PROGESTIN 16-ALPHA, 17-ALPHA-DIOXOLANE KETALS AS MOLECULAR PROBES FORTHE PROGESTERONE-RECEPTOR - SYNTHESIS, BINDING-AFFINITY, AND PHOTOCHEMICAL EVALUATION

Chemical probes for steroid receptors have proven useful in providing molecular details about important hormone-receptor interactions. A ser ies of progestin 16alpha,17alpha-dioxolane ketals of acetophenone or s ubstituted acetophenones that bind to the progesterone receptor (PgR) with comparable or higher affinities than the natural ligand, progeste rone, have been prepared and evaluated as potential in vitro and in vi vo probes for the progesterone receptor. p-Azidoacetophenone ketal 6, the tetrafluoro analog 8, and the p-(benzoyl)acetophenone ketal 9 demo nstrate the required combination of high relative binding affinity (RB A) (6 = 15%, 8 = 14%, 9 = 6.6%, progesterone = 13%, R5020 = 100%) and photoinactivation efficiency (6 = 80%, 8 = 77%, 9 = 29% at 30 min) req uired for potential photoaffinity labeling reagents for the PgR. The s ynthesis of azide 6 has been modified to accommodate a palladium-catal yzed tritium gas hydrogenolysis of an iodoaryl precursor in the final stage of the synthetic sequence; this procedure has been verified by h ydrogenation. In addition, the progestin p-fluoroacetophenone ketal 10 was selected for preparation in fluorine-18-labeled form, on the basi s of its high affinity for the PgR (RBA = 53%). Fluorine-18-labeled pr ogestins may be evaluated as potential diagnostic imaging agents for P gR-positive breast tumors. The radiochemical syntheses and further bio chemical results with the fluorine-18-labeled ketal 10 and the tritium -labeled aryl azide 6 will be presented in an accompanying paper and e lsewhere.