Loa Jacky, Chow Pierce, Zhang Kai
Department of Experimental Surgery, Singapore General Hospital, BLK 9, Level 3, Outram Road, Singapore, 169608, Singapore.
Cancer Chemother Pharmacol. 2009 May;63(6):1007-16. doi: 10.1007/s00280-008-0802-y. Epub 2008 Sep 3.
To study anticancer activities of 68 plant polyphenols with different backbone structures and various substitutions and to analyze the structure-activity relationships.
Antiproliferative activity of 68 plant polyphenols on human liver cancer cells were screened by the 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide method. Structure-activity relationships were analyzed by comparison of their activities with selected structures. Cell cycle progression was assayed by flow cytometry analysis and apoptosis was analyzed by DNA fragment assay.
Based on their backbone structures, 68 polyphenols were sub-classed to flavonoids (chalcones, flavanones, flavones and isoflavones), chromones and coumarins. The order of their potency to suppress the human liver cancer cells is chalcones > flavones > chromones > isoflavones > flavanones > coumarins. Chalcones comprise the most potent group with IC(50) values ranging from 21.69 to 197 microM. Top nine most potent chalcones in the group have hydroxylation at 2'-carbon position in B-ring. Flavones ranked second in their potencies. Quercetin, 4-hydroxyflavone and luteolin are three hydroxyflavones with highest potencies in this group. Their IC(50) values are 30.81, 39.29 and 71.17 microM, respectively. Chromones, isoflavones, flavanones and coumarins showed much lower potencies when compared to the first two groups with IC(50) ranges of 61 to >400, 131 to >400, 138 to >400 and 360.85 to >400 microM, respectively. In mechanistic studies, the most potent chalcone, 2,2'-dihydroxychalcone could induce G2/M arrest and then apoptosis of the cancer cells.
An analysis of structure-activity relationship showed that following structures are required for their inhibitory potencies on human liver cancer cells: (1) of the six sub-classes of the polyphenols tested, the unique backbone structure of chalcones with a open C-ring; (2) within the chalcone group, hydroxyl substitution at 2'-carbon of B-ring; (3) hydroxyl substitution at 3'-carbon in B-ring of flavones. However, some other structures were found to decrease their potencies: e.g. substitutions by sugar moieties in flavones. These data are valuable for design and modification of new polyphenols, which could be potential antiproliferative agents of cancer cells.
研究68种具有不同主链结构和各种取代基的植物多酚的抗癌活性，并分析其构效关系。
采用3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴盐法筛选68种植物多酚对人肝癌细胞的抗增殖活性。通过比较它们与选定结构的活性来分析构效关系。采用流式细胞术分析细胞周期进程，通过DNA片段分析检测细胞凋亡。
根据主链结构，68种多酚被分为黄酮类（查耳酮、黄烷酮、黄酮和异黄酮）、色酮类和香豆素类。它们抑制人肝癌细胞的效力顺序为：查耳酮＞黄酮＞色酮＞异黄酮＞黄烷酮＞香豆素。查耳酮是最有效的一组，IC50值范围为21.69至197μM。该组中效力最强的前九种查耳酮在B环的2'-碳位有羟基化。黄酮的效力排名第二。槲皮素、4-羟基黄酮和木犀草素是该组中效力最高的三种羟基黄酮。它们的IC50值分别为30.81、39.29和71.17μM。与前两组相比，色酮、异黄酮、黄烷酮和香豆素的效力要低得多，IC50范围分别为61至＞400、131至＞400、138至＞400和360.85至＞400μM。在机制研究中，最有效的查耳酮2,2'-二羟基查耳酮可诱导癌细胞G2/M期阻滞并随后凋亡。
构效关系分析表明，它们对人肝癌细胞的抑制效力需要以下结构：（1）在所测试的多酚的六个亚类中，查耳酮具有独特的开放C环主链结构；（2）在查耳酮组内，B环2'-碳位有羟基取代；（3）黄酮类B环3'-碳位有羟基取代。然而，发现其他一些结构会降低它们的效力，例如黄酮类中糖基的取代。这些数据对于设计和修饰新的多酚具有重要价值，这些多酚可能是潜在的癌细胞抗增殖剂。
