Synthesis and Evaluation of New Cathepsin D Inhibitors

说明(申请人提供)：组织蛋白酶B和D被认为是两种主要的分解代谢蛋白。组织蛋白酶B和D被认为在几种类型的癌症的转移潜能中起着重要的作用。一些研究人员发现，转移性B16黑色素瘤与非转移性黑色素瘤相比，组织蛋白酶B活性高度升高。有越来越多的文献将半胱氨酸蛋白酶组织蛋白酶B与肿瘤的恶性联系起来。此外，乳腺肿瘤组织中高活性的组织蛋白酶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活性组织蛋白酶D的高水平。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。 继续设计和合成组织蛋白酶D的(羟乙基)胺同工酶抑制剂，类似于天冬氨酸氨基HIV-1蛋白酶的有效抑制剂。在这个项目的初始阶段，一些(羟乙基)胺异构体已被证明是组织蛋白酶D活性的非常有效的抑制剂。此外，还提出了组织蛋白酶B的乙醛和缩氨基硫脲抑制剂的设计和合成。新化合物将使用适当的蛋白酶检测来评估它们对组织蛋白酶B或D的抑制作用。然后将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。这个项目是作为一项研究工作而设计的，它将允许本科生通过改善这个本科院校的研究环境，在分子建模、有机合成、仪器技术、酶分析、动力学研究和数据统计处理方面进行培训。

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.