Xue Wei, Song Bao-An, Zhao Hong Ju, Qi Xing Bao, Huang Yin Jiu, Liu Xin Hua
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Guizhou University, Guiyang 55002, PR China.
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Guizhou University, Guiyang 55002, PR China.
Eur J Med Chem. 2015 Jun 5;97:155-63. doi: 10.1016/j.ejmech.2015.04.063. Epub 2015 May 1.
Telomere and telomerase were closely related to occurrence and development of some cancers. To enhance ability of myricetin moiety for inhibiting telomerase, we designed a series of novel myricetin derivatives based on reasonable analysis. The telomerase inhibition assay showed that compound 6d displayed the most potent inhibitory activity with IC50 value of 0.91 μM. The anticancer activity assay showed that 6d exhibited high activity against human breast cells MDA-MB-231. The docking simulation of compound 6d was performed to get the probable binding model, the results demonstrated that the furan ring inserted into the active site deeply and had hydrophobic interactions with residues of Phe 568, Pro 627, four methoxy groups had hydrophobic interactions with residues of Phe 568, Pro 627, Lys 902, Val 904 and Pro 929. Western blot results showed that expression of p65 and TERT protein was clearly down-regulated by compound 6d. These data support further studies for the rational design of more efficient p65 and TERT modulators.
端粒和端粒酶与某些癌症的发生和发展密切相关。为了增强杨梅素部分抑制端粒酶的能力，我们在合理分析的基础上设计了一系列新型杨梅素衍生物。端粒酶抑制试验表明，化合物6d表现出最有效的抑制活性，IC50值为0.91 μM。抗癌活性试验表明，6d对人乳腺癌细胞MDA-MB-231具有高活性。对化合物6d进行对接模拟以获得可能的结合模型，结果表明呋喃环深深插入活性位点并与Phe 568、Pro 627的残基具有疏水相互作用，四个甲氧基与Phe 568、Pro 627、Lys 902、Val 904和Pro 929的残基具有疏水相互作用。蛋白质免疫印迹结果表明，化合物6d可明显下调p65和TERT蛋白的表达。这些数据支持进一步研究以合理设计更有效的p65和TERT调节剂。
