Synthesis and Evaluation of New Cathepsin D Inhibitors

描述（由申请人提供）：组织蛋白酶B和D被认为是两种主要的分解代谢蛋白酶。组织蛋白酶B和D已被认为在几种癌症的转移潜能中发挥重要作用。一些研究人员发现，与非转移性黑色素瘤相比，转移性B16黑色素瘤表达高水平的组织蛋白酶B活性。越来越多的文献将半胱氨酸蛋白酶组织蛋白酶B与恶性肿瘤联系起来。此外，乳腺肿瘤组织中组织蛋白酶D的高活化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指标。

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.