BIOLOGICALLY ACTIVE STEROID ANALOGS

这个实验室设计并合成了第一个生物活性 具有类固醇所需特性的伽马发射类固醇 受体研究 这些类固醇，C-16 α-卤代类似物， 雌二醇被发现是化学稳定的，并结合到雌激素 高亲和力的受体。 16 α-125碘-雌二醇的合成 无载体形式（2，200 Ci/mmol），现在通常用于许多领域 实验室以高灵敏度测量雌激素受体。 类似物 将合成16 α-碘-雌二醇， 代谢更稳定并因此适合于体内应用的雌激素 雌激素反应性肿瘤的成像。 这些化合物将被合成 使用我们开发的快速合成技术， 以及净化伽马射线发射器 123 I化合物将用于 体内成像，以检测动物中含有雌激素受体肿瘤 模型和人类。 我们已经证明 16 α-125 I-碘-雌二醇对雌激素敏感性有特异性细胞毒性 细胞 这种效应是由DNA在衰变过程中的破坏引起的。 125 I，并需要通过雌激素将激素近似于DNA 受体的 将进行进一步的实验以评估该细胞 在类固醇代谢以及DNA 修复发生。 动力学研究将确定药物的剂量关系。 γ-发射体对细胞的杀伤作用，并评估DNA修复抑制剂是否 加强这种效果。 125 I标记的类固醇将用于 实验，以确定，在完整的细胞，DNA结合区的 雌激素反应基因中的雌激素受体。 两种类固醇 对雌激素受体具有高亲和力，并且其结构具有 潜在的烷化剂，将被合成标记与[3 H]，作为 雌激素受体的亲和探针。 两种孕激素类似物 用125 I标记的已经合成，并已发现， 以高亲和力结合孕酮受体。 这些化合物将 无载体合成及其与其它甾体的相互作用 将测量结合蛋白和受体。 的类似物 糖皮质激素将用125 I合成，并作为配体进行测试。 糖皮质激素受体

This laboratory designed and synthesized the first biologically active Gamma-emitting steroids with the characteristics necessary for steroid receptor studies. These steroids, the C-16Alpha-halogenated analogs of estradiol were found to be chemically stable and to bind to the estrogen receptor with high affinity. 16Alpha-125I-Estradiol was synthesized in carrier free form (2,200 Ci/mmol) and is now generally used in many laboratories to measure estrogen receptors with great sensitivity. Analogs of 16Alpha-iodo-estradiol will be synthesized in attempts to produce estrogens that are more stable metabolically and thus suitable for in vivo imaging of estrogen responsive tumors. These compounds will be synthesized with 123I using techniques we have developed which allows rapid synthesis and purification of the Gamma-emitter. The 123I compound will be used for in vivo imaging, to detect estrogen receptor containing tumors in animal models and in humans. We have demonstrated that 16Alpha-125I-iodo-estradiol is specifically cytotoxic to estrogen sensitive cells. This effect is caused by destruction of DNA during the decay of 125I and requires the approximation of the hormone to DNA by the estrogen receptor. Further experiments will be performed to assess this cell killing in vitro under conditions where steroid metabolism, as well as DNA repair occurs. Kinetic studies will determine the dose relationship of the Gamma-emitter to cell killing and assess whether DNA repair inhibitors potentiate this effect. The 125I-labelled steroid will be used in an experiment to determine, in intact cells, the DNA binding region of the estrogen receptor in an estrogen responsive gene. Two steroids which bind with high affinity to the estrogen receptor and whose structures have the potential of alkylating agents, will be synthesized labelled with [3H], as affinity probes for the estrogen receptor. Two analogs of progestins labelled with 125I have already been synthesized and have been found to bind to the progesterone receptor with high affinity. These compounds will be synthesized carrier-free and their interaction with other steroid binding proteins and receptors will be measured. Analogs of glucocorticoids will be synthesized with 125I and tested as ligands for the glucocorticoid receptor.