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209. Recent developments in corticoid synthesis
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Abstracts
208. RADIOHALOGENATED ESTROGENS: IMAGING AGENTS FOR HUMAN BREAST TUMORS Katzenellenbogen,J. A.,a McElvan b Landvatter, S. W.,a Heiman, D. F.,a Carlson, K. .,a and Welch, M. J.z,,;;: Chemistry, Univ. of Illinois, Urbana, IL 61801, USA, &lallinckrodt Inst., Washington Univ. Med. School, St. Louis, MO 63110,USA The presence of estrogen receptors in many human breast tumors provides a potential mechanism for the selective uptake of estrogens. Thus, estrogens labeled with gammaemitting radionuclides could be used to image human breast tumors using single photon detection or positron emission tomography. We have prepared derivatives of steroidal and non-steroidal estrogens that are labeled with the radiohalogens bromine-77 (t-1/2 = 57 h),iodine-125 (t-1/2 = 60 d), or fluorine-18 (t-1/2 = 2 h). These compounds are designed so as to have high affinity for the estrogen receptor and relatively low affinity for non-receptor proteins (i.e., high binding selectivity). Some of these compounds, such as 16cr(Br-77)-bromoestradiol and 16a(Br-77)-bromo-ll&methoxyestradiol are taken up with high selectivity by the uterus of immature rats and can achieve uterus to non-target ratios as high as 15-25. The uterine uptake is mediated by the estrogen receptor, since it can be blocked selectively by co-injection of unlabeled estradiol. Cold chase experiments have demonstrated that long-term uterine retention of these compounds is the result of a ligand recapture process. The selectivity of target tissue uptake in adult rats depends upon the stage of the estrus cycle. DMBAinduced mammary tumors in adult rats can be Imaged during diestrus, and preliminary studies indicate that estrogen-receptorpositive breast tumors inhumanscan be imaged.
289.
RECENT
DEVELOPMENTS
IN
CORTICOID
SYNTHESIS
DoTrong, M., Kreiser, W. and Strube, E. Organische Chemie, UniversititDortmund, Otto-Hahn-Strasse, 4600 Dortmund 50. W.-Germany. The industrial production of corticoids is mainly based on one of two processes, the microbial 11 O-hydroxylation of cortexolone or the transformation of desoxycholic acid. The latter route, arising from a patent due to Kendall et. al. (1948), is rather lengthy. We felt that a few improvements were necessary, and were indeed able to shorten this sequence from 36 to 22 steps by first transforming desoxycholic acid to the corresponding A 11-12-olefin, which in turn yielded the 11-ketone on reaction with iodine and PCC, followed by reductive work up. On the other hand, the side chain degradation was achieved by oxidative decarboxylation, isomerisation of the resulting A 22-23-olefin and ozonolysis.
18. STEROID 210.
RESISTANCE
IDENTIFICATION OF AN ANTIBODY DIRECTED AGAINST 17-HYDROXYPROGESTERONE IN A WOMANWITH PRIMARY INFERTILITY. Cllatterton, R.T., Jr., Cheesman, K.L., and Gaynor, L.V., Department of Obstetrics and Gynecology;Northwestern University Medical School, Chicago, Illinois, 60611, USA The development of sensitivity to endogenous steroid hormones has rarely been Steroids are generally considered to be too small to be antireported in humans. genie. In the present case, a 30-year-old woman had recurrent oral and perineal rashes which appeared just prior to the time of ovulation and subsided with the onset of menses. Suppression of the symptoms was noted with oral contraceptives and with danazol therapy. Serum was assayed for binding by the Scatchard procedure. The Ka for C3H117-hydroxyprogesterone (C3H]17-HP) was 2 x 1010 M-1, and the binding capacities of samples drawn during the follicular and luteal phases of the menstrual cycle were 19 and 11 ng/ml, respectively. No similar binding component was found in sera pooled from 10 control subjects. After equilibration of sera with C3H]17-HP, essentially all bound radioactivity was eluted from a DEAE cellulose column in the IgG fraction. Relative binding of progesterone, 20a-hydroxy-4-pregnen-3-one, corticosthat inhibited [3H]17-HP binding terone, OOC, and cortisol, based on concentrations This to the high affinity globulin by 50% were 16, 13, 20, 8 and 5X, respectively. is the first characterization of spontaneously occurring antisteroid antibodies in the human.
