Abstract：
:Nur77 is a steroid orphan receptor that plays a critical role in regulating proliferation, differentiation, and apoptosis, including acting as a switch for Bcl-2 function. We previously reported that the octaketide cytosporone B (Csn-B) is a natural agonist for Nur77. In this study, we synthesized a series of Csn-B analogues and performed a structure-activity analysis that suggested criteria for the development of a unique pharmacophore to activate Nur77. The components of the pharmacophore necessary for binding Nur77 included the benzene ring, the phenolic hydroxyl group, and the acyl chain of the Csn-B scaffold, whereas the key feature for activating the biological function of Nur77 was the ester group. Csn-B analogues that bound Nur77 tightly not only stimulated its transactivation activity but also initiated mitochondrial apoptosis by means of novel cross-talk between Nur77 and BRE, an antiapoptotic protein regulated at the transcriptional level. Notably, the derivative n-amyl 2-[3,5-dihydroxy-2-(1-nonanoyl)phenyl]acetate exhibited greater antitumor activity in vivo than its parent compounds, highlighting particular interest in this compound. Our findings describe a pathway for rational design of Csn-B-derived Nur77 agonists as a new class of potent and effective antitumor agents.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Liu JJ,Zeng HN,Zhang LR,Zhan YY,Chen Y,Wang Y,Wang J,Xiang SH,Liu WJ,Wang WJ,Chen HZ,Shen YM,Su WJ,Huang PQ,Zhang HK,Wu Qdoi
10.1158/0008-5472.CAN-09-3160subject
Has Abstractpub_date
2010-05-01 00:00:00pages
3628-37issue
9eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-09-3160journal_volume
70pub_type
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