Functionalized N(2-oxyiminoethyl) piperazinyl quinolones as new cytotoxic agents

Abstract

Purpose: The prokaryotic type II topoisomerases (DNA gyrase and topoisomerase IV) and the eukaryotic type II topoisomerases represent the cellular targets for quinolone antibacterial agents and a wide variety of anticancer drugs, respectively. In view of the mechanistic similarities and sequence homologies exhibited by the two enzymes, tentative efforts to selectively shift from an antibacterial to an antitumoral activity was made by synthesizing a series of functionalized N-(2-oxyiminoethyl)piperazinyl quinolones, in which the C-7 piperazine ring of antibacterial quinolones, ciprofloxacin and norfloxacin, is attached by a certain N-[2-(furan-2-yl)-2-oxyiminoethyl] and N-[2-(thiophen-2-yl)-2-oxyiminoethyl] moieties. Thus, as part of a continuing search for potential anticancer drug candidates in the N-substituted piperazinyl quinolones series, the cytotoxicity evaluation of functionalized N-(2-oxyiminoethyl) piperazinyl quinolones was our interest.

Methods: The growth inhibitory activities of synthesized N-[2-(furan-2-yl)-2-oxyiminoethyl] and N-[2-(thiophen-2-yl)-2-oxyiminoethyl] piperazinyl quinolones were determined against seven cancer cell lines using an in vitro cell culture system (MTT assay).

Results: Preliminary screening showed that some of N-(2-oxyiminoethyl) piperazinyl quinolone analogs containing O-benzyl group displayed in vitro cytotoxic activity comparable or higher than reference drug etoposide.

Conclusions: These studies demonstrate that introduction of O-benzylmoiety on oxime group of N-(2-oxyimino) piperazinyl quinolone series changes the biological profile of piperazinyl quinolones from antibacterial to cytotoxic activity. As can be deduced from these data, O-benzyl functionalized N-(2-oxyiminoethyl) piperazinyl quinolones have excellent potential as a new class of cytotoxic agents.