cytosporone-b and Stomach-Neoplasms

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.

Topics: Animals; Apoptosis; Drug Delivery Systems; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Models, Molecular; Molecular Conformation; Nerve Tissue Proteins; Nuclear Receptor Subfamily 4, Group A, Member 1; Phenylacetates; Stomach Neoplasms; Structure-Activity Relationship; Transcription, Genetic; Xenograft Model Antitumor Assays