Synthesis of Stable Isotope-Labeled Steroids as Internal Standards

作为内标的稳定同位素标记类固醇的合成

• 批准号: 7584940
• 金额: $ 14.01万
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2008-02-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7584940
• 关键词: Synthesis; Stable; Isotope; Labeled; Steroids

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.

NCI最近开发的一种方法允许使用液相色谱-质谱法（LC-MS-MS）同时分析来自人尿液小样本的15种雌激素代谢物。流行病学研究表明，在循环和尿液中雌激素水平高的妇女中发现乳腺癌的风险增加。雌激素在绝经后妇女激素替代疗法中的应用也与卵巢癌有关。这些类固醇激素的准确测量可能会导致更好地理解和诊断癌症。该分析方法的精密度要求使用这些代谢物的稳定重原子同位素异构体作为内标物。只有少数市售同位素异构体是合适的。研究计划概述了几种雌激素和雄甾烷的合成，这些雌激素和雄甾烷的分子量至少比天然化合物高3 amu。在分析中，合成被设计为将重原子标记放置在在任何化学反应或分析条件下都不会发生交换的位置，从而保持最终产品的同位素完整性。所述化学性质适合商业规模生产，在这种情况下约为100 mg，如II期RFP所建议的。此外，化学是非常好的先例，因此所描述的项目具有非常高的成功概率。