Inhibiting Glc Cer biosynthesis to fight cancer growth

该提案包括化合物的设计，合成和评估，以抑制癌症在体内扩散过程中的关键酶。肿瘤转移依赖于细胞表面碳水化合物，特别是鞘糖脂（GSL）水平的增加。酶神经酰胺葡糖基转移酶（GlcT-1）催化GSL生物合成的第一步，并且其失活减缓肿瘤生长和转移的速率。在本文中，在产生GlcT-1抑制剂文库的组合方法的背景下描述了该酶的全新抑制剂的设计。为了提高这些化合物的检测速度。，我们提出了一种新的测定法，其是转移的体外模型。我们将探索这些抑制剂在模拟正常血流的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定量为施加于肿瘤细胞的抑制剂的类型和量的函数。所提出的合成物将作为应用于肿瘤细胞的抑制剂的类型和量的函数进行定量。拟定的合成路线还将提供代谢稳定的GSL的均质样品，以帮助确定哪种GSL负责动态流动条件下的粘附。

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.