title: New antiproliferative 7-(4-(N-substituted carbamoylmethyl)piperazin-1-yl) derivatives of ciprofloxacin induce cell cycle arrest at G2/M phase.
abstract: New N-4-piperazinyl derivatives of ciprofloxacin 2a-g were prepared and tested for their cytotoxic activity. The primary in vitro one dose anticancer assay experienced promising cytotoxic activity against different cancer cell lines especially non-small cell lung cancer. Independently, compounds 2b, 2d, 2f and 2g showed anticancer activity against human non-small cell lung cancer A549 cells (IC50=14.8, 24.8, 23.6 and 20.7μM, respectively) compared to the parent ciprofloxacin (IC50 >100μM) and doxorubicin as a positive control (IC50=1μM). The flow cytometric analysis for 2b showed dose dependent G2/M arrest in A549 cells. Also, 2b increased the expression of p53 and p21 and decreased the expression of cyclin B1 and Cdc2 proteins in A549 cells without any effect on the same proteins expression in WI-38 cells. Specific inhibition of p53 by pifithrin-α reversed the G2/M phase arrest induced by the 2b compound, suggesting contribution of p53 to increase. Taken together, 2b induced G2/M phase arrest via p53/p21 dependent pathway. The results indicate that 2b can be used as a lead compound for further development of new derivatives against non-small cell lung cancer.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
authors.forename: Hamada H H
authors.initials: HHH
authors.lastname: Mohammed
authors.affiliation: Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
authors.forename: Amer Ali
authors.initials: AA
authors.lastname: Abd El-Hafeez
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
authors.forename: Samar H
authors.initials: SH
authors.lastname: Abbas
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
authors.forename: El-Shimaa M N
authors.initials: EMN
authors.lastname: Abdelhafez
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt. Electronic address: gamal.aborahma@mu.edu.eg.
authors.forename: Gamal El-Din A
authors.initials: GEA
authors.lastname: Abuo-Rahma
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; D002939:Ciprofloxacin
keywords: Antiproliferative; Ciprofloxacin; Cytotoxicity; G(2)/M cell cycle arrest; p53/p21 pathway