2022 Volume 80 Issue 8 Pages 755-765
Phaeosphaeride A was originally isolated from the endophyte FA39 as an inhibitor of STAT3-DNA binding along with its inactive diastereomer phaeosphaeride B. Among proteins in the STAT (signal transducer and activator of transcription) family, STAT3 plays a crucial role in various cellular processes, including cell proliferation, survival, and differentiation. STAT3 could be a potential target for molecular-targeted cancer therapy because it is constantly activated in most solid tumors. Therefore, the STAT3 inhibitor phaeosphaeride A has been recognized as a promising seed compound for anticancer drug development.
After its isolation in 2006, our and other groups’ longstanding synthetic efforts toward phaeosphaeride A resulted in the total synthesis and structural revision of the natural product, which was subsequently confirmed by X-ray crystal structure analysis. In addition, a biomimetic acid-mediated transformation of phaeosphaeride A to phaeosphaeride B was successfully achieved to verify the hypothetical biosynthesis of phaeosphaeride B from phaeosphaeride A.
This article reviews the total synthesis and biological evaluations of phaeosphaerides A and B, and related molecules. Also, synthetic studies toward related natural products, including paraphaeosphaeride C, and structure-activity relationship studies of phaeosphaeride derivatives are discussed.
