Synthesis And Biological Studies Of Pyridyl-Substituted Corrole Derivatives

Malignant tumor, also called cancer generates more and more threat to public health. The third nationwide residents death investigation published by Ministry of Public Health in 2008 indicates that the first cause of urban death is malignant tumor. Chemical medication (chemotherapy for short) is one of principal means of cancer treatment currently which can significantly promote the livability of cancer patients. However, most of chemotherapeutics presently have low selectivity and toxic side-effect, what's more, it brings about great pain to the patients. Therefore, the design of neotype anticancer drug with high selectivity becomes the hot field in anticancer research.G-rich DNA sequence can form a second level structure--G-quadruplex structure through Hoogsteen hydrogen bond. Many important biological functional areas in human genome are rich in guanine bases, such as the end of telomere DNA, the promoter region in oncogene and so on. Research suggests that the formation of G-quadruplex can prevent the elongation of telomere or the expression of down-regulated gene. Consequently, the synthesis of small molecules which induce and stabilize the G-quadruplex structure become the hotspot of antidrug research in recent years.Corrole is a planar tetrapyrrole macrocyclic compound similar to porphyrin which has aromaticity with 18πelectron conjugation. Reports have proof that water-soluble corrole exhibits good inhibition activity to fibroblast growth factor which makes it a kind of potential new-type anticancer drugs.On the basis of the anti-cancer strategy targeted to G-quadruplex DNA, two categories of cationic corroles with meso-pyridine groups were designed and synthesized in this thesis. In addition, systematic research about the interaction between the corroles and G-quadruplex structure in vitro was also performed. Results indicate that cationic corrole isomers with three meso-pyridine groups are good G-quadruplex ligands. In circular dichroism(CD) assay, these corroles induced the formation of parallel and anti-parallel mixed G-quadruplex structure. This conclusion was further demonstrated by ATm assay, PCR stop assay in which the lowest IC50 value for Corrole 11 is 2.28μM. In Surface Plasmon Resonance (SPR) assay, the selectivity of nine corrole isomers between G-quadruplex DNA and double-strand DNA was investigated. The result shows that all of these corroles have good selectivity which the highest ratio value is 502. It also suggests that high symmetric Corroles (Corrole 10,14,18) have lower selectivity than that of corroles with similar structure but low symmetric. We conclude that introduction of asymmetric factors will promote the selectivity of the compounds.The results in biological assays of six A2B-type corroles indicate that three positive-charged Corrole 31 can induce the formation of G-quadruplex structure while two positive-charged C orrole24-28 cannot. Therefore, we deduce that the number of positive charge in side chains of corroles will produce relatively big impact on the ability of inducing the formation of G-quadruplex DNA. In other words, the increasing number of charge promotes the formation of G-quadruplex DNA.