Inhibiting Glc Cer biosynthesis to fight cancer growth

抑制 Glc Cer 生物合成以对抗癌症生长

• 批准号: 6340170
• 负责人: MICHAEL D SHULTZ
• 金额: $ 2.41万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6340170
• 关键词: analog; antineoplastics; carbamates; cell adhesion; cell cell interaction; cell line; ceramides; chemical structure function; drug design /synthesis /production; enzyme inhibitors; glycosphingolipids; hexosyltransferase; metastasis; neoplasm /cancer pharmacology; neoplastic cell; neoplastic growth; sphingosine

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.

这项建议包括设计、合成和评估化合物，以抑制癌症在体内传播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，尤其是糖鞘糖脂(GSLS)。神经酰胺葡萄糖转移酶(GlcT-1)催化GSL生物合成的第一步，其失活减缓了肿瘤的生长和转移速度。在这里，在组合方法的背景下描述了一种全新的该酶抑制剂的设计，以产生GlcT-1抑制剂的文库。为了提高这些化合物的检测速度，我们提出了一种新的检测方法，即体外转移模型。我们将探索在模拟正常血流的条件下，这些抑制物对几种癌细胞系转移能力的影响。高转移肿瘤细胞与E-和P-选择素结合的能力将作为应用于肿瘤细胞的抑制剂的类型和数量的函数来量化。建议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。建议的合成路线还将提供代谢稳定的GSL的均质样品，以帮助识别在动态流动条件下哪种GSL负责粘连。