SYNTHESIS AND PURIFICATION OF BIOLOGICALLY IMPORTANT STEROID ANALOGS

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This project is concerned with the preparation of iodinated derivatives and analogs of steroid hormones in the androgen and glucocorticoid families. Synthetic procedures will be developed which will permit the incorporation of radioactive iodine (125I and 123I) into compounds which have either androgenic or glucocorticoid activity. Labeled androgens are expected to be useful for the sensitive detection of androgen responsive tumors such as prostate cancer and for quantifying the androgen receptor in vitro. The radioiodinated androgens will also have great utility for the autoradiographic studies of tissues, such as brain, in which the androgen receptor is present, but localized in specific cells or regions. Such studies have great potential value in elucidating the role of androgens in processes such as the sexual differentiation of the brain in fetal development. Labeled compounds with glucocorticoid activity will be valuable in mapping and imaging of glucocorticoid receptor rich regions of the brain also. Since the specific neurophysiological mechanisms by which corticosteroids influence neuronal function are not fully understood, such studies are of increasing importance in defining and understanding the role and function of these compounds in the brain. In this study the synthetic methodology will be worked out for the nonradioactive iodinated steroids, which will be purified and fully characterized using standard analytical techniques. The nonradioactive compounds will be tested for receptor binding in competition assays. Compounds found to be effective competitors will be prepared with the radioactive label and tested more fully for binding affinity (ka or Kd), specificity and binding to steroid plasma binding proteins. Eventually, their hormonal or antihormonal activity, receptor mediated distribution in vivo, nuclear translocation and metabolism will also be determined.