2. Academic Validation
  3. 17β-Hydroxywithanolides as Sensitizers of Renal Carcinoma Cells to Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) Mediated Apoptosis: Structure-Activity Relationships

17β-Hydroxywithanolides as Sensitizers of Renal Carcinoma Cells to Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) Mediated Apoptosis: Structure-Activity Relationships

  • J Med Chem. 2017 Apr 13;60(7):3039-3051. doi: 10.1021/acs.jmedchem.7b00069.
Ya-Ming Xu 1,  Alan D Brooks 2 3,  E M Kithsiri Wijeratne 1,  Curtis J Henrich 2 4,  Poonam Tewary 2 3,  Thomas J Sayers 2 3,  A A Leslie Gunatilaka 1
Affiliations

Affiliations

  • 1 Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona , 250 E. Valencia Road, Tucson, Arizona 85706, United States.
  • 2 Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.
  • 3 Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, Maryland 21702, United States.
  • 4 Molecular Targets Laboratory, National Cancer Institute-Frederick , Frederick, Maryland 21702, United States.
PMID: 28257574 DOI: 10.1021/acs.jmedchem.7b00069
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.

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