Synthesis and Evaluation of New Cathepsin D Inhibitors

描述（由申请方提供）：组织蛋白酶B和D被认为是两种主要的分解代谢蛋白酶。组织蛋白酶B和D已被认为在几种类型的癌症的转移潜能中起重要作用。一些研究者发现，转移性B16黑色素瘤相对于非转移性黑色素瘤表达高度升高的组织蛋白酶B活性。越来越多的文献将半胱氨酸蛋白酶组织蛋白酶B与肿瘤恶性联系起来。此外，乳腺肿瘤组织中高活化的组织蛋白酶D水平与复发和转移的发生率增加有关。在结肠癌、前列腺癌、子宫癌和卵巢癌中也发现了高水平的活性组织蛋白酶D。事实上，组织蛋白酶B和D水平最近已被用作预测乳腺癌和子宫癌患者预后的标志物。 继续的设计和合成（羟乙基）胺等排体抑制剂的组织蛋白酶D，这是类似于有效的抑制剂的乙酰基HIV-1蛋白酶，提出。在该项目的初始阶段，这些（羟乙基）胺电子等排体中的一些已被证明是组织蛋白酶D活性的非常有效的抑制剂。此外，还提出了醛类和缩氨基硫脲类组织蛋白酶B抑制剂的设计与合成。将使用适当的蛋白酶试验评价新化合物对组织蛋白酶B或D的抑制作用。然后进行详细的动力学研究，并绘制合成抑制剂的结构-活性相关性。该项目旨在作为一项研究工作，这将使本科生在分子建模，有机合成，仪器技术，酶测定，动力学研究和数据的统计处理，通过在这个本科机构的研究环境的增强培训。

DESCRIPTION (provided by applicant): Cathepsins B and D are considered to be two of the main catabolic proteinases. Cathepsins B and D have been suggested to play important roles in the metastatic potential of several types of cancer. Several investigators have found that metastatic B16 melanomas express highly elevated cathepsin B activity relative to non-metastatic melanomas. There is an increasing body of literature that links the cysteine protease cathepsin B with tumor malignancy. Also, 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 B and D levels have recently been used as a markers to predict the prognosis of breast cancer and uterine cancer patients. A continuation of the design and the synthesis of (hydroxyethyl)amine isostere inhibitors of cathepsin D, which are similar to potent inhibitors of the aspartyl HIV-1 protease, are proposed. In the initial phase of this project some of these (hydroxyethyl)amine isosteres have proven to be very potent inhibitors of cathepsin D activity. In addition, the design and synthesis of aldehyde and thio-semicarbazone inhibitors of cathepsin B is also proposed. The new compounds will be evaluated for their inhibition of cathepsin B or D using appropriate 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.