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

Abstract

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 N-phenylpyrrolamide based inhibitors. The most potent inhibitor, 47d, had an IC₅₀ value of 0.67 μM against DNA topoisomerase IIα. 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 IIα.

Keywords: ATP-competitive; Anticancer; Catalytic inhibitor; Cytotoxic; Human DNA topoisomerase II.