Synthesis and bioactivity of novel xanthone and thioxanthone L-rhamnopyranosides
Synthesis and bioactivity of novel xanthone and thioxanthone L-rhamnopyranosides
复制标题
新型呫吨酮和噻吨酮L-吡喃鼠李糖苷的合成及生物活性
DOI：
10.1039/c5ra02846a
复制
发表时间：
2015-01-01
期刊：
影响因子：
3.9
通讯作者：
Cui, Zi-ning
中科院分区：
文献类型：
--
作者：
Song, Gao-peng;Li, Su-mei;Cui, Zi-ning
设计并合成了一系列口山酮和噻吨酮鼠李糖苷类化合物。体外细胞毒性和拓扑异构酶抑制活性进行了评价。生物活性测定结果表明，蒽基上引入2，3-二-O-乙酰基-α-L-吡喃鼠李糖基有助于提高蒽的体外细胞毒性。蒽的修饰对肿瘤细胞生长抑制活性有重要影响。有趣的是，在这些蒽类似物中观察到细胞毒性和拓扑异构酶I活性之间的一致性，这表明将聚亚甲基胺侧链或吡唑环掺入蒽醌发色团中能够同时增强拓扑异构酶I抑制活性和细胞毒性。其中，化合物11作为新的先导化合物被发现，其对12种肿瘤细胞株显示出广泛的体外细胞毒活性，并具有潜在的抗多药耐药能力。化合物11可通过内源性和外源性途径诱导KB细胞凋亡。流式细胞仪分析显示，用化合物11处理KB细胞导致细胞凋亡，伴随着细胞周期停滞在G2/M期。此外，化合物11引起拓扑异构酶I催化活性的显著和剂量依赖性抑制。
A series of xanthone and thioxanthone rhamnopyranosides were designed and synthesized. Their in vitro cytotoxicity and topoisomerase inhibitory activity were evaluated. The bioassay results indicated that the introduction of the 2,3-di-O-acetyl-a-L-rhamnopyranosyl moiety to anthracene was helpful to improve the cytotoxicity in vitro. The modifications of anthracene had an important effect on the tumor cell growth inhibitory activity. Interestingly, consistency was observed between the cytotoxicity and topo I activity in these anthracene analogs, suggesting that the incorporation of either a polymethyleneamine side chain or a pyrazole ring into the anthraquinone chromophore was able to enhance topo I inhibitory activity as well as cytotoxicity simultaneously. Among them, compound 11 as a new lead compound was discovered, which showed wide in vitro cytotoxicity against 12 tumor cell lines and potential antimultidrug resistance capability. It was proved that compound 11 could induce cell apoptosis in KB cells via both extrinsic and intrinsic pathways. Flow cytometric analysis exhibited that treatment of KB cells with compound 11 led to cell apoptosis accompanied by cell cycle arrest at the G2/M phase. Furthermore, compound 11 caused a significant and dose-dependent inhibition of topoisomerase I catalytic activity.