State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing 210009, China.
Med Chem. 2012 Nov;8(6):1012-25. doi: 10.2174/1573406411208061012.
In order to explore the detailed structure-activity relationship (SAR) around xanthone scaffold bearing hydroxyl and prenyl moieties, twenty-nine natural and non-natural hydroxylated and prenylated xanthones have been synthesized and evaluated for their in vitro anti-proliferative activities against five human cancer cell lines, including HepG2 (hepatocelluar carcinoma), HCT-116 (colon carcinoma), A549 (lung carcinoma), BGC823 (gastric carcinoma) and MDAMB- 231 (breast carcinoma). The SAR analysis revealed that the anti-proliferative activity of the xanthones is substantially influenced by the position and number of attached hydroxyl and prenyl groups, and the presence of hydroxyl group ortho to the carbonyl function of xanthone scaffold contributes significantly to their cytotoxicity. The new prenylated xanthone 20 with a relatively simple structure, namely 1,3,8-trihydroxy-2-prenylxanthone, was found to exhibit potent antitumor activities comparable to α-mangostin against all the five cancer cell lines. Further mechanistic studies suggested that compound 20 induces apoptosis and causes cell cycle arrest at S phase in HepG2 cells. These results have highlighted compound 20 as a new potential lead candidate for future development of novel potent broad-spectrum antitumor agents.
为了探索具有羟基和异戊烯基的呫吨酮骨架的详细结构-活性关系（SAR），我们已经合成了 29 种天然和非天然的羟基化和异戊烯基化呫吨酮，并评估了它们对五种人癌细胞系（包括 HepG2（肝细胞癌）、HCT-116（结肠癌细胞）、A549（肺癌细胞）、BGC823（胃癌细胞）和 MDAMB-231（乳腺癌细胞））的体外抗增殖活性。SAR 分析表明，呫吨酮的抗增殖活性受到附着的羟基和异戊烯基的位置和数量的极大影响，并且呫吨酮骨架的羰基功能的邻位羟基的存在对其细胞毒性有很大贡献。具有相对简单结构的新型异戊烯基化呫吨酮 20，即 1,3,8-三羟基-2-异戊烯基呫吨酮，被发现对所有五种癌细胞系均表现出与 α-密桔素相当的强大抗肿瘤活性。进一步的机制研究表明，化合物 20 诱导 HepG2 细胞凋亡并导致细胞周期停滞在 S 期。这些结果突出了化合物 20 作为未来开发新型广谱抗肿瘤药物的新的潜在候选药物。
