Structure-based design, synthesis and biological testing of piperazine-linked bis-epipodophyllotoxin etoposide analogs

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.

Anticancer; COMPARE; DNA; Docking; Epipodophyllotoxin; Etoposide; K562 cells; Molecular modeling; Structure-based design; Topoisomerase II.