Structural modification of ellipticine derivatives with alkyl groups of varying length is influential on their effects on human DNA topoisomerase II: a combined experimental and computational study

The compounds reducing tumor cell viability and disrupting DNA topoisomerase reactions have been widely used in anticancer drug development. Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) is a potent intercalating agent that interferes with nucleic acid processing through interaction with DNA topoisomerase II. Although ellipticine is a well-characterized compound, it is not a widely-accepted drug due to the adverse effects detected upon administration. We have previously reported two novel ellipticine derivatives, N-methyl-5-demethyl ellipticine (ET-1) and 2-methyl-N-methyl-5-demethyl ellipticinium iodide (ET-2) as potent compounds targeting DNA topoisomerase II. This study covers an extended synthesis, characterization, and activity data for five new salts of N-methyl 5-demetyl ellipticine (Z-1, Z-2, Z-4, Z-5 and Z-6) having several organic halides and their effects on human topoisomerase II enzymes. Moreover, combined in silico studies were conducted for better understanding of modes of action of studied molecules at the binding pocket of target. Our results showed that three of the derivatives (Z-1, Z-2, and Z-6) have considerable effect on the catalytic activity of human topoisomerase II implying the influence of alkyl groups added to the parental structure of ellipticine.