ATP-competitive inhibitors of human DNA topoisomerase II? with improved antiproliferative activity based on N-phenylpyrrolamide scaffold

ATP-competitive inhibitors of human DNA topoisomerase II show potential for becoming the successors of topoisomerase II poisons, the clinically successful anticancer drugs. Based on our recent screening hits, we designed, synthesized and biologically evaluated new, improved series of N-phenylpyrrolamide DNA topoisomerase II inhibitors. Six structural classes were prepared to systematically explore the chemical space of Nphenylpyrrolamide based inhibitors. The most potent inhibitor, 47d, had an IC50 value of 0.67 mu M against DNA topoisomerase II alpha. Compound 53b showed exceptional activity on cancer cell lines with IC50 values of 130 nM against HepG2 and 140 nM against MCF-7 cancer cell lines. The reported compounds have no structurally similarity to published structures, they are metabolically stable, have reasonable solubility and thus can serve as promising leads in the development of anticancer ATP-competitive inhibitors of human DNA topoisomerase II alpha.

Automated summary

Based on recent screening hits, we developed and evaluated a series of new and improved N-phenylpyrrolamide DNA topoisomerase II inhibitors. These compounds show potential in becoming successors to topoisomerase II poisons, as they exhibit high inhibitory activity and metabolic stability.