BIOLOGICALLY ACTIVE STEROID ANALOGS

本实验室设计并合成了第一个具有生物活性的 具有类固醇所需特征的伽马发射类固醇 受体研究。这些类固醇，C-16α卤代类似物 研究发现，雌二醇在化学上是稳定的，并能与雌激素结合。 具有高亲和力的受体。合成了16α-125I-雌二醇。 无载体形式(2,200 cI/mmo1)，现在通常用于许多 实验室以极高的灵敏度测量雌激素受体。类比 将合成16个α-碘-雌二醇，以尝试生产 代谢更稳定的雌激素，因此适合体内使用 雌激素反应性肿瘤的成像。这些化合物将被合成 123I使用我们开发的技术，允许快速合成 以及对伽马发射器的提纯。123I化合物将用于 活体成像检测动物体内含有雌激素受体的肿瘤 模型和人体内。我们已经证明了 16α-125I-碘雌二醇对雌激素敏感的特异性细胞毒作用 细胞。这种影响是由于DNA在腐烂过程中被破坏而引起的 125I，并要求雌激素使荷尔蒙接近DNA。 受体。将进行进一步的实验来评估该细胞 在体外杀死类固醇代谢以及DNA的条件 修复就会发生。动力学研究将确定药物的剂量关系 伽马发射器对细胞的杀伤作用并评估DNA修复抑制剂 强化这一效应。125I标记的类固醇将用于 在完整细胞中确定DNA结合区的实验 雌激素反应基因中的雌激素受体。两种类固醇可以结合 与雌激素受体有高亲和力，其结构具有 烷基化试剂的潜力，将合成标记有[~3H]，As 雌激素受体的亲和探针。孕激素的两个类似物 已经合成了标记有125I的化合物，并发现 与孕激素受体高亲和力结合。这些化合物将 无载体合成及其与其他类固醇的相互作用 将测量结合蛋白和受体。类似于 糖皮质激素将用125I合成，并作为 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.