Investigation On Synthesis And Biologicalactivity Of Triazine Porphyrin Derivatives

At present, the anticancer drugs can not be selectively transported to the cancer cells. They kill the cancer cells at the same time damnify the normal cells severely. Therefore, it is an important issue in medicine and pharmaceutics to develop new anticancer prodrugs that are more active and specific in killing cancer cells.According to the therory of drug designing, there are two important methods to design new drug: 1) analog design—based on the presently clinical drugs or compounds with biological activities, which are modified structurally in order to get new drugs with lower toxicity and higher anticancer activity than the precursor; 2) combination principles—functionals of two kinds of drugs were combined into one molecule which may achieve good selectivity, reduce their toxicity and enhance therapeutic efficacy, or may get other's strong points to offset one's weakness, exert independently therapeutic function of the two drug or the two functionals of two kinds of drugs and obtain dual action capacities. Therefore, the aim of this thesis is to design and synthesize new compounds containing antitumor groups, nine of 10 kinds of porphyrins bearing 1,3,5-triazine derivatives are new, and preliminarily investigate their biological activities and anticancer activities toward MCF-7 cell. First, porphyrins were used as photosensitizers in the treatment of cancer. After the administration of photosensitizer, subsequent illumination with light of an appropriate wavelength creates a photochemical reaction that results in DNA and malignant tissue destruction. What's more, there were higher (above 10 times) concentration of porphyrins around the malignant tissues than around the normal tissues and specification and split to some kinds of DNA, which will influence the genetic expression and stop proliferation of the cell. Second, triazine derivatives family is a kind of drugs clinically used to cure the MCF-7. It was possible to get new porphyrin compounds with higher anticancer activity and specification toward malignant tissues if they were combined into one molecule. The main contents includes following:1. After 5-(4-hydroxyl)phenyl-10, 15, 20-triphenylporphyrin was synthesized by Adler's method, We are taking advantage of three chlorine atoms in the cyanuric tricholoride molecule have high activity, they can be substituted by nucleophilic reagent step by step depending on temperatures. The synthesis of triazine-porphines from the reaction of the porphine with hydroxyl group and triazine and other nucleophiles was discussed, and the effect of the nucleophilicity, stereochemistry of the nucleophiles and the reaction temperatures on the structures of the triazine-porphines were studied, and some new aromatic aldehydes were synthesized from the triazne derivatives by Vilsmeier reaction,2. In order to synthesize novel more effective anticancer drugs, The 5-(4-(4,6-dichlorotriazine-2-oxy))phenyl-10, 15, 20-triphenylporphyrin was obtained firstly by treatment of 5-(4-hydroxyl)phenyl-10, 15, 20-triphenylporphyrin with cyanuric tricholoride in room temperature, ten porphyrin-triazine compounds( nine of 10 kinds of compounds are new) were synthesized in one-pot method with high yield by adding the alcohol or amine to the reaction mixture of directly, and the porphyrin-triazine compounds were purified by column chromatography; Stepwise substitution of cyanuric chloride with alcohol or amine takes advantage of the temperature-dependent reaction of three chlorine atoms in triazine by different nucleophiles; enabling the synthesis of the triazine derivatives in high yield. Furthermore six new aromatic aldehydes were synthesized from the triazne derivatives. Their structures were characterized by MS, 1H NMR and elemental analysis.3. The anticancer activities of some triazine derivatives porphyrins were investigated in vitro using the 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Their cytotoxic activity were evaluated in vitro against MCF-7. All compounds showed similar activity against MCF-7 cells when compared to and tetraphenylporphyrin in the absent of light.4. We investigated the interaction of triazine derivatives porphyrin compounds with Bovine Serum Albumin (BSA) and calf thymus DNA by fluorescence spectra and UV/Vis spectra. This can provide some valuable messages for further studying the anticancer mechanism of triazine derivatives porphyrin compounds. Experimental results show that these porphyrins can enter into the hydrophobic cavity of BSA by the“hydrophobic force”to form a stable complex, which might change the protein's secondary structure. It is also shown that, with the steric hindrance of substituents increasing, the binding constant of BSA and porphyrin decreased, while the binding distancer of them increased. However, the binding number is not influenced by substituents. The results for study of the interaction between porphyrin-triazine compound and DNA indicated that the stable complexes were formed between DNA and porphyrin-triazine compound, and the porphine core of porphyrin-triazine compounds could intercalate into DNA base pairs plane. The largest binding number of DNA with porphyrins is 82.