الفهرس 
Title : Design, Synthesis and Biological Evaluation of Some New Quinolone Derivatives as Potential Chemotherapeutic Agents
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Abstract
To exploit the advantageous properties of approved drugs to hasten anticancer drug discovery, we designed and synthesized a series of fluoroquinolone (FQ) analogs via functionalization of the acid hydrazides of moxifloxacin, ofloxacin and ciprofloxacin. Under the NCI-60 Human Tumor Cell Line Screening Assay, VIf was the most potent among moxifloxacin derivatives whereas IXd was the only ofloxacin derivative with significant effects and ciprofloxacin derivatives were devoid of activity. VIf and IXd were further selected for five dose evaluation where they showed potent growth inhibition with a mean GI50 of 1.78 and 1.45 µM, respectively. IXd elicited a more potent effect reaching sub-micromolar level on many cell lines including MDA-MB-468 and MCF-7 breast cancer cell lines (GI50 = 0.41 and 0.42 µM, respectively), NSCLC cell line HOP-92 (GI50 = 0.50 µM) and CNS cell lines SNB-19 and U-251 (GI50 = 0.51 and 0.61 µM, respectively). VIf and IXd arrested MCF-7 cells at G1/S and G1, respectively and induced apoptosis mainly through the intrinsic pathway as shown by the increased ratio of Bax/Bcl-2 and caspase-9 with a lesser activation of the extrinsic pathway through caspase-8. Both compounds inhibited topoisomerase with preferential activity on type II over type I and IXd was marginally more potent than VIf. Docking study suggests VIf and IXd bind differently to Topo II compared to etoposide. VIf and IXd possess high potential for oral absorption, low CNS permeability and low binding to plasma proteins as suggested by in silico ADME calculations. Collectively, VIf and IXd represent excellent lead molecules for the development of cytotoxic agents from quinolone scaffolds