TY - JOUR
T1 - 17β-Hydroxywithanolides as Sensitizers of Renal Carcinoma Cells to Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) Mediated Apoptosis
T2 - Structure-Activity Relationships
AU - Xu, Ya Ming
AU - Brooks, Alan D.
AU - Wijeratne, E. M.Kithsiri
AU - Henrich, Curtis J.
AU - Tewary, Poonam
AU - Sayers, Thomas J.
AU - Gunatilaka, A. A.Leslie
N1 - Funding Information:
Financial support for this work from Arizona Biomedical Research Commission and the University of Arizona College of Agriculture and Life Sciences is gratefully acknowledged. This project has also been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN26120080001E and in part by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We thank Ashley Babyak for technical assistance and Prof. Maria C. F. Oliveira of Departamento de Quiḿ ica Organ̂ ica e Inorgan̂ ica, Universidade Federal do Ceará, Brazil, and Prof. Lijiang Xuan, Center for Modernization of TCM, Shanghai Institute of Materia Medica, P. R. China, for obtaining HRESIMS data for some withanolides.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/4/13
Y1 - 2017/4/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85017525785&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85017525785&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.7b00069
DO - 10.1021/acs.jmedchem.7b00069
M3 - Article
C2 - 28257574
AN - SCOPUS:85017525785
SN - 0022-2623
VL - 60
SP - 3039
EP - 3051
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -