Synthesis And Sonodynamic Activities Of Novel Fluoroquinolone Compounds

Cancer, as one of major killers, severely affects peoples’health all over the world. Traditional therapies including surgical cutting, chemotherapy, radioactivity treatment, PDT (Photodynamic therapy, PDT) and so on, still remain to be the major choice for most human cancers. Despite great success with conventional cancer therapies, they suffer from numerous shortcomings such as systemic toxicity, low selectivity, drug resistance and potential long-term side effects. Therefore, it is urgently needed for the development of new treatments with high selectivity insignificant toxicity and side effect.SDT (Sonodynamic therapy, SDT) is a novel promising approach for cancer treatment which is developed on the base of the clinical application of PDT. SDT involves administration of a a chemical (a sonosensitizer or a chemotherapeutic drug), then followed by activation by ultrasound exposure to induce tumor cells apoptosis. The activation of sonosensitizers makes molecular oxygen around the dug molecular convert to various highly reactive oxygen species, which causes irreversible damages of tumor cells or tumor associated vasculature. As a kind of mechanical wave, ultrasound can penetrate a internal tumor target and activate drugs, hence achieve accurate targeting therapy of tumor. For the past decades, lots of pre-clinical studies showed that SDT could exert selective anti-tumor effects, yet the clinical application will be still limited before a good sonosensitizers had been developed. So far, most researchs about sonosensitizers are still resticted to hematoporphyrine and its derivatives. However, the shortcomings of these compouds, low tumor affinity and long clearance time and are liable to cause severe Phototoxicity, determin that they are difficult to be used in clinical practice extensively.In this regard, it becomes increasingly important to explore novel sonosensitizers with fewer side effects. Fluoroquinolones have been widely used clinically for treating infectious diseases which has a broad spectrum of activity against Gram-positive and Gram-negative bacteria and have few side effects. The results showed that fluoroquinolones also showed anti-tumor activity in many kind of cancer cells. Recently, series of researchs have demonstrated the sonodynamic activity of few fluoroquinolones, such as ciprofloxacin(CPFX), gatifloxacin, lomefloxacin and sparfioxacin. Prophase works showed that, under ultrasound irradiation, CPFX can damage the BSA more serious, and the damage of BSA is directly proportional to the increase of US irradiation time and solution temperature.CPFX can also enhance cell death induced by ultrasound sonification. If CPFX sonodynamic activity and accumulation in tumors can be improved, this agent might have potential for clinical application. As evident from literature survey, the effect of substitution at C-3 position of the CPFX has not been studied extensively to produce new agents with better sonodynamicl profile. Accordingly, to explore the potential of 3-carbooxylic quinolone derivatives(CPFD) as sonosensitizers agents, we have synthesized some novel enoxacin analogues, by introducing aromatic amines at C-3 position. In following of the study, BSA was used as a protein model to investigate the intensifying effects of CPFD ultrasonically induced protein damage by UV-vis and fluorescence spectra. It was showed that CPFD could enhance ultrasonically induced BSA damage. The damage degree of BSA, much higher than that of CPFX, was direct ratio to US irradiation time and concentration of CPFD. Based on the study of BSA damage by CPFD, compound C3 and C4 were selected to study the effect of growth inhibition on Escherichia coli. The results showed that both C3 and C4 could enhance ultrasonically induced antimicrobial activities. Furthermore, in order to identify the mechanism enhancement of BSA damage and inhibition induced by ultrasound, oxidation-extraction photometry method was used to detected whether reactive oxygen was produced in the solution system. Experimental results indicated that US could activate CPFD to produce ROS, which were mainly determined as singlet oxygen (1O2) and hydroxyl radical (OH), and the yield are both higher than the correspondings of CPFX. All the results revealed that both the new synthesized compounds have a higher ultrasonic activity than that of CPFX with different extent.