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

Ya Ming Xu, Alan D. Brooks, E. M.Kithsiri Wijeratne, Curtis J. Henrich, Poonam Tewary, Thomas J. Sayers, A. A.Leslie Gunatilaka

Research output: Research - peer-reviewArticle

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.

LanguageEnglish (US)
Pages3039-3051
Number of pages13
JournalJournal of Medicinal Chemistry
Volume60
Issue number7
DOIs
StatePublished - Apr 13 2017

Fingerprint

Structure-Activity Relationship
Renal Cell Carcinoma
Tumor Necrosis Factor-alpha
Apoptosis
Ligands
3-rhamnopyranosyl(1-4)-glucopyranosyl-12-diacetoxy-20-hydroxywitha-5,24-dienolide
Withanolides
Biological Products
Libraries
Survival Rate
Pharmaceutical Preparations
Neoplasms
Therapeutics
withaferin A
Lead

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

17β-Hydroxywithanolides as Sensitizers of Renal Carcinoma Cells to Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) Mediated Apoptosis : Structure-Activity Relationships. / Xu, Ya Ming; Brooks, Alan D.; Wijeratne, E. M.Kithsiri; Henrich, Curtis J.; Tewary, Poonam; Sayers, Thomas J.; Gunatilaka, A. A.Leslie.

In: Journal of Medicinal Chemistry, Vol. 60, No. 7, 13.04.2017, p. 3039-3051.

Research output: Research - peer-reviewArticle

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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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