ER+ breast cancer raises a significant diagnostic challenge since resistance invariably develops to the current endocrine therapies. 70% of breast cancers are ER+, which results from the overexpression of estrogen receptor. ER mediates strong anti-inflammatory signaling in ER+ tissues. Once activated with estradiol (E2), ER inhibits inflammatory gene expression via protein-protein interactions that block NF-kappa B transcriptional activity. Importantly, NF-kappa B is a primary mediator of resistance in many cancers, including breast cancer. All current endocrine suppressive treatments block this palliative signaling pathway, along with the desired proliferative pathway. Thus, there is a significant unmet clinical need for novel endocrine treatments for breast cancer that can ameliorate patient outcome in resistant populations, be less prone to resistance development, retain anti-inflammatory action, and cause fewer side effects. Following the hypothesis driven approach, the work described here introduces structural analogs of an innovative ligand scaffold, 5,6-bis-(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonic acid phenyl ester, termed OBHS, which reduces gene activation through ligand-induced shifts in helices 8 and 11, thereby indirectly modulating helix 12 of ER (hence, indirect antagonists). This new class of ligands with a bicyclic hydrophobic core retains strong anti-inflammatory effects while dialing out the proliferative effects of E2 (similar to Selective Estrogen Receptor Modulators, SERMS), and could potentially replace the current endocrine therapies of breast cancer. In this work, we carried out rational design and syntheses of two series of OBHS analogs, namely OBHS-A (for acetamido derivatives), and OBHS-P (for propargyl derivatives), while we explored a synthetic methodology for a third series of OBHS compounds. Many analogs from the OBHS-A series exhibited high binding affinity. For example, the exo diastereomer of 2.11a, 2.11b, 2.11c, 2.11d, and 2.11e exhibited Relative Binding Affinities (RBAs) of 22.6%, 10.5%, 19.5%, 12.1%, and 14.4%, respectively. As observed before, endo OBHS compounds exhibited lower binding affinities than exo compounds. The RBA values with acetamide, and isobutyramide (i.e. short hydrophobic chains) were very comparable to each other. However, unexpectedly the propionamide compound showed lower binding affinity than butyramide. Nevertheless, we consider OBHS analogs with RBA values greater than 1% (Kd = 20 nM) to be very potent. This data is only the first step in a battery of assays that will be conducted eventually on these compounds. In particular, our emphasis is in ascertaining and improving the NF-kappa B mediated anti-inflammatory property, where these compounds have shown promising activity in conjunction with their anti-proliferative activity. / Master of Science