7-((4-Substituted)piperazin-1-yl) derivatives of ciprofloxacin: Synthesis and in vitro biological evaluation as potential antitumor agents

Ciprofloxacin (CP), an antibiotic has been shown to have antiproliferative and apoptotic activities in several cancer cell lines. Moreover, several reports have highlighted the interest of increasing the lipophilicity to improve the antitumor efficacy. These studies have led us to synthesize new CP derivatives of various lipophilicities and to evaluate their activity in five human cancer cell lines. With an easy and cost-efficient procedure, 31 7-((4-substituted)piperazin-1-yl) derivatives of CP were prepared that displayed IC50 values ranging from mu M to mM concentrations and are non-toxic in vivo in healthy mice as shown by their maximal tolerated dose (MTD) indices >80 mg/kg. Several derivatives displayed higher in vitro antitumor activity than parent CP however this was not dependent on the lipophilicity of the substituent. Among all synthesized derivatives, the most potent were 2 and 6h whose IC50 values were <= 10 mu M in three (derivative 2) or four (derivative 6h) cancer cell lines. (C) 2009 Elsevier Ltd. All rights reserved.