Structure-activity-relationship study of semi-synthetically modified fusicoccins on their stabilization effect for 14-3-3-phospholigand interactions. (1st November 2022)

• Record Type: Journal Article
• Authors: Ogino, Nanami; Masuda, Ryoma; Lynn Punzalan, Louvy; Yamashita, Emi; Igaue, Shota; Inoue, Yoshihisa; Ohkanda, Junko
• Is Part Of: Bioorganic & medicinal chemistry. Volume 73(2022)
• Publication Date: 2022-11-01
• Subjects: Fusicoccin -- Structure-activity-relationship -- 14-3-3 protein -- Phospholigand -- Stabilization -- Antiproliferation activity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.117020
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The diterpene glucoside fusicoccin-A (FC-A) is a fungal phytotoxin that stabilizes the interaction of plant 14-3-3 protein and plasma membrane H + -ATPase by forming a stable ternary complex. Previous studies demonstrated that structurally modified FC-A derivatives exhibit significant antitumor activities but their synthesis involves an explosive reagent, limiting their utility and opportunities for further structure–activity-relationship studies. In this study, we synthesized a series of FC derivatives by introducing various substituents on the fusicoccan scaffold and on the glucoside moiety, and evaluated their stabilization effects on the binding of 14-3-3 to fluorescently labeled mode-1 and mode-3 phosphopeptides. The results showed that introducing an amino group at the 6′-position of the glucoside moiety improves stabilization. Furthermore, cell-based evaluation demonstrated that 6′-amino benzyl 21b exhibits higher antiproliferative activity than previously developed FC agents.