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Designing of natural product-like compounds using natural products as template structures is an important strategy for the discovery of new drugs. Gambogic acid (GA), which is a Garcinia natural product with a unique caged xanthone scaffold, inhibits potent antitumor activity both in vitro and in vivo. This review summarized the researches on the identification of the antitumor pharmacophore of GA, and the design, structural optimization and structure-activity relationship (SAR) of natural product-like caged xanthones based on it.

Gambogic acid (GA), a natural product, was identified as a promising antitumor agent. To further explore the structure-activity relationship of GA and discover novel GA derivatives as antitumor agents, 19 novel GA derivatives modified at C(34) were synthesized and evaluated against A549, BGC-823, U251, HepG2, and MB-231 cancer cell lines by cellular assays. Among them, 15 compounds were found to be more potent than GA against some cancer cell lines. Notably, compound 3 possessed potent inhibitory activities against five cell lines with IC(50) values ranging between 0.24 and 1.09 μM. Compounds 9 and 18 were seven to eightfold more active than GA against A549 cell line. Chemical modification at C(34) of GA by introducing of hydrophilic aliphatic amines resulted in increased activity and improved drug-like properties. These findings will enhance our understanding of the SAR of GA and can lead to the discovery of novel GA derivatives as potential antitumor agents., (Copyright © 2012 Verlag Helvetica Chimica Acta AG, Zürich.)