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

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.