Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 7, Pages 3039-3051Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00069
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Funding
- Arizona Biomedical Research Commission
- University of Arizona College of Agriculture and Life Sciences
- National Cancer Institute, National Institutes of Health [HHSN26120080001E]
- Intramural Research Program of NIH
- Frederick National Lab, Center for Cancer Research
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Renal cell carcinoma (RCC) is a cancer with poor prognosis, and the 5-year survival rate of patients with metastatic RCC is 5-10%. Consequently, treatment of metastatic RCC represents an unmet clinical need. Screening of a 50 000 member library of natural and synthetic compounds for sensitizers of RCC cells to TRAIL-mediated apoptosis led to identification of the 17 beta-hydroxywithanolide (17-BHW), withanolide E (1), as a promising lead. To explore structure-activity relationships, we obtained natural and semisynthetic withanolides 1, 2a, 2c, and 3-36 and compared their ability to sensitize TRAIL-mediated apoptosis in a panel of renal carcinoma cells. Our findings revealed that 17-BHWs with a alpha-oriented side chain are superior to known TRAIL-sensitizing withanolides belonging to withaferin A class with a beta-oriented side chain and demonstrated that the 17-BHW scaffold can be modified to enhance sensitization of RCCs to TRAIL-mediated apoptosis, thereby assisting development of natural-product-inspired drugs to treat metastatic RCC.
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