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
  • 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.