The Synthesis and Characteristics of Nonsteroidal Antiestrogens; Hydroxytamoxifen and N,N-Dimethyl Analog of Nafoxidine
Introductory Remarks and Statement of Purpose: Estrogens and estrogen mimetic compounds have long been known to be potent growth promoters. It is also well established that within the cells of estrogen target organs there are proteins which act as specific receptors and as such bind estrogen against a concentration gradient (1). Additionally, these proteins are capable of carrying the estrogenic molecule across the nuclear membrane in an as yet not fully understood, thermally activated mechanism. Once inside the nucleus, the estrogenic molecule (that is estrogenic in binding ability) will then either enhance or diminish transcription, translocation, and subsequently protein growth. As growth promoters, the estrogens have also been found to enhance the growth of some forms of tumor tissue, which mimic classic estrogen target organs. As such the need for effective anti-estrogens becomes clear in that minimizing the amount of estrogen available (or the degree to which it can be utilized) it is possible to reduce or even negate the growth of hormone-responsive tumors. The exact nature of what constitutes an estrogenic versus anti-estrogenic compound remains mechanistically uncertain and subsequently has relied largely on empirical data and related rationalizations. The comparison series found in Figure 1 illustrates some of the fundamental characteristics considered to be of importance regarding the efficacy of any particular antagonist in relation to several agonists. For example, the nonpolar aromatic side chain, as well as the aminoether side chain are thought to be of key importance in the effective antagonism of the estrogenic response. Furthermore, there is an activated estrogen-receptor complex known to be crucial to the induction of protein synthesis which seems a likely avenue through which effective estrogen antagonism may be pursued. This plan of attack is more viable in view of the so called promiscuous nature of the estrogen receptor, which is to say that it is susceptible to binding with compounds other than its' intended. Subsequently, strong, irreversible binding of the receptor to a biologically inactive compound is considered of key importance to effective estrogen antagonism.
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School of Chemistry and Materials Science (COS)
O'Shaughnessy, Brian, "The Synthesis and Characteristics of Nonsteroidal Antiestrogens; Hydroxytamoxifen and N,N-Dimethyl Analog of Nafoxidine" (1984). Thesis. Rochester Institute of Technology. Accessed from
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Physical copy available from RIT's Wallace Library at QP572.E85 O78 1984