Synthesis And Characterization Of Porphyrins Containing Nitrogen Mustard And Piperazine Derivatives Substituents And Investigation On Their Biological Activities

Porphyrins can enrich around the cancer tissues and have special binding activity toward malignant cells, while nitrogen mustard and piperazine derivatives are two kinds of drugs clinically used. It was possible to get porphyrin compounds with higher anticancer activity and specification toward malignant tissues if they were combined with nitrogen mustard and piperazine derivatives into one molecule. But the key to get such kind of compound is synthesis. The yields of the total synthesis of the porphyrins containing nitrogen mustard and piperazine derivatives would greatly influence the study and application of the compounds. So this thesis is centered on the route and method of synthesizing such kind of porphyrins. According to the theory and methods of drugs design(designing analog design and combination principles), the aim of this thesis is to design and synthesize new compounds containing antitumor groups, including 18 kinds of porphyrins bearing nitrogen mustard and piperazine derivatives, and to preliminarily investigate their bioactivities and anticancer activities toward liver cancer cells . Details as follows:1. Total syntheses of 18 kinds of new porphyrins containing nitrogen mustard and piperazine derivatives. 12 kinds of new intermediates were also synthesized during the total synthesis. Six kinds of halogenoalkylamino benzaldehydes had been synthesized via modified alkylation of aniline using epoxides, chlorination and formylation. It was not reported yet that benzaldehydes containing polyhalogeno alkylamino and substituted amino groups with strong alkalescence via Vilsmeier Reaction. Modified Vilsmeier Reaction was developed to synthesize corresponding benzaldehydes in relatively high yields.2.Modification of presently synthetic methods of porphyrins was also made to synthesize substituted porphyrins via condensation of substituted benzaldehydes and pyrrole. Due to the hydrolysis of halogenoalkylamino and reaction of halogenoalkyl and pyrrole and polypyrrole, it was impossible to obtain the desired substituted porphyrins using Adler method which used propanoic acid as solvent under reflux condition. Substituted porphyrins were synthesized in high yields by modification of Lindsey method that was suitable for synthesis of porphyrins containing nitrogen mustard andpiperazine derivatives, which was not reported yet. If using the typical methods of Adler and Lindsey, it was very difficult to prepare such kinds of porphyrins using direct condensation of substituted benzaldehydes and pyrrole and it was impossible for preparation of piperazinyl porphyrins. Therefore, proper procedure had been developed to synthesize such kind of porphyrins via modification of Lindsey method such as changing the catalyst, increasing the ratio of pyrrole to substituted benzaldehydes, extending the reaction time, controlling the reaction temperature etc.3. Investigation of the biological activities. Fluorescence spectra were used to study the interaction between porphyrins and Bovine Serum Albumin (BSA). Research results showed that porphyrins could bind to BSA to form steady complexes by hydrophobic force. In order to examine the anticancer activities of porphyrins containing nitrogen mustard and piperazine derivatives, liver cancer cells were cultivated to measure the activities of porphyrins using MTT method. Relationship between structure and activities was studied by investigation of anticancer activities of substituted porphyrins toward malignant tissues such as liver cancer cells.