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

• Published in: Chinese journal of chemistry Vol. 30; no. 1; pp. 35 - 42
• Main Author: 李想 张晓进 汪小涧 李念光 林昌军 高原 于卓沁 郭青龙 尤启冬
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 2012; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Subjects: 4-oxa-tricyclo[4.3.1.03; 4‐oxa‐tricyclo[4.3.1.03,7]dec‐2‐one; 7]dec-2-one; anti-tumor activity; Chemistry; Chemistry, Multidisciplinary; gambogic acid; MCF-7细胞; Physical Sciences; SAR studies; Science & Technology; synthesis; Tumors; 体外抗肿瘤活性; 修改; 反应合成; 抗肿瘤剂; 活性评价; 酮衍生物; 黄酸; synthesis; 4-oxa-tricyclo; APOPTOSIS; 03; gambogic acid; ANGIOGENESIS; PHOSPHORYLATION; CELL-CYCLE ARREST; KAPPA-B; SAR studies; 1; BIOMIMETIC TOTAL-SYNTHESIS; 3; anti-tumor activity; 7]dec-2-one; CONSTRUCTION; GROWTH; INHIBITS PROLIFERATION
• ISSN: 1001-604X; 1614-7065
• DOI: 10.1002/cjoc.201100045

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- [4.3.1.03.7]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-lge were synthesized utilizing a Claisen/Diel-Alder cascade reaction. Subsequently, these compounds were evaluated for their in vitro antitumor 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 antitumor 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.