Abstracts
208. RADIOHALOGENATED ESTROGENS: IMAGING AGENTS FOR HUMAN BREAST TUMORS Katzenellenbogen,J. A.,a McElvan b Landvatter, S. W.,a Heiman, D. F.,a Carlson, K. .,a and Welch, M. J.z,,;;: Chemistry, Univ. of Illinois, Urbana, IL 61801, USA, &lallinckrodt Inst., Washington Univ. Med. School, St. Louis, MO 63110,USA The presence of estrogen receptors in many human breast tumors provides a potential mechanism for the selective uptake of estrogens. Thus, estrogens labeled with gammaemitting radionuclides could be used to image human breast tumors using single photon detection or positron emission tomography. We have prepared derivatives of steroidal and non-steroidal estrogens that are labeled with the radiohalogens bromine-77 (t-1/2 = 57 h),iodine-125 (t-1/2 = 60 d), or fluorine-18 (t-1/2 = 2 h). These compounds are designed so as to have high affinity for the estrogen receptor and relatively low affinity for non-receptor proteins (i.e., high binding selectivity). Some of these compounds, such as 16cr(Br-77)-bromoestradiol and 16a(Br-77)-bromo-ll&methoxyestradiol are taken up with high selectivity by the uterus of immature rats and can achieve uterus to non-target ratios as high as 15-25. The uterine uptake is mediated by the estrogen receptor, since it can be blocked selectively by co-injection of unlabeled estradiol. Cold chase experiments have demonstrated that long-term uterine retention of these compounds is the result of a ligand recapture process. The selectivity of target tissue uptake in adult rats depends upon the stage of the estrus cycle. DMBAinduced mammary tumors in adult rats can be Imaged during diestrus, and preliminary studies indicate that estrogen-receptorpositive breast tumors inhumanscan be imaged.
289.
RECENT
DEVELOPMENTS
IN
CORTICOID
SYNTHESIS
DoTrong, M., Kreiser, W. and Strube, E. Organische Chemie, UniversititDortmund, Otto-Hahn-Strasse, 4600 Dortmund 50. W.-Germany. The industrial production of corticoids is mainly based on one of two processes, the microbial 11 O-hydroxylation of cortexolone or the transformation of desoxycholic acid. The latter route, arising from a patent due to Kendall et. al. (1948), is rather lengthy. We felt that a few improvements were necessary, and were indeed able to shorten this sequence from 36 to 22 steps by first transforming desoxycholic acid to the corresponding A 11-12-olefin, which in turn yielded the 11-ketone on reaction with iodine and PCC, followed by reductive work up. On the other hand, the side chain degradation was achieved by oxidative decarboxylation, isomerisation of the resulting A 22-23-olefin and ozonolysis.
18. STEROID 210.
RESISTANCE
IDENTIFICATION OF AN ANTIBODY DIRECTED AGAINST 17-HYDROXYPROGESTERONE IN A WOMANWITH PRIMARY INFERTILITY. Cllatterton, R.T., Jr., Cheesman, K.L., and Gaynor, L.V., Department of Obstetrics and Gynecology;Northwestern University Medical School, Chicago, Illinois, 60611, USA The development of sensitivity to endogenous steroid hormones has rarely been Steroids are generally considered to be too small to be antireported in humans. genie. In the present case, a 30-year-old woman had recurrent oral and perineal rashes which appeared just prior to the time of ovulation and subsided with the onset of menses. Suppression of the symptoms was noted with oral contraceptives and with danazol therapy. Serum was assayed for binding by the Scatchard procedure. The Ka for C3H117-hydroxyprogesterone (C3H]17-HP) was 2 x 1010 M-1, and the binding capacities of samples drawn during the follicular and luteal phases of the menstrual cycle were 19 and 11 ng/ml, respectively. No similar binding component was found in sera pooled from 10 control subjects. After equilibration of sera with C3H]17-HP, essentially all bound radioactivity was eluted from a DEAE cellulose column in the IgG fraction. Relative binding of progesterone, 20a-hydroxy-4-pregnen-3-one, corticosthat inhibited [3H]17-HP binding terone, OOC, and cortisol, based on concentrations This to the high affinity globulin by 50% were 16, 13, 20, 8 and 5X, respectively. is the first characterization of spontaneously occurring antisteroid antibodies in the human.