Synthesis of Stable Isotope-Labeled Steroids as Internal Standards

我们的目标是区域特异性地合成稳定同位素标记的类固醇，用于液相色谱-质谱（LC-MS）测定内源性类固醇激素，如雌激素，雄激素和孕激素，被认为在各种癌症（如乳腺癌，子宫内膜癌，卵巢癌和前列腺癌）中发挥关键作用。这项工作的长期目标是开发雌酮、雌二醇和孕酮衍生物的合成方法，该方法既可重现，又能得到高纯度的同位素标记的类固醇，其中同位素在不可交换的位置掺入。 本提案中的研究旨在通过检查各种合成替代品来验证我们的方法，以满足可重现合成的标准，将稳定同位素标记物放置在不可交换的位置，使得类固醇标记为至少M+3，在良好至高产的整体过程中。 长期目标是扩大这些稳定的同位素标记的类固醇的化学合成，并将它们联合收割机组合在一个或多个试剂盒中。这些稳定同位素标准品将允许学术和临床实验室建立灵敏、准确的LC-MS方法，用于测量生物样品中的内源性类固醇激素，并使实验室之间的测量标准化。

Our goal is to regiospecifically synthesize stable-isotope labeled steroids for use in liquid chromatography-mass spectroscopy (LC-MS) assays for endogenous steroid hormones such estrogens, androgens, and progestogens that are believed to play critical roles in various cancers (such as breast, endometrial, ovarian and prostate). The long term goal of this work is to develop synthetic methodology for estrone, estradiol and progesterone derivatives that is both reproducible, and that gives high purity isotopically labeled steroids with the isotopes incorporated at non-exchangeable positions. The research in this proposal is designed to verify our methodology by examining various synthetic alternatives in order to meet the criteria of a reproducible synthesis, placement of the stable isotope labels at non-exchangeable positions such that the steroids are labeled to at least M+3, in a good to high yielding overall process. The long term goal is to scale up the chemical syntheses of these stable isotope-labeled steroids and combine them in one or more kits. These stable isotope standards will permit academic and clinical laboratories to establish sensitive, accurate LC-MS method~ for measuring endogenous steroid hormones in biologic samples and to standardize the measurements across laboratories.