SYNTHESIS AND EVALUATION OF NEW CATHEPSIN D INHIBITORS

新型组织蛋白酶 D 抑制剂的合成与评价

• 批准号: 6164140
• 负责人: ROSE M MCCONNELL
• 金额: $ 11.51万
• 依托单位: UNIVERSITY OF ARKANSAS AT MONTICELLO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-18 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6164140
• 关键词: active sites; cathepsin D; chemical structure function; computer simulation; drug design /synthesis /production; fluorimetry; protease inhibitor; spectrometry

Cathepsin D is a lysosomal aspartic protease found in all mammalian cells and is considered to be one of the main catabolic proteinases. It is synthesized as an inactive proenzyme of MW 52 kDa, called procathepsin D. Its activation involves the removal of a 44 amino acid peptide chain. Cathepsin D has been suggested to play a role in the metastatic potential of several types of cancer. A high activated cathepsin D level in breast tumor tissue has been associated with an increased incidence of relapse and metastasis. High levels of active cathepsin D have also been found in colon cancer, prostate cancer, uterine cancer and ovarian cancer. In fact cathepsin D levels have recently been used as a marker to predict the prognosis of breast cancer and uterine cancer patients. The design, via computer molecular modeling, and the synthesis of (hydroxyethyl)amine isostere inhibitors that are similar to potent inhibitors of the aspartyl HIV-1 protease is proposed. The compounds will be evaluated for their inhibition of cathepsin D using appropriate esterase and proteinase assays. Detailed kinetic studies will then be performed and structure-activity correlations will be drawn for the synthetic inhibitors. This project is designed as a research effort, which will allow undergraduate students training in molecular modeling, organic synthesis, instrumental techniques, enzyme assays, kinetic studies, and statistical treatment of data through the enhancement of the research environment at this undergraduate institution.

组织蛋白酶D是在所有哺乳动物细胞中发现的溶酶体天冬氨酸蛋白酶， 被认为是主要的分解代谢蛋白酶之一。 它被合成为分子量为52 kDa的无活性酶原，称为组织蛋白酶原D。 它的激活涉及去除44个氨基酸的肽链。cathepsin D已被认为在几种肿瘤的转移潜能中发挥作用。 癌症的类型。乳腺肿瘤组织中高水平的激活组织蛋白酶D， 与复发和转移的发生率增加有关。高 在结肠癌、前列腺癌、乳腺癌和乳腺癌中也发现了活性组织蛋白酶D的水平。 癌症、子宫癌和卵巢癌。事实上，组织蛋白酶D水平 最近被用作预测乳腺癌预后的标志物， 子宫癌患者。 通过计算机分子模型的设计， 类似于有效抑制剂的（羟乙基）胺电子等排体抑制剂 的乙酰基HIV-1蛋白酶。将对化合物进行评价， 它们使用适当的酯酶和蛋白酶抑制组织蛋白酶D 测定。然后将进行详细的动力学研究， 将绘制合成抑制剂的相关性。这个项目是 作为一项研究工作，这将使本科生培训 在分子建模、有机合成、仪器技术、酶 分析，动力学研究和数据的统计处理， 改善这所本科院校的研究环境。