Synthesis And Anti-tumor Application Of Dehydroabietic Acid Pyridine Ruthenium Complexes

Objective:Cancer is currently one of the major diseases that plague mankind.Platinum drugs play an outstanding performance in anti-tumor clinical,but their severe side effects and drug resistance limit their wide use.In order to improve the side effects and drug resistance of platinum drugs,based on the active skeleton of rosin,the coordination function of thiodicarboxylic acid and the potential anti-tumor activity of ruthenium pyridine,a new type of high efficiency and low toxicity is developed to improve the clinical shortcomings of platinum drugs.Dehydrorosin-piperazine thiodicarboxylic acid-pyridine ruthenium anti-tumor complex.Methods:Using dehydroabietic acid as a raw material,chlorinate dehydroabietic acid in dichloromethane solution of oxalyl chloride,and then condensed with N-boc-piperazine in dry dichloromethane in the presence of triethylamine,and Under the action of tetrafluoroacetic acid,boc is removed to produce dehydrorosin piperazine 4,and then a series of dehydrorosin piperazine-dithioformic acid derivatives（5a-5i）are synthesized through condensation reaction,and a complex is selected from it.The complex was coordinated with a series of pyridine ruthenium intermediate complexes,and five dehydrorosin-piperazine dithioformic acid-pyridine ruthenium complexes（6a-6e）were prepared.The structures of all compounds were confirmed by ¹HNMR,¹³CNMR and ESI-MS;MTT experiments were used to determine the effects of the compounds on T-24（human bladder cancer cells）,Hep G-2（human liver cancer cells）,and 3T3-L-1（embryo fibroblasts Cells）,MGC-803（human gastric cancer cells）,A549（human non-small cell lung cancer cell line）,A5449-DDP（cisplatin-resistant human non-small cell lung cancer cell line）,CNE-2（nasopharyngeal carcinoma cells）,MDA-MB-231（human breast cancer cancer cells）and A2780（human ovarian cancer cancer cells）,and the inhibitory activity of representative complex 6a on human bladder cancer cells T-24 tumor xenografts in nude mice was further determined.Finally,through Hoechst-33258 staining,ROS staining,Ca²⁺staining,comet staining,AO staining,cell cycle distribution,apoptosis and Western blotting,the anti-tumor mechanism of complexes 6a and 6c was studied.Results:Nine novel dehydroabietic acid piperazine dithiocarbamate derivatives and five novel dehydroabietic acid piperazine dithiocarbamate-pyridine ruthenium metal anti-tumor complexes were synthesized.The results of MTT experiment showed that the inhibitory activity of compound 5a-5i on selected tumor cell lines is not ideal.Complexes 6a,6c and 6d have excellent cytotoxic effects on selected cell lines,with IC₅₀ of 1.19±0.88～5.16±2.91μM,1.00±2.21～5.534,respectively.The range of±0.81μM and 2.93±0.79～52.68±1.72μM.Among them,the IC₅₀ of complexes 6a,6c and 6d to MGC-803,T24,Hep G2,CNE-2 and MDA-MB-231 are all lower than cisplatin,indicating that the activity is better than cisplatin.In addition,complexes 6a and 6c have no obvious drug resistance to A549-DDP cells,with IC₅₀ values of 2.610±1.86μM and 3.527±2.35μM,respectively.T-24 human ovarian cancer transplantation nude mice tumor inhibitory activity experiment showed that the inhibition rate of 6a at high dose was 43.0%（p<0.001）,which was equivalent to cisplatin（47.3%,p<0.001）.Mechanism studies have shown that complexes 6a and 6c can cause DNA damage,block the T-24 cell cycle in G1 phase,induce apoptosis,and be accompanied by down-regulation of the expression level of anti-apoptotic protein Bcl-2 and pro-apoptosis The up-regulated expression level of protein Bax.Conclusions:Synthesized nine new dehydrorosin piperazine dithiocarbamate derivatives and five new dehydrorosin piperazine dithiocarbamate-pyridine ruthenium complexes,of which 6a and 6c showed excellent anti-tumor activity.The inhibitory activity of some tumor cell lines is even better than that of cisplatin,and there is no obvious drug resistance to A549-DDP cells;6a and 6c induce DNA damage to promote cell cycle arrest in G1 phase and induce cell apoptosis;The study demonstrated that based on the active skeleton of rosin,the coordination function of thiodicarboxylic acid and the potential anti-tumor activity of ruthenium pyridine,and improved the clinical shortcomings of platinum drugs.