Anti-proliferative activity, molecular modeling studies and interaction with calf thymus DNA of novel ciprofloxacin analogues

Abstract

In our pursuit to expand new potential anticancer leads, a series of eighteen novel 1-cyclopropyl-6-fluoro-4-oxo-7-(4-substituted piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid analogues have been synthesized, characterized and evaluated anti-proliferative activity against five human cancer cell lines such as A549 (lung cancer), Mia Paca (pancreatic cancer), HeLa (cervical cancer), MDA MB-231 (breast cancer), MCF-7 (breast cancer) and normal embryonic kidney cell line (HEK) were carried out using MTT assay. Few of the synthesized analogues exhibited potent anticancer activity against the cancer cell lines at a lower concentration. The synthesized compounds showed the less toxic effect on normal human embryonic kidney cell line (HEK) compared with doxorubicin. Noticeably, compound 3o exhibited potent activity against all five cancer cell lines compared with ciprofloxacin. Further study exposed that compound 3o could competently intercalate into calf thymus DNA to form 3o-DNA complex which might block DNA replication to apply anti-proliferative activity. Docking simulation studies supported by molecular interactions with DNA type II topoisomerase. These derivates can become lead structures for the development of potential anticancer drugs.

Structural parameters of the interaction between ciprofloxacin and human topoisomerase-II β enzyme: toward new 19F NMR Chemical Shift probes

“…These compounds exert antibacterial activity because of inhibition of two bacterial enzymes, DNA gyrase and topoisomerase II enzymes [5,6]. The later are considered to be the primary target of several anticancer agents, such as doxorubicin and etoposide [7][8][9], being under continuous investigation aiming new anticancer drugs development, once some evidences indicate increased levels of topoisomerase II in several types of proliferating cancer cells, including Gallbladder cancer [10] , aggressive breast cancer [10][11][12], epithelial ovarian cancer [10,[13][14][15], lymphomas and sarcomas [16][17][18], colon cancer [10] and some others. Speaking more specifically about breast cancer, increased levels of this enzyme are associated with more aggressive breast cancer, being related to increased expression of the oncogene HER2 neu, being also related to predicted diseaserelated death, lymph node metastasis, and advanced tumor stage [19].…”

Structural Parameters of the Interaction between Ciprofloxacin and Human Topoisomerase-II β Enzyme: Toward New 19F NMR Chemical Shift Probes

“…The latter is considered to be the primary target of several anticancer agents, such as doxorubicin and etoposide [7][8][9]. Researchers continue to investigate the development of new anticancer drugs based on evidence indicating increased levels of topoisomerase II in several types of proliferating cancer cells, including gallbladder cancer [10], aggressive breast cancer [10][11][12], epithelial ovarian cancer [10,[13][14][15], lymphomas and sarcomas [16][17][18], and colon cancer [10]. Increased levels of this enzyme associated with aggressive breast cancer are related to increased expression of the oncogene HER2 neu, predicted disease-related death, lymph node metastasis, and advanced tumor stage [19].…”