Synthesis Of Several Iodoporphyrin Compounds And Evaluation Of Their Properties

Cancer is a leading cause of death worldwide, accounting for8.2million deaths in2012. It is expected that annual cancer cases will rise from14million in2012to22million within the next two decades, seriously affecting human survival and development. If detected early, the majority of cancers can be cured by surgery and radiation therapy. However, most cases are advanced in clinic, and can not be treated with surgery. Radiotherapy and chemotherapy will cause loss of appetite, hair loss and other side effects, which bring patients great pain. Hence, new strategies on cancer treatments must be developed. In recent years, photodynamic therapy has attracted extensive attention for its good applicability, low toxicity and non-drug-resistance. Porphyrins have received extensive attention in photodynamic therapy and radionuclide therapy for their unique photosensitivity and good tumor affinity. They can combine photodynamic therapy and radionuclide therapy together, and have promising application in cancer treatment.Five porphyrins bearing different electronic effect substituents were synthesized. The antibacterial properties and cytotoxicity of porphyrin-mediated photodynamic therapy were evaluated.131I was chosen to label porphyrins with well photodynamic properties. After the labeling conditions optimized, the radiolabeled compounds were obtained with high radiochemical purity. Their in vitro and in vivo properties were studied and anti-tumor properties were preliminary evaluated. The detailed contents are as follows:(1) Five different electronic effect substituents (-hydrogen,-methoxyl,-hydroxyl-nirro,-amino) of porphyrins, one metalloporphyrin and two fullerene-porphyrins were synthesized through Adler reaction, Vilsmeier-Haack reaction and1,3dipolar cycloaddition reaction. The compounds were characterized by1R,1H NMR and MS.(2) Compounds TPP、TPPNO2、TPPNH2、TPPOH、TPPOCH3and CuTPPOCH3were chosen as templates to study their antimicrobial activity at different concentrations and doses of light. Plate count method was used in the experiments. In order to study the influence of metal ion complexation of copper on the antibacterial properties, compound CUTPPOCH3was also chosen as compared with compound TPPOCH3. The results demonstrated that porphyrins’ antimicrobial activity was obviously dependent on the dose of light and concentration, and was not shown in dark, which was a a prominent advantage. Among them, TPPOH had a better antimicrobial activity. When complexed with paramagnetic Cu ion at the center of the porphine ring, the antimicrobial activity decreased. Inhibitory effects of all compounds against gram-positive bacteria Staphylococcus aureus were significantly better than that of gram-negative bacteria Escherichia coli.(3) The cytotoxity of compounds TPP、TPPNO2、TPPNH2、TPPOH and TPPOCH3against human hepatoma HepG2, SMMC-7721cells and normal liver HL-7702cells was also studied. The cytotoxicity was obviously dependent on the dose of light and concentration, and was not shown in dark, which was accorded with that of antimicrobial activity. TPPOH owned significant killing ability to cells under light. No obvious selective cytotoxicity of these porphyrins was observed on these cells.(4) The molecular structures of compounds TPPNH2and TPPOH, and their radiolabeled compounds were optimized using Density Functional Theory with B3LYP method. Their Mulliken charge distribution and energy were calculated and analyzed. The most probable iodination site of compounds TPPNH2and TPPOH was forecasted theoretically.(5) Preparation conditions of131I-TPPOH and131I-TPPNH2, using chloramine-T as an oxidant, were optimized regarding pH, precursor, chloramine-T and reaction time. The radiochemical purity of131I-TPPOH and131I-TPPNH2was determined by paper chromatography. The optimized radiolabeling conditions for TPPOH were:pH5.5, TPPOH concentration2mg/mL, chloramine-T concentration0.25mg/mL, reaction temperature20℃, and reaction time15min. The optimized radiolabeling conditions for TPPNH2were:pH1.5, TPPNH2concentration2mg/mL, chloramine-T concentration3mg/mL, reaction temperature95℃, and reaction time40min. They were both stable in vitro saline and in vivo. The results demonstrated that1) the radioactivity in blood was cleared rapidly;2) they had a specific affinity to liver and lung;3) their main excretion pathway was liver;4) They showed a time-dependent accumulation and retainable characteristics in tumor. These results supported their potential value of131I-TPPOH and131I-TPPNH2for tumor therapy agents.(6) The tumor inhibition effects of131I-TPPOH and131I-TPPNH2were studied under the dual role of photodynamic and β-ray therapy. The results indicated that both131I-TPPOH and131I-TPPNH2had potential for tumor therapy. But131I-TPPOH had better tumor inhibition effect and less toxicity, and was potential as a dual-mode therapeutic agent.