Rational Design and Synthesis of Amplified Therapeutic/Diagnostic Agents Targeting the Estrogen Receptor.

摘要

Estradiol tolerates the presence of large functional groups off of the 11-β position while retaining a reasonable relative binding affinity to Estrogen Receptor-alpha; (ER-alpha). Although RU 39,4112, a prototypical 11-β substituted estradiol derivative, has been considered as a potent therapeutic anti-estrogen, it also has the potential for serving as a highly ER-selective targeting agent. Because there is over-expression of ER in breast cancer cells, it is a logical biological target for compounds like RU 39,411 or its analogs. In this study, I will apply this information to design and synthesize a novel and selective delivery system for breast cancer tumor cells.;Our current interest lies in the design and development of a novel targeted tri-valent drug delivery system that will improve the selectivity of therapeutic and diagnostic agents for breast cancer. By linking together three estrogen receptor selective 11-β substituted estradiol molecules through a use of a Newkome tri-ester, we expect to achieve a greater affinity, as well as selectivity for estrogen receptor expressing (ER+) cancer cells. In order to avoid interactions between the sterically demanding termini, oligoethylene glycol (OEG) chains will be used as linkers. This should provide sufficient distance between the three anti-estrogens, giving them greater ability to interact independently with adjacent membrane estrogen receptors. This process would generate a clustering effect which is predicted to improve endocytosis and uptake of the carrier. The OEG chains may also enhance pharmacokinetic properties and improve metabolic stability.;The convergent approach described in this thesis, which uses readily available starting materials, was developed for the preparation of these amplified targeting molecules. By placing an azido group at the termini each of the three amide derivatives on the Newkome tri-amide, they can be coupled to any component having a corresponding alkyne with the use of "Click Chemistry" in the final "convergent" step. In this case, the alkyne is present on the 4-methylaminoethoxyphenyl component of the 11-β position of the estradiol. Endosomal uptake, as well as the relative binding affinity for the estrogen receptor will then be determined for these trivalent compounds and compared to the monovalent analogs in the future direction of the project.