BIOLOGICALLY ACTIVE STEROID ANALOGS

这个实验室开创了伽马发射的设计和合成领域。 广泛存在的类固醇激素受体的生物活性配体 用于激素作用的临床和基础研究。最近，我们有 开发了一种新的体外放射自显影技术，使 占用(激活)和未占用雌激素的特异性检测 受体。这项技术使用了我们的雌激素配体11beta- 甲氧基-16α[125]碘雌二醇可定量测定雌激素 在24小时内异质组织中的受体。被占据的受体 表示受体群体中已被激活的部分 在体内由激素决定，并与DNA密切相关。它反映了 生理上相关的受体群体。它可以提供一个极好的 雌激素--乳腺癌雌激素敏感性的决定因素 类似孕激素受体的刺激标志物。我们将测量 乳腺肿瘤标本中的总雌激素受体和占位性雌激素受体 技术，并将结果与免疫组织化学分析结果进行比较。 这些肿瘤为雌激素受体和孕激素受体。最近，我们 合成了一种新型配体7α[125]碘-5α-二氢睾酮 对于具有良好亲和力、良好特异性的雄激素受体 作为非常低的非特异性结合。我们将合成几个7α- [125]旨在增加亲和力和保护类固醇的碘类似物 用于体内成像的新陈代谢的细胞核。这些[125]标有 雌激素和雄激素将用于激素作用的研究 大脑。我们已经合成了几种雌二醇的类似物，它们已经被 用羧酸修饰，对 雌激素受体，因此不是雌激素样物质。当转换为 非极性短链酯这些不带电荷的衍生物与高 与雌激素受体结合，产生明显的局部雌激素样物质 效果。因为它们很容易被酯酶切割成带电的 不具有雌激素活性的羧基化合物，它们非常不稳定，而且 静脉给药不会引起全身雌激素效应 或者皮下注射。他们是一类新的高度有效的局部表演 雌激素。我们打算合成一系列这些烷基酯。 雌二醇核中特定位置的不同链长和 执行结构活动分析以确定最佳候选者 用作局部活性雌激素。这种独特的雌激素将提供一种 绝经后妇女阴道病的重要治疗药物 萎缩，但全身性雌激素是禁忌症。其中几个 这些羧基化合物将被转化为酰胺，以设计一种 用于治疗雌激素敏感型乳房的纯抗雌激素 癌症。这些研究将为诊断和诊断提供独特的试剂 乳腺癌妇女的治疗以及荷尔蒙作用的探测。

This laboratory has pioneered the design and synthesis of gamma-emitting biologically active ligands for steroid hormone receptors that are widely used for clinical and basic studies of hormone action. Recently, we have developed a novel technique of in vitro autoradiography that allows the specific detection of occupied (activated) as well as unoccupied estrogen receptor. This technique, which uses our estrogenic ligand, 11beta- methoxy-16alpha[125]iodoestradiol, allows quantification of estrogen receptor in heterogeneous tissues within 24 hours. The occupied receptor represents that portion of the receptor population that has been activated by hormone in vivo, and is tightly associated with DNA. It mirrors the physiologically relevant receptor population. It can provide an excellent determinant of estrogen sensitivity of breast cancer, an estrogen stimulated marker similar to progesterone receptor. We will measure the total and occupied estrogen receptor in breast tumor specimens using this technique and compare the results with the immunohistochemical analysis of these tumors for estrogen receptor and progesterone receptor. Recently, we have synthesized 7alpha[125]iodo-5alpha-dihydrotestosterone, a novel ligand for the androgen receptor with good affinity, excellent specificity as well as very low non-specific binding. We will synthesize several 7 alpha- [125]iodo-analogs designed to increase affinity and protect the steroid nucleus from metabolism for use in in vivo imaging. These [125] labeled estrogens and androgens will be used in studies of hormone action in the brain. We have synthesized several analogs of estradiol that have been modified with carboxylic acids, and have little or no affinity for the estrogen receptor and are therefore not estrogenic. When converted to nonpolar short chain esters these non-charged derivatives bind with high affinity tot he estrogen receptor and produce marked local estrogenic effects. Since they are readily cleaved by esterases into the charged carboxylic compounds which are not estrogenic they are very labile and do not induce generalized estrogenic effects when administered intravenously or subcutaneously. They are a novel class of highly potent locally acting estrogen. We intend to synthesize a series of these alkyl esters of varying chain length at specific positions in the nucleus of estradiol and perform a structure activity analysis to determine the best candidate for use as a locally active estrogen. This unique estrogen would provide an important therapeutic agent for menopausal women suffering from vaginal atrophy but for whom systemic estrogens are contraindicated. Several of these carboxyl compounds will be converted to amides in order to design a pure antiestrogen for use in the treatment of estrogen sensitive breast cancer. These studies will provide unique agents for the diagnosis and treatment of women with breast cancer as well as probes of hormone action.