Date of Award
Master of Science (MS)
John Fitzmaurice Valliant
A stereoselective synthesis of closo carborane analogues of Tamoxifen was developed where the products represent a new platform for developing metabolically robust Selective Estrogen Receptor Modulators (SERMs). Using an ionic liquid-mediated insertion reaction and a highly conjugated ene-yne prepared stereoselectively, the A-ring in the backbone of Tamoxifen was replaced with an ortho carborane cluster. X-ray crystal structures of a key intermediate and the final target along with NMR spectroscopy confirmed that the product was in fact the desired Z isomer, which showed superior chemical stability to Tamoxifen both in solution and the solid state even when exposed to light for extended periods of time. Using microwave heating, it was however possible to convert up to 50% of a sample of the Z isomer to the corresponding E isomer, which was isolated by HPLC and fully characterized. Inhibition assays using both isomers and a simple aryl carborane that is known to target the ER were conducted using estrogen receptor (ER) positive and ER negative human breast cancer cell lines with and without estradiol (E2) present. The Z carborane isomer was able to inhibit cell proliferation better than Tamoxifen in an E2 free environment, while the E isomer was able to inhibit cell growth better than Tamoxifen when E2 is present.
Degradation of the claso carborane Tamoxifen analogue to the nido species under basic and aqueous conditions, using traditional or microwave heating, resulted in E-Z isomerization, but is was found that in the presence of aprotic solvents, the nido species could be prepared as a single geometric isomer. With the nido species in hand the carborane Tamoxifen analogue was metalated (Re/⁹⁹ᵐTc) and iodinated (¹²⁷l). The technetium analogue was evaluated in a cell uptake assay which showed binding to human breast cancer cells MCF-7.
Beer, Michael L., "THE SYNTHESIS AND EVALUATION OF CARBORANE SERMS" (2010). Open Access Dissertations and Theses. Paper 4449.
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