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 IC(50) values ranging from microM 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 IC(50) values were 10 microM in three (derivative 2) or four (derivative 6h) cancer cell lines.
Azéma
Joëlle
J
Université de Toulouse, UPS, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, Groupe de RMN et Synthèse Biomédicales, 118 route de Narbonne, 31062 Toulouse cedex 9, France. azema@chimie.ups-tlse.fr
Guidetti
Brigitte
B
Dewelle
Janique
J
Le Calve
Benjamin
B
Mijatovic
Tatjana
T
Korolyov
Alexander
A
Vaysse
Julie
J
Malet-Martino
Myriam
M
Martino
Robert
R
Kiss
Robert
R
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity
D000970:Antineoplastic Agents; D010879:Piperazines; D000077489:Piperazine; D002939:Ciprofloxacin