Inhibiting Glc Cer biosynthesis to fight cancer growth

这项提议包括设计、合成和评估化合物，以抑制癌症在体内扩散过程中的一种关键酶。肿瘤转移依赖于细胞表面碳水化合物水平的增加，特别是鞘糖脂（GSLs）。神经酰胺糖基转移酶（GlcT-1）催化了GSL生物合成的第一步，它的失活减慢了肿瘤的生长和转移速度。在此，在组合方法生成GlcT-1抑制剂文库的背景下，描述了该酶的全新抑制剂的设计。以提高这些化合物可以被测试的速度。，我们提出了一种新的检测方法，即体外转移模型。我们将探讨这些抑制剂在模拟正常血流条件下对几种癌细胞系转移能力的影响。高转移性肿瘤细胞与E-和p -选择素结合的能力将被量化为应用于肿瘤细胞的抑制剂的类型和数量的函数。所提出的合成将被量化为应用于肿瘤细胞的抑制剂的类型和数量的函数。所提出的合成路线还将提供代谢稳定的GSL的均质样品，以帮助确定在动态流动条件下哪种GSL负责粘附。

This proposal encompasses the design, synthesis and evaluation of compounds to inhibit a key enzyme in the process by which cancer spreads through the body. Tumor metastasis relies on an increased level of cell surface carbohydrates, especially glycosphingolipids (GSLs). The enzyme ceramide glucosyltransferase (GlcT-1) catalyses the first step in GSL biosynthesis and its inactivation slows the rate of tumor growth and metastasis. Herein, the design of an entirely new inhibitor of this enzyme is described in the context of a combinatorial approach to generate libraries of GlcT-1 inhibitors. To increase the rate at which these compounds can be tested., we propose a new assay that is an in vitro model for metastasis. We will explore the effect of these inhibitors have on the metastatic abilities of several cancer cell lines under conditions that mimic normal blood flow. The ability of highly metastatic tumor cells to bind with E- and P-selectin will be quantified as a function of the type and amount of inhibitor applied to the tumor cells. The proposed synthetic will be quantified as a function of the type and amount of inhibitor applied to the tumor cells. The proposed synthetic route will also provide homogenous samples of metabolically stable GSLs to help identify which GSL is responsible for adhesion under dynamic flow conditions.