Synthesis and Anti‐tumor Evaluation of B‐ring Modified Caged Xanthone Analogues of Gambogic Acid

Abstract

Gambogic acid (GA, 1), the most prominent member of Garcinia natural products, has been reported to be a promising anti-tumor agent. Previous studies have suggested that the planar B ring and the unique 4-oxa-tricyclo-[4.3.1.0 3,7 ]dec-2-one caged motif were essential for anti-tumor activity. To further explore the structure-activity relationship (SAR) of caged Garcinia xanthones, two new series of B-ring modified caged GA analogues 13a-13e and 15a-15e were synthesized utilizing a Claisen/Diel-Alder cascade reaction. Subsequently, these compounds were evaluated for their in vitro anti-tumor activities against A549, MCF-7, SMMC-7721 and BGC-823 cancer cell lines by MTT assay. Among them, 13b-13e exhibited micromolar inhibition against several cancer cell lines, being approximately 2-4 fold less potent in comparison to GA. SAR analysis revealed that the peripheral gem-dimethyl groups are essential for maintaining anti-tumor activity and substituent group on C1 position of B-ring has a significant effect on potency, while modifications at C-2, C-3 and C-4 positions are relatively tolerated. These findings will enhance our understanding of the SAR of Garcinia xanthones and lead to the development of simplified analogues as potential anti-tumor agents.

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

“…The unsaturated double bond at C-8/8a appears to significantly contribute to apoptosis induction and antitumor activity [99,109,159,160]. Additionally, the Theodorakis and You research groups have independently reported that the gem-dimethyl groups at C-28 and C-33 are crucial for these compounds' cytotoxicity [97,161]. However, the presence of a C-33 gem-dimethyl has been found to be inessential for cytotoxicity against HepG2 cells; substitution of this moiety by hydrogen atoms is tolerated but oxidation of C-33 to carbonyl have been found to decrease the activity [104].…”

“…In contrast, the aromaticity of the A ring must be maintained, because oxidation of the A ring to quinone leads to a complete loss of activity [163]. The presence of a hydroxyl group at the C-1 position is an important structural feature for antitumor activity [102,161,163] and has been found to enhance IKKβ inhibitory activity [158]. Activity is preserved when the hydroxyl group is methylated or acylated [159], but replacing the hydroxyl group with a prenyl group is unfavorable [161].…”

“…The presence of a hydroxyl group at the C-1 position is an important structural feature for antitumor activity [102,161,163] and has been found to enhance IKKβ inhibitory activity [158]. Activity is preserved when the hydroxyl group is methylated or acylated [159], but replacing the hydroxyl group with a prenyl group is unfavorable [161]. 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].…”

Synthetic Chiral Derivatives of Xanthones: Biological Activities and Enantioselectivity Studies

“…Zhang et al [ 113 , 114 , 115 , 116 ] synthesized a series of caged xanthone derivatives to improve the physicochemical properties and in vivo cytotoxic potency. For that, they relied on MAD28 synthesis and characterization of the derivatives.…”

“…Some interesting SAR considerations have been highlighted, such as the importance of the periphery gem-dimethyl groups in maintaining the anti-tumor activity, the effect of the substituent at C-1 position of B-ring on activity, since hydroxyl group at C-1 position enhanced the potency while prenyl group reduces it, and, that the change of hydroxyl or prenyl groups in carbons C-2, C-3 and C-4 had no significant effect on the anti-tumor activity. These events indicated that referred sites can be used to improve drug-like properties [ 114 ].…”