This laboratory designed and synthesized the first biologically active Gamma-emitting steroids with the characteristics necessary for steroid receptor studies. These steroids, the C-16Alpha-halogenated analogs of estradiol were found to be chemically stable and to bind to the estrogen receptor with high affinity. 16Alpha-125I-Estradiol was synthesized in carrier free form (2,200 Ci/mmol) and is now generally used in many laboratories to measure estrogen receptors with great sensitivity. Analogs of 16Alpha-iodo-estradiol will be synthesized in attempts to produce estrogens that are more stable metabolically and thus suitable for in vivo imaging of estrogen responsive tumors. These compounds will be synthesized with 123I using techniques we have developed which allows rapid synthesis and purification of the Gamma-emitter. The 123I compound will be used for in vivo imaging, to detect estrogen receptor containing tumors in animal models and in humans. We have demonstrated that 16Alpha-125I-iodo-estradiol is specifically cytotoxic to estrogen sensitive cells. This effect is caused by destruction of DNA during the decay of 125I and requires the approximation of the hormone to DNA by the estrogen receptor. Further experiments will be performed to assess this cell killing in vitro under conditions where steroid metabolism, as well as DNA repair occurs. Kinetic studies will determine the dose relationship of the Gamma-emitter to cell killing and assess whether DNA repair inhibitors potentiate this effect. The 125I-labelled steroid will be used in an experiment to determine, in intact cells, the DNA binding region of the estrogen receptor in an estrogen responsive gene. Two steroids which bind with high affinity to the estrogen receptor and whose structures have the potential of alkylating agents, will be synthesized labelled with [3H], as affinity probes for the estrogen receptor. Two analogs of progestins labelled with 125I have already been synthesized and have been found to bind to the progesterone receptor with high affinity. These compounds will be synthesized carrier-free and their interaction with other steroid binding proteins and receptors will be measured. Analogs of glucocorticoids will be synthesized with 125I and tested as ligands for the glucocorticoid receptor.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037799-02
Application #
3175641
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1984-08-01
Project End
1987-07-31
Budget Start
1985-08-01
Budget End
1986-07-31
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
Bowlby, Deborah A; Brown, Theodore J; Hochberg, Richard B et al. (2016) In vitro Autoradiographic Analysis of Regional Changes in Estrogen Receptor Alpha in the Brains of Cycling Female Rats. Neuroendocrinology 103:538-51
Hanson, Robert N; Hua, Edward; Hendricks, J Adam et al. (2012) Synthesis and evaluation of 11?-(4-substituted phenyl) estradiol analogs: transition from estrogen receptor agonists to antagonists. Bioorg Med Chem 20:3768-80
Hanson, Robert N; McCaskill, Emmett; Tongcharoensirikul, Pakamas et al. (2012) Synthesis and evaluation of 17?-(dimethylphenyl)vinyl estradiols as probes of the estrogen receptor-? ligand binding domain. Steroids 77:471-6
Olmsted, Sandra L; Tongcharoensirikul, Pakamas; McCaskill, Emmett et al. (2012) Synthesis and evaluation of 17?-E-20-(heteroaryl)norpregn-1,3,5(10),20 tetraene-3,17?-diols [17?-(heteroaryl)vinyl estradiols] as ligands for the estrogen receptor-? ligand binding domain (ER?-LBD). Bioorg Med Chem Lett 22:977-9
Haddad, Terra; Gershman, Rachel; Dilis, Robert et al. (2012) Synthesis and evaluation of 4-(substituted styryl/alkenyl)-3,5-bis(4-hydroxyphenyl)-isoxazoles as ligands for the estrogen receptor. Bioorg Med Chem Lett 22:5999-6003
Hanson, Robert N; Kirss, Rein; McCaskill, Emmett et al. (2012) Targeting the estrogen receptor with metal-carbonyl derivatives of estradiol. Bioorg Med Chem Lett 22:1670-3
Hanson, Robert N; Hua, Edward; Labaree, David et al. (2012) Convergent synthesis of a steroidal antiestrogen-mitomycin C hybrid using ""click"" chemistry. Org Biomol Chem 10:8501-8
Nettles, Kendall W; Bruning, John B; Gil, German et al. (2008) NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses. Nat Chem Biol 4:241-7
McCarthy, Thomas L; Hochberg, Richard B; Labaree, David C et al. (2007) 3-ketosteroid reductase activity and expression by fetal rat osteoblasts. J Biol Chem 282:34003-12
Kahn, Michael G C; Konde, Emmanuel; Dossou, Francis et al. (2006) Microwave-enhanced nucleophilic fluorination in the synthesis of fluoropyridyl derivatives of [3,2-c]pyrazolo-corticosteroids, potential glucocorticoid receptor-mediated imaging agents. Bioorg Med Chem Lett 16:3454-8

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