The synthesis of tamoxifen and 4-hydroxytamoxifen analogs for estrogen receptor-targeted applications

Breast cancer is the second leading cause of cancer death in the United States. Tamoxifen a potent anti-estrogen, has been used for several years as the premiere treatment for this disease. As such, tamoxifen and other anti-estrogns (endogenous and synthetic) have generated great interest as estrogen receptor (ER) ligands as targets for chemotherapeutic applications. The prevalence of breast cancer and the accompanying mortality demands that better methods for early detection of breast cancer be developed. To this end, many researchers now employ anti-estrogen compounds as targeting elements of imaging agents. This dissertation describes two non-stereoselective syntheses of compounds designed as ER ligands for diagnostic imaging applications. Furthermore, this dissertation details the synthesis of a tamoxfien analog that may be used in ER-targeted gene therapy applications.; Chapter 2 presents the syntheses of lipidic tamoxifen and a 4-hydroxy analog from a common stilbene intermediate. Derivatization of either the B-ring or the ethyl sidechain, or both of these tamoxifen substructures, is possible using the new synthetic route. Two representative lipids families were prepared to illustrate this feature. Incorporation of these tamoxifen-labelled lipids into the lamellae of liposomal MRI formulations potentially could enhance the conspicuity and imaging of tissue rich in ER.; Chapter 3 presents the synthesis of a novel 4-hydroxytamoxifen-diethylenetriaminepentaacetic acid conjugate (HOTam-DTPA). The optimized reaction sequence consists of ten steps and features a novel dianion reaction. Inspiration for the design of HOTam-DTPA was derived from literature describing limitations of previous attempts to prepare ER-targeted constructs. The innovative features of HOTam-DTPA include (i) an L-aspartic acid-derived DTPA chelate moiety attached to (ii) N,N′-dimethylethylenediamine serving as a hydrophilic spacer that is attached to the (iii) terminus of tamoxifen's ethyl sidechain. A competitive ER bind assay using [3H]-17β-estradiol showed that HOTam-DTPA is a potent ER ligand and its relative binding affinity is only ∼10-fold lower than that of tamoxifen.; Chapter 4 describes new syntheses of α-hydroxytamoxifen and 4-hydroxy-α-hydroxytamoxifen. These compounds are important components of studies on the mechanism of tamoxifen-DNA adduct formation. The parallel synthetic routes features a condensation reaction between substituted benzophenones and phenylacetonitrile. The target compounds were afforded in 73 and 27% overall yields, respectively, for each of the three-step syntheses.