Xu Ya-Ming, Brooks Alan D, Wijeratne E M Kithsiri, Henrich Curtis J, Tewary Poonam, Sayers Thomas J, Gunatilaka A A Leslie
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.
Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.
J Med Chem. 2017 Apr 13;60(7):3039-3051. doi: 10.1021/acs.jmedchem.7b00069. Epub 2017 Mar 21.
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.
肾细胞癌（RCC）是一种预后较差的癌症，转移性肾细胞癌患者的5年生存率为5%-10%。因此，转移性肾细胞癌的治疗是一项尚未满足的临床需求。对一个包含50000种天然和合成化合物的文库进行筛选，以寻找肾癌细胞对TRAIL介导的凋亡的敏化剂，结果鉴定出17β-羟基睡茄内酯（17-BHW），即睡茄内酯E（1），作为一种有前景的先导化合物。为了探索构效关系，我们获得了天然和半合成的睡茄内酯1、2a、2c以及3-36，并比较了它们在一组肾癌细胞中使TRAIL介导的凋亡敏化的能力。我们的研究结果表明，具有α取向侧链的17-BHW优于已知的属于睡茄素A类且具有β取向侧链的TRAIL敏化睡茄内酯，并证明可以对17-BHW支架进行修饰，以增强肾癌细胞对TRAIL介导的凋亡的敏化作用，从而有助于开发受天然产物启发的药物来治疗转移性肾细胞癌。
