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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15CA086933-02
Application #
6701177
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Lees, Robert G
Project Start
2000-09-18
Project End
2006-06-30
Budget Start
2004-03-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$81,576
Indirect Cost
Name
University of Arkansas at Monticello
Department
Type
Schools of Arts and Sciences
DUNS #
City
Monticello
State
AR
Country
United States
Zip Code
71656
McConnell, Rose M; Inapudi, Kalyani; Kadasala, Naveen et al. (2012) New cathepsin D inhibitor library utilizing hydroxyethyl isosteres with cyclic tertiary amines. Med Chem 8:1146-54