Yadav Arun A, Chee Gaik-Lean, Wu Xing, Patel Daywin, Yalowich Jack C, Hasinoff Brian B
College of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Ave, Winnipeg, Manitoba R3E 0T5, Canada.
College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA.
Bioorg Med Chem. 2015 Jul 1;23(13):3542-51. doi: 10.1016/j.bmc.2015.04.022. Epub 2015 Apr 16.
Drugs that target DNA topoisomerase II, such as the epipodophyllotoxin etoposide, are a clinically important class of anticancer agents. A recently published X-ray structure of a ternary complex of etoposide, cleaved DNA and topoisomerase IIβ showed that the two intercalated etoposide molecules in the complex were separated by four DNA base pairs. Thus, using a structure-based design approach, a series of bis-epipodophyllotoxin etoposide analogs with piperazine-containing linkers was designed to simultaneously bind to these two sites. It was hypothesized that two-site binding would produce a more stable cleavage complex, and a more potent anticancer drug. The most potent bis-epipodophyllotoxin, which was 10-fold more growth inhibitory toward human erythroleukemic K562 cells than etoposide, contained a linker with eight methylene groups. All of the mono- and bis-epipodophyllotoxins, in a variety of assays, showed strong evidence that they targeted topoisomerase II. COMPARE analysis of NCI 60-cell GI50 endpoint data was also consistent with these compounds targeting topoisomerase II.
靶向DNA拓扑异构酶II的药物，如鬼臼毒素类的依托泊苷，是临床上一类重要的抗癌药物。最近发表的依托泊苷、切割后的DNA与拓扑异构酶IIβ三元复合物的X射线结构显示，复合物中两个插入的依托泊苷分子被四个DNA碱基对隔开。因此，采用基于结构的设计方法，设计了一系列含哌嗪连接子的双鬼臼毒素类依托泊苷类似物，使其能同时结合这两个位点。据推测，双位点结合会产生更稳定的切割复合物，从而得到一种更有效的抗癌药物。最有效的双鬼臼毒素对人红白血病K562细胞的生长抑制作用比依托泊苷强10倍，其连接子含有八个亚甲基。在各种检测中，所有的单鬼臼毒素和双鬼臼毒素都有充分证据表明它们作用于拓扑异构酶II。对NCI 60细胞系GI50终点数据的COMPARE分析也与这些化合物作用于拓扑异构酶II的结果一致。
