Synthesis Of Beta-carbolines Dimmers And Their Anticancer Activity Evaluation

Cancer is one of the main diseases which threat to human health and life.At present,seeking compounds with antitumor activity from natural drug,and carrying on the structure of the modification is an important way to research and develop antineoplastic drugs.In our country treatment for gastric cancer with Peganum harmala L.seeds has a history of nearly 30 years.But the range of application of Peganum harmala L.seeds is limited to a great extent due to their toxicity.We screened three kinds of ?-carbolines with good antitumor activity from Peganum harmala L