Synthesis and Anti‐tumor Evaluation of B‐ring Modified Caged Xanthone Analogues of Gambogic Acid
Synthesis and Anti‐tumor Evaluation of B‐ring Modified Caged Xanthone Analogues of Gambogic Acid
复制标题
DOI：
10.1002/cjoc.201100045
复制
发表时间：
2012
影响因子：
5.4
通讯作者：
Xiang Li;Xiaojin Zhang;Xiaojian Wang;Nianguang Li;Changjun Lin;Yuan Gao;Zhuoqin Yu;Q. Guo;Q. You
中科院分区：
文献类型：
--
作者：
Xiang Li;Xiaojin Zhang;Xiaojian Wang;Nianguang Li;Changjun Lin;Yuan Gao;Zhuoqin Yu;Q. Guo;Q. You
藤黄酸（GA，1）是藤黄属天然产物中最重要的成员，是一种很有前途的抗肿瘤药物。先前的研究表明，平面B环和独特的4-氧杂-三环[4.3.1.03，7]十二碳-2-酮笼状基序对于抗肿瘤活性是必需的。为了进一步研究笼状藤黄黄酮类化合物的构效关系，利用Claisen/Diel-桤木级联反应合成了两个新系列的B环修饰笼状藤黄黄酮类化合物13 a-13 e和15 a-15 e.随后，通过MTT测定法评价这些化合物对A549、MCF-7、SMMC-7721和BGC-823癌细胞系的体外抗肿瘤活性。其中，13 b-13 e对几种癌细胞系表现出微摩尔抑制，与GA相比效力低约2-4倍。SAR分析显示，外周偕二甲基基团对于维持抗肿瘤活性是必不可少的，并且B-环C1位上的取代基对效力具有显著影响，而C-2、C-3和C-4位上的修饰相对耐受。这些发现将增强我们对Garciniaxanthones的SAR的理解，并导致简化类似物作为潜在的抗肿瘤药物的发展。
Gambogic acid (GA,1), the most prominent member ofGarcinianatural 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 cagedGarciniaxanthones, two new series of B‐ring modified caged GA analogues13a–13eand15a–15ewere synthesized utilizing a Claisen/Diel‐Alder cascade reaction. Subsequently, these compounds were evaluated for theirin vitroanti‐tumor activities against A549, MCF‐7, SMMC‐7721 and BGC‐823 cancer cell lines by MTT assay. Among them,13b–13eexhibited 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 ofGarciniaxanthones and lead to the development of simplified analogues as potential anti‐tumor agents.