Synthesis of Stable Isotope-Labeled Steroids as Internal Standards

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A method recently developed at the NCI permits the simultaneous analysis of 15 estrogen metabolites from small samples of human urine using Liquid Chromatography-Mass Spectroscopy (LC-MS-MS). Epidemiological studies have suggested that an Increased risk of breast cancer has been found In women with high circulatory and urinary levels of estrogen. The use of estrogens In hormone replacement therapy in post-menopausal women has also been implicated In ovarian cancer. The accurate measurement of these steroid hormones may lead to better understanding and diagnoses of cancers. The precision of this analytical method requires the use of stable heavy atom isotopomers of these metabolites as Internal standards. Only a few of the commercially available isotopomers are suitable. The Research Plan outlines the synthesis of several estrogens and androstanes that would have molecular weights of at least +3 amu over the natural compounds. Of critical importance for use In the assay, the syntheses have been designed to place the heavy-atom labels in positions that will not exchange under any of the chemical reactions or the conditions of the assay, thus preserving the Isotopic integrity of the final products. The chemistry described is amenable to the commercial scale production, in this case approximately 100 mg, as suggested by the Phase II RFP. In addition, the chemistry Is very well precedented and the project as described therefore has a very high probability of success.