Synthesis and Bioevaluation of Novel Oxa-Caged Garcinia Xanthones as Anti-Tumour Agents

Abstract

Gambogic acid (GA), a special category of Garcinia xanthones, has attracted great attention owing to its striking bioactivities and unique structure. To further explore its structure-activity relationship, we prepared seven novel oxa-caged Garcinia xanthones that were for the first time varied at the C-2 position of B ring and at the C-21/22 or C-23 position of the prenyl group in the caged scaffold. Some compounds exhibited strong anti-proliferation activities in different cancer cell lines. Particularly, compound 8 showed more potent cytotoxic activity and better selectivity towards the A549 cell line than GA. Oxa-caged xanthones 8 was identified as an A549 cell apoptosis inducer through observations of morphological changes and Annexin-V/PI double-staining assay. Additionally, the structure-activity relationships of these new analogues were discussed.

Structural diversity and biological activities of caged Garcinia xanthones: recent updates

“…Modifications of the C-27/28 double bond to a dihydroxyl or epoxy group enhance cytotoxicity against the A549, MCF-7 and BGC-823 cell lines, among which the epoxy group confers better inhibition than the dihydroxyl group, except against A549 cells [162]. Functionalization of the carboxylic acid moiety at C-29 appears to be tolerated, thus indicating that this group could be modulated to improve physiochemical properties [99,109,159].…”

“…Functionalization of the carboxylic acid moiety at C-29 appears to be tolerated, thus indicating that this group could be modulated to improve physiochemical properties [99,109,159]. Introduction of an electron withdrawing group at C-29 improves the inhibitory activity against A549 cells [162]. Moreover, introduction of a hydrophilic amine side chain at C-31 maintains cytotoxicity while increasing water solubility and cell permeability, whereas a hydrophobic amine moiety diminishes the bioactivity [104].…”

“…The positions of hydroxyl, prenyl or fused pyran moieties on C-2, C-3 and C-4 have no significant correlation with antitumor activity [104,158,161]. Meanwhile, a free hydroxyl group at C-3 decreases the cytotoxicity [163], but converting it to methoxymethyl ether enhances the activity [162].…”

Synthetic Chiral Derivatives of Xanthones: Biological Activities and Enantioselectivity Studies

“…In another study, Miao et al [ 117 ] developed small molecule entities inspired by the structure of gambogic acid. They focused on modifications of the prenyl moiety of the caged xanthones which led to synthesize seven derivatives 149 – 155 ( Figure 14 ), which were tested for anti-tumor activity [ 117 ].…”

“…Although these experiments were preliminary, the results suggested that promising agents with anti-tumor activities could be obtained by modification at C-2 position of the B ring and at C-21/22 or C-23 position of the prenyl group in the caged scaffold. The formation of dihydroxy and epoxy groups of the double bond at C-21/22 and the introduction of an electron-withdrawing group at C-23 evidently affected the anti-proliferation activity [ 117 ]. In Table 1 a summary of the synthetic CDXs inspired in natural xanthones and their described biological activities are presented, as well as the associated references.…”