpose of this study is to prepare and evaluate a new class of nonsteroidal antiestrogens which are superior to those currently used in the treatment of breast cancer. Presently, no antiestrogens are available which are devoid of estrogenic (uterotropic) activity. Data presented in this proposal indicate that a lead compound, Analog II, is devoid of uterotropic activity in mouse uteri, which is unlike other antiestrogens in existence. Analog II has been found to be either as effective or more effective than tamoxifen (a clinically used antiestrogen with uterotropic activity) in the treatment of established tumors and the prevention of tumorigenesis in the 7,12-dimethylbenz( )anthracene (DMBA)-induced rat mammary tumor model. Based on these findings with Analog II and the steric features in existing antiestrogens, a new class of antiestrogens is proposed. Consequently, these new analogs, when prepared, will be prepared, will be examined in assay systems for their estrogenic, antiestrogenic and effect on gonadotropin secretion in vivo and receptor binding activity in vitro. All compounds will be evaluated further in a MCF-7 human breast cancer cell line to assess antitumor activity. Active members of this novel class of antiestrogens which lack estrogen agonist activity in humans would significantly improve the treatment of estrogen-dependent tumors in patients with breast cancer. Also, those compounds which have very few side effects would be useful prophylactically in preventing the genesis of estrogen-dependent tumors in women who are in the high risk category.