(I) Synthesis and CoMFA evaluation of 4HTA and its diphenylethylene analogues and (II) Synthesis and evaluation of phenyl acetyl 1-hydroxy geminalbisphosphonic acid as a model system for the attachment of a bisphosphonic acid functionality to the triphen

Part I of the dissertation describes the synthesis of a series of novel diphenylethylenes by the previously optimized procedure used to prepare their triphenylethylene analogue, 4HTA. It was predicted that, like 4HTA, these compounds would exhibit significant affinity for the estrogen receptor. However, the relative binding affinities of the diphenylethylenes indicated that they did not behave as predicted.;In order to rationalize their observed binding affinities, the diphenylethylenes were then subjected to the 3D-QSAR/CoMFA molecular modeling tool (Sybyl 6.3, Tripos). The CoMFA model was comprised of a molecular database of twenty-five triphenylethylenes with varying structural features and affinities for the estrogen receptor. The resulting analysis suggested that the lack of steric bulk in the diphenylethylenes, as compared to their triphenyl counterparts, was the primary contributing factor to their low receptor affinity.;The model was then used to determine structural modifications to the diphenylethylenes which would result in an increase in their binding affinity. These modifications were used to construct two new hypothetical diphenylethylene ER ligands using the Cambridge database and SYBYL. Analysis of the ligands by the CoMFA model indicated that the modifications would be successful in improving estrogen receptor binding affinity for the diphenylethylenes.;Part II of this project focused on the synthesis of a geminal bisphosphonate analogue of a triphenylethylene. Using phenyl acetyl chloride as a model system for 4HTA, two synthetic approaches, designed to attach a 1-hydroxy geminal bisphosphonic acid moiety to the molecule, were assessed. Both procedures worked reasonably well. The final products were verified by thin layer chromatography and $sp1$H NMR.