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目的研究新合成的有机锗化合物与DNA的相互作用,为从分子水平上揭示它们的抗癌作用机理提供资料,为进一步设计合成更为有效的抗癌药物提供理论指导。方法综合应用紫外-可见分光光度法(UV-Vis)、热变性(Melting Temperature Studies)、荧光光谱变化(Fluorescence Titration Experiments)、黏度测定(Viscosity Measurements)等方法,研究了4种化合物与3种DNA,既小牛胸腺DNA(ct-DNA)、22-mers poly(dA.dT)和22-mers poly(dG.dC)的相互作用。结果4种化合物与CT-DNA结合后,4种化合物的UV-Vis均发生了不同程度的减色效应和红移现象,预示着4种化合物可能通过插入方式与DNA发生作用。由化合物与ct-DNA、22mer poly(dA.dT)和22mer poly(dG.dC)作用的热变性曲线可以看出,3种DNA的热变性温度Tm均有提高,意味着药物与DNA的插入结合。发现4药物小分子对CT-DNA黏度均有影响,随着药物浓度的增加,DNA溶液的黏度也随之增大。3种DNA均能使4种化合物的荧光发生淬灭,通过计算得出相应的结合常数,属于中等强度的结合,结合常数介于103～105M-1之间。结论药物与DNA作用后,药物的UV-Vis变化、DNA的热变性温度和黏度的变化均说明4种有机锗化合物是以插入结合方式与DNA发生作用的。以上研究结果说明,新型结构的有机锗化合物各功能基团之间产生了协同作用,它们均能与DNA发生明显的相互作用,并且很可能改变原有的有机锗倍半氧化物的抗癌作用机理,产生直接细胞毒作用,因而提高了整体化合物的抗癌活性。对进一步合成高效低毒的有机锗抗癌药物、揭示它们的作用机理具有重要的参考价值。
OBJECTIVE: To study the interaction between newly synthesized organic germanium compounds and DNA, provide information for revealing their anti-cancer mechanism at the molecular level, and provide theoretical guidance for the further design and synthesis of more effective anti-cancer drugs. Methods The UV-Vis, Melting Temperature Studies, Fluorescence Titration Experiments and Viscosity Measurements were used to study the effects of four compounds and three kinds of DNA , Both the interaction of calf thymus DNA (ct-DNA), 22-mers poly (dA.dT) and 22-mers poly (dG.dC). Results After binding of CT-DNA and four compounds, UV-Vis of the four compounds all had different hypochromic and redshift effects, indicating that four compounds could interact with DNA through the insertion. According to the thermal denaturation curves of the compounds with ct-DNA, 22mer poly (dA.dT) and 22mer poly (dG.dC), the thermal denaturation temperature Tm of all three kinds of DNA increased, which means the insertion of the drug and DNA Combined. It was found that 4 small molecules of drugs affected the viscosity of CT-DNA. With the increase of drug concentration, the viscosity of DNA solution also increased. All three kinds of DNA can quench the fluorescence of the four compounds, and the corresponding binding constants are obtained by calculation, which are moderately strong bounds, and the binding constants are between 103 and 105M-1. Conclusion The change of UV-Vis, DNA thermal denaturation temperature and viscosity of the drug after the interaction between drug and DNA both indicate that the four organic germanium compounds interact with DNA through the insertion and binding. The above results show that the new structure of organic germanium compounds have a synergy between the various functional groups, they both have a significant interaction with DNA, and is likely to change the original organic germanium sesquioxide anti-cancer effect Mechanism, resulting in direct cytotoxicity, thereby enhancing the overall anticancer activity of the compound. It has important reference value for further synthesis of highly effective and low toxicity organic germanium anti-cancer drugs and reveal their mechanism of action.