【作者】 史蕾；

【导师】 江焕峰； 刘海洋；

【作者基本信息】 华南理工大学 ， 应用化学， 2010， 博士

【摘要】 近几年,能够和核酸结合并且导致核酸断裂的大环化合物由于在DNA结构探针及开发有效的人工核酸酶方面具有潜在的应用性,因此引起了人们的广泛关注。Corrole是一类具有18-p电子的大环化合物,其化学结构类似于卟啉,只是少了一个间位的亚甲基。作为一种新型的光敏剂,Corrole和卟啉相比具有独特的优点,如:在可见光区具有更强的吸收、更大的斯托克斯位移以及在新陈代谢中更容易分解。已有大量文献报导,卟啉类光敏剂能够选择性的聚集在肿瘤细胞并且在光照的条件下引起细胞的损伤,并且卟啉诱导的DNA光断裂在过去几年里已经被广泛关注。但是,关于Corrole及其衍生物光损伤DNA的研究还非常少,大量新颖的合成和功能研究等待人们去开拓。作者在查阅了大量文献的基础上,设计合成了一系列Corrole单体和Corrole-吩噻嗪二元体化合物,并且系统的研究了它们的光谱性质、与DNA的结合模式及光催化断裂DNA性能。主要工作包括以下几个方面:一.合成了一系列Corrole的周边苯环上分别连有F、Cl、Br、I原子及未被卤素取代的单羟基Corrole。稳态和飞秒时间分辨荧光光谱数据显示,这些卤代Corrole的光谱性质表现出明显的重原子效应。荧光量子产率和荧光寿命随着卤素重原子相对原子质量的升高而降低。此现象应该是由增加的系间跃迁常数(Kisc)引起的,其中,Corrole周边苯环的氢被碘原子取代后,化合物表现出最低的荧光量子产率(0.040)和最高的系间跃迁常数(388.28′10-3 ns-1)。另外,这一系列化合物在光催化下,能够把超螺旋pBR 322 DNA(Form I)切割成缺刻型DNA(Form II),且光断裂DNA的效果随着Corrole周边取代的卤素相对原子质量的增加而提高。这几种Corrole敏化生成单线态氧的量子产率的规律和化合物切割DNA的活性一致。说明这几种卤代Corrole光催化DNA的活性也遵循重原子效应。这部分工作对于探索新型、高效的PDT光敏剂具有重要意义。二.设计合成了一系列单羟基Corrole和Corrole-吩噻嗪二元体。其中,Corrole-吩噻嗪二元体在室温下,选用DBU做催化剂能够得到60-95%的收率。Corrole-吩噻嗪二元体具有更高的荧光量子产率和更长的荧光寿命。此现象应该归因于吩噻嗪的的加入,因为吩噻嗪被认为是一种能够有效降低有机半导体材料离子化电势(ionicpotential)的结构基团,而且吩噻嗪分子具有扭曲的蝴蝶型构象,所以吩噻嗪分子能够阻止π-π堆积和链间激基复合物的形成,因而能改善光电功能材料的性质。另外,Corrole-吩噻嗪二元体和Corrole单体相比具有更加有效的光切割DNA活性、更高的敏化单线态氧量子产率和更强的DNA结合模式。三.合成了三种Corrole-吩噻嗪Ga(III)配合物。检测了它们的稳态吸收和发射光谱以及时间分辨荧光光谱。通过荧光量子产率和单指数荧光衰减曲线计算了其辐射跃迁常数和无辐射跃迁常数。三种Ga(III)Corrole配合物具有很强的Soret带和Q带吸收,更高的荧光量子产率,分别为0.502, 0.443和0.494。另外,这三种Ga(III)Corrole配合物的辐射跃迁常数和自由Corrole相比也大幅提高,分别为20.9′107 s-1, 16.78′107 s-1和21.11′107 s-1,但荧光寿命反而降低。琼脂糖凝胶电泳实验发现,这三种Ga(III)Corrole配合物在光照下也能把超螺旋DNA断裂为缺刻型DNA。四.合成了单羟基Corrole Cu(III)和Corrole-吩噻嗪Cu(III)配合物。性质研究发现,这两种Cu(III)Corrole配合物能够保护DNA免受双氧水的损伤,且Corrole-吩噻嗪Cu(III)的保护效果更强。此现象的发现对于设计新型的理想的超氧化岐化酶(SOD)具有重要意义。更多还原

【Abstract】 Macrocyclic compounds which could bind and cleave nucleic acids are of current interest for their importance as reagents to retrieve structural and genetic information of DNA and to develop efficient chemical nucleases. Corrole is an 18-p electron macrocycle having a direct pyrrole-pyrrole linkage. Its ring structure is in close resemblance to porphyrin. As a PDT photosensitizer, Corrole has the advantages of having more intense absorption of visible light, larger Stokes shift and less robust during metabolism as compared to porphyrin. It is well known that porphyrin photosensitizer might be localized in tumor cell, and caused tumor cell damage under irradiation. The porphyrin mediated DNA photo-cleavage has well been documented in the past years. However, less attention has been paid to the DNA photocleavage by Corrole derivatives so far. A large number of novel synthesis and function of Corroles waiting for people to open up. On the basis of careful investigation of the most recent references, we have designed and synthesized a series of Corrole and Corrole-phenothiazine dyads, and have studied their spectral properties、DNA binding and DNA photocleavage activities.Firstly, a series of mono-hydroxyl Corroles bearing fluorin, chlorine, bromine and iodine atoms on its 10-phenyl group was synthesized. Steady state and time-resolved fluorescence spectra measurement show that the halogen atoms on the meso- phenyl group exhibit significant heavy atom effect on their photophysical property. The fluorescence quantum yield and the lifetime of these Corroles decrease with the increasing of atomic weight of halogen atom. These may be understood by the increasing Kisc caused by the heavy atom effect of halogen atoms. From the heavy atom effect of view, Corrole bearing iodine atom present the lowest fluorescence quantum yield (0.040) and the highest intersystem crossing rate constant (388.28′10-3 ns-1). DNA photocleavage properties of these halogenated mono-hydroxyl Corroles were also investigated. It was found that these Corroles were able to cleave supercoiled pBR 322 DNA (Form I) into nicked-circular DNA (Form II). The DNA photocleavage activity increase with the increasing of atomic weight of halogen atom. The photosensitized singlet oxygen (Ф_△) quantum yield by these Corroles also follows that same order, showing the photocleavage activity is related to the heavy atom effect of halogen atoms on Corroles. This work will be helpful in giving insight into the PDT activity of halogenated Corroles.Secondly, a series of mono-hydroxyl Corroles and Corrole-phenothiazine dyads was successfully synthesized. The Corrole-phenothiazine dyads could be efficiently prepared at room temperature in the presence of DBU with yields of 60-95%. The Corrole-phenothiazine dyads exhibit higher fluorescence quantum yield and longer singlet exited lifetime than their parent mono-hydroxyl Corroles. The enhanced fluorescence quantum yield and lifetime may be caused by the introduction of phenothiazine unit, which is known as an excellent building block for impeding aggregation and intermolecular excimer formation. As compared to Corrole monomer, these Corrole-phenothiazine dyads exhibit significant enhanced DNA photocleavage activity、higher singlet oxygen quantum yields and DNA binding activities.Thirdly, three Corrole-phenothiazine Gallium (III) complexes have been synthesized. The steady-state absorption and emission spectra and the time-resolved fuorescence decay profiles have been measured in toluene and the radiative and nonradiative rate constants have been obtained from the fluorescence quantum yields and monoexponential fluorescence lifetimes. The absorption spectra reveal that the Corrole unit of the Gallium (III) dyad exhibit stronger Soret band and Q band. The fuorescence quantum yields of these Gallium (III) Corrole complexes are 0.502, 0.443 and 0.494, and the radiative rate constans are 20.9′107 s-1, 16.78′107 s-1 and 21.11′107 s-1, which are obviously higher than their free base Corroles, wheras the lifetime were somewhat shorter. Agarose gel electrophoresis shows that these Gallium (III) Corroles could also cleave supercoiled DNA (Form I) to nicked-circular DNA (Form III ) under irradiation.Finally, mono-hydroxyl Corrole copper (III) and Corrole-phenothiazine copper (III) complexes have been synthesized. These two copper (III) Corrole complexes could proteCT DNA against the damage of H2O2, and the Corrole-phenothiazine copper (III) complex exhibit improved activities. This kind of information is crucial for the design of an optimal catalyst for the dismutation of superoxide。更多还原