Study On The Sonodynamic Activities And Structure Activity Relationships Of 3,7-diaminophenothiazinium Derivatives

In recent years, photodynamic therapy (PDT) has made significant achievements in the treatment of cance and it has been used in clinical treatment of superficial cancer. Sonodynamic therapy (SDT) is a novel anti-tumor method developed on the basis of PDT. The method utilizes sonosensitizers which can be activated to produce anti-tumor factor under ultrasonic irradiation, then kill tumor cells and inhibit tumor growth. Compared with PDT, SDT could kill cancer cells with minimal damage to normal cells, and precisely focus on a specic tumor location and effectively activate or enhance the enrichment of the sonosensitizer surrounding the tumor sites. Therefore, SDT overcomes the disadvantages of PDT, such as large side effects and toxicity, damage to normal tissues and the limited penetrability of light, which makes sure the therapies of the various superficial and deep tumor to achieve better anti-tumor effects.Although SDT is still in the stages of clinical testing stage, SDT has good prospects for the treatment of deep tumor tissues. Scholars have high expectations in the treatment of malignant tumors by SDT. So far, the investigations of SDT includes the type of sonosensitizers, the mechanisms of SDT, the treatment parameters of ultrasound and the combination of another technology. Filtrating new sonosensitizers is one of the main content of SDT. The study has confirmed that phenothiazinium derivatives have sonodynamic activity, which indicate phenothiazinium derivatives can be used as an sonosensitizer in the SDT. In this study, the series of symmetric 3,7-diaminophenothiazinium derivatives were synthesised. The obtained results are as follow:1. Phenothiazine and I2 are used starting materials to synthesis the intermediate enothiazin-5-ium tetraiodide hydrate, which then react with a series of amines,5 kinds of 3.7-diamino-phenothiazine compound were synthesized. By MS and 1H NMR the structures of the compounds were characterized.2. The interactions between 3,7-diaminophenothiazinium derivatives and bovine serum albumin (BSA) under physiological conditions were studied absorption and fluorescence spectra. In this section, the mechanism, association constants, binding distance and conformational changes of BSA were determined.3. Selecting BSA as a model protein, the sonodynamic damage to protein in presence of D1,D4 in the case of different concentrations and different ultrasound time were studied. The results show that D1 and D4 at the concentration of 2.5mol/L and 2.0mol/L reach the maximum extent of the damage to BSA at the same ultrasound time, respectively. When the compounds were in the same concentration, the damage of BSA increased with the increasing ultrasonic time.4. The kinds of generated Reactive oxygen species(ROS) under ultrasonic irradiation in the presence of 3,7-diaminophenothiazinium derivatives were confirmed by the oxidation-extraction photometry method with several ROS scavengers. The influence on the amount of reactive oxygen species were investigated. These results would be expected to provide theory basis for the design and development of phenothiazinium sonosensitizers for SDT.