Discovery of Novel Bioactive Compounds from Rhamnaceae Plants: The Initial Steps

The Rhamnaceae family, commonly called the buckthorn family, contains approximately 55 genera and 950 species of flowering plants. Phylogenetic analysis revealed that Rhamnaceae plants can be categorized to three clades, rhamnoid, ampeloziziphoid, and ziziphoid [1]. Enormous phytochemicals including triterpenoids, flavonoids, alkaloids, and quinones have been reported from Rhamnaceae plants. Among these, ceanothane-type triterpenoids have been mainly reported from the ziziphoid species, while quinone derivatives have been isolated from the rhamnoids. Recently, our group has endeavored to establish a chemical library from Rhamnaceae plants and to screen their bioactivities. Herein, the early results of our project will be briefly described.

Unprecedented yellow phenyl polyene triglycoside pigments, named berchemin A-C, were isolated from the unripened fruits of Berchemia berchemiifolia. Their chemical structures were established by spectroscopic and chemical analysis. The evaluation of their bioactivities is still ongoing.

Eighteen new ceanothane- and lupane-type triterpenoids and three novel catechin-bound ceanothane-type triterpenoid derivatives, along with twelve previously reported ones, were isolated from the roots of Z. jujuba [2, 3]. A LC-MS dereplication was performed based on them, and six new triterpenoids were additionally isolated from Hovenia dulcis. These triterpenoids were subjected to various bioactivity screening assays. 2-O-phenolic ester derivatives of alphitolic acid inhibited the proteasome activity and effectively induced the killing of human myeloma RPMI8226 cells resistant to carfilzomib, a FDA-approved proteasome inhibitor drug. The results from the molecular docking simulation suggest that the deubiquitinase USP7 is a potential target for these compounds, and further validation efforts are ongoing.

[1] Richardson JE et al, American Journal of Botany 2000; 87: 1309 – 1324.

[2] Kang KB et al, Journal of Natural Products 2016; 79: 2364 – 2375.

[3] Kang KB et al, Journal of Natural Products 2017; 80: 1048 – 1054.