SELENOSTEROIDS AS POTENTIAL ESTROGEN-DEPENDENT TUMOR IMAGING AGENTS
Abstract
Despite the rapid development of radiopharmaceuticals in nuclear medicine, there is no radiopharmaceutical that can be used routinely to visualize estrogen-dependent breast tumors by external detection. The availability of such a compound would also help in differentiating between receptor-positive and receptor-negative tumors and consequently in designing the appropriate therapeutic approach. The present investigation is the first making use of selenium derivatives of estrogens for this purpose. Several steroidal estrogens were prepared and characterized with selenium attached to the D ring of estrone and estradiol or to carbon-20 of ethynylestradiol. Estrone was converted to the 17-spiro derivative with dimethylsulfonium methylide. Epoxide opening was accomplished with either sodium phenylselenide or sodium methylselenide to provide 16(alpha)-{(phenylseleno)methyl}-17(beta)-estradiol and 16(alpha)-{(methylseleno)methy}-17(beta)-estradiol, respectively, in excellent yields. 17(alpha)-{(Phenylseleno)ethynyl}-17(beta)-estradiol and 17(alpha)-{(methylseleno)ethynyl}-17(beta)-estradiol were obtained by the interaction of the lithium salt of ethynylestradiol with appropriate diselenide. Labeling at the 16(alpha)-position of estrone was carried out with n-butyllithium and the appropriate selenide to give 16(alpha)-(methylseleno)estrone and 16(alpha)-(phenylseleno)estrone. The latter compound was stereospecifically reduced with LiALH(,4) to 16(alpha)-(phenylseleno)-17(beta)-estradiol. Competitive binding studies of the foregoing compounds revealed that 17(alpha)-{(methylseleno)ethynyl}-17(beta)-estradiol had the highest binding affinity for estrogen receptors. In all cases, the phenylseleno derivatives had lower binding affinity than the corresponding methylseleno derivatives. It was concluded that the binding decreases as the steric size of the substituent increases: SeCH(,3) > CH(,2)SeCH(,3) > SePh > CH(,2)SePh. Also, it was observed that the position of the substituent plays a very important role. 16(alpha)-(Methylseleno)estrone had an affinity that was 57% of that of estrone, while 17(alpha)-{(methylseleno)ethynyl}-17(beta)-estradiol had only 10.8% of that of ethynylestradiol. Thus the 16(alpha)-position tolerates a methylseleno groups reasonably well. Even though the phenylseleno group at the 16(alpha)-position on estradiol and estrone greatly reduced the binding affinity, it would be interesting to compare the binding affinity of the methylseleno derivative of both estrone and estradiol.
Degree
Ph.D.
Subject Area
Pharmacology
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.