Synthesis And Antitumor Activity Evaluation Of Porphyrin Derivatives

Early in1940s, the scientists had found that hematoporphyrin can selectively be concentrated in thetumor tissue. And then, studies have also confirmed the characteristics of porphyrins that it canconcentration in the tumor cell. In other words, porphyrin compounds with the function of targetedpositioning on the tumor cells. The difficulties of cancer treatment lie in tumor metastasis. During thetransfer, the tumor cells attacked the surrounding tissue constantly, degradated the extracellular matrix andcaused the spread of cancer. Researches have shown that: in tumor tissue, the The matrixmetalloproteinases (MMPs) always over-expression, especially the MMP-2and MMP-9have a closelyrelationship with tumor metastasis. At present, due to poor selectivity, there are some adverse reactions inclinical practice.According to the characteristics of porphyrin compounds, we use the principle of MMPI design,designed and synthesised seven potential selectivity MMPI， and conducted a preliminary study on thebiological activity，expect to filter out the compounds which have selective anti-tumortransfer function.The main contents were sunmmarized as following:(1)Introduced the targeted positioning mechanism of the porphyrin compounds on tumor cells and themodify strategies of matrix metalloproteinase inhibitor structural. Summaried porphyrins anticancer drugsand matrix metalloproteinase inhibitors’ and research progress.(2) Accroding to the principles of drug flattening in drug design, use porphyrin as the carrier structureby introduction the possible MMPI groups, we designed and synthesized a series porphyrin-ferulic acidsand sulfur-containing porphyrin derivatives, and characterized their structures by1H NMR, UV, MS andElemental analysis.(3) We carried out a preliminary study on the porphyrin compounds interaction with tumor cells byMTT assay. Studies have shown that all the porphyrins and its derivatives inhibit the growth of Hela andBel-7402cells, and showing a concentration-dependent. Their IC50values with Hela and Bel-7402cellswere: compound A2,10.93μmol/L,13.58μmol/L; compound A1, A3, A4, A5are all during100-150μmol/L;But their don’t have a obvious selective differences between Hela and Bel-7402tumor cells. Thiolporphyrin compounds: compounds B2, B3, B4, inhibition concentration of both tumor cells IC50values arebelow100μmol and especially, the IC50values of compound B4were43.47μmol/L and40.41μmol/L, inorder of the IC50values are B1> B2> B3> B4.(4) We determined the influence of these compounds on the tumor cell NO release. The experimentalresults show that: With the increasing compounds concentration, the content of NO release by the tumorcells are different, showing the concen-tration-dependent. Overall, compound A1and compound A4own thebetter ability to promote the tumor cells to release NO, the NO releasing were about500(mmol/L)/g, and other compounds remained in the ranges100-300(mmol/L)/g. The ability of promote cell release NO isroughly the same between Hela and Bel-7402cells, there was no specific selectivity.(5) By SDS-PAGE gelatin zymography electrophoresis assay, we studied the porphyrin and their ferulicacid derivatives’ ability of inhibit gelatinase in Hela cells. The experimental resuLts show that theporphyrin and their feruLic acid derivatives on the molecuLar weight gelatinase in72KD has a specificselectivity, and the enzyme activity decreased gradually with increasing compounds concentration.