| Literature DB >> 28257574 |
Ya-Ming Xu1, Alan D Brooks2,3, E M Kithsiri Wijeratne1, Curtis J Henrich2,4, Poonam Tewary2,3, Thomas J Sayers2,3, A A Leslie Gunatilaka1.
Abstract
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 17β-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 α-oriented side chain are superior to known TRAIL-sensitizing withanolides belonging to withaferin A class with a β-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.Entities:
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Year: 2017 PMID： 28257574 PMCID： PMC6986374 DOI： 10.1021/acs.jmedchem.7b00069
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446