Human DNA topoisomerase II is a well-known and important target of anticancer drugs. Due to limitations of the currently clinically used inhibitors of this target, there is intense research ongoing to find compounds with alternative mode of inhibition, among which ATP-competitive inhibitors show the highest potential. The ATP-binding site of human DNA topoisomerase II contains unique structural elements specific to the GHKL superfamily of ATPases. Members of the GHKL superfamily, which include bacterial topoisomerases type II, share a high three-dimensional similarity of ATP-binding sites. Through systematic screening of the in house library of ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV, a new chemotype of ATP-competitive inhibitors of human DNA topoisomerase II was discovered. Initially, we identified 20 hit compounds of different structural types. As the most promising, 1,2,4-substituted N- phenylpyrrolamides were selected for further optimization. New series of topoisomerase II inhibitors were prepared with the help of the preliminary structure-activity relationship (SAR) that was based on the primary N-phenylpyrrolamide hits and the structure-based design. New inhibitors can be divided into six structural types, all of which possess a N-phenylpyrrolammide scaffold. Compounds of types IV and VI were selected because of their very good inhibitoy activity on topoisomerase II (IC50 values in the submicromolar and low micromolar range) as well as ther excellent cytotoxic activity on MCF-7 and HepG2 cancer cell lines. The outstanding compound is 130g with submicromolar IC50 value on HepG2 cancer cell line. Compound 46d, despite weaker topo IIα inhibitory activity, also shows excellent cytotoxic activity on cancer cell lines MCF-7 and HepG2, which is probably due to its dual inhibitory activity on topoisomerase II and Hsp90, which is also a known target in new anticancer drug development. Further development of such dual topoisomerase II and Hsp90 inhibitors would be an interesting approach of development of new highly cytotoxic compounds, which has not yet been well investigated according to our literature search. Compounds 46d, 112a and 112b (the latter two represent compounds of structural type VI) were also evaluated on NCI-60 panel of cancer cell lines where they showed very good cytotoxic activities, especially against colon and central nervous system cancer and melanoma cell lines. Compound 46d and compounds of structural types IV and VI (especially 130g) therefore show potential to be further developed into potent topoisomerase II inhibitors as potential anticancer drugs.
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