Design,synthesis,antitumor Activity And Ct-DNA Binding Study Of Photosensitive Drugs Based On Porphyrin Framework

Objective:A series of new porphyrin-chrysin photosensitizers were synthesized by modifying the structure of the porphyrin skeleton,and the biological activity was used to evaluate the preliminary photosensitizers.By exploring the interaction mode of photosensitizing drugs and ct-DNA,understanding the mechanism of action of porphyrin-chrysin photosensitizing drugs at the molecular level will provide valuable information for the design of new targeted antitumor drugs.Methods:In this study,a series of Porphyrin-Chrysin photosensitizers have been prepared by esterification and condensation drug synthesis methods,and their structures have been confirmed by ¹H NMR,MS,and UV-vis.The DPBF method was used to evaluate the singlet oxygen production capacity of porphyrin-chrysin photosensitizers.The anti-proliferative activity of photosensitive drugs on human cervical cancer HeLa cells and human lung cancer A549 cells under light and dark conditions was evaluated by the MTT method.Using UV absorption titration,fluorescence quenching,and circular dichroism,the interaction mode of Porphyrin-Chrysin photosensitizer and DNA was explored at the molecular level.Comparative of Molecular Field Analysis was used to study the three-dimensional quantitative conformation of compounds.The molecular docking method was used to study the combination of the compound with human serum albumin?HSA?and phosphatidylinositol 3-kinase?PI3K?,and the mechanism of action between compounds and proteins.Results:In this study,singlet oxygen detection results show that all target compounds have a strong singlet oxygen generation capacity.Anti-tumor in vitro experiments showed that compound 4a-4e,5g and 5h had a good inhibitory effect on human cervical cancer HeLa cells and human lung cancer A549 cells,and their effect was significantly better than porphyrin and chrysin,and was better than the positive control drug 5-fluorouracil.Free-base porphyrin compounds 4a-4e,5a-5e bind to ct-DNA in a surface self-stacking manner,and zinc metal porphyrin compounds 4f-4j,5f-5j bind to ct-DNA in an inserting manner.The target compound can enhance the activity by increasing the positive charge,reducing the space volume,or introducing a strong electron-withdrawing group at the para position of the benzene ring at the meso position of the porphyrin.Conclusions:In this study,20 novel Porphyrin-Chrysin photosensitizers were successfully synthesized,and their proliferative activity against human cervical cancer HeLa cells and human lung cancer A549 cells was evaluated in vitro and the effect of compound-targeting DNA was studied.The results showed that the anti-tumor activity was positively correlated with the degree of DNA binding,in which compound4c showed the strongest photodynamic therapeutic effect on HeLa cells,with an IC₅₀ value of only 6.26?M,and compound 5g showed the strongest photodynamic therapeutic effect on A549 cells,with an IC₅₀ value of only13.88?M.Increasing the positive charge of the porphyrin ring and introducing a strong electron-withdrawing group at the para position of the meso position of the porphyrin ring or reducing the space volume of the compound can enhance the antitumor activity.The antitumor activity of all compounds may be deeply affected by their binding to proteins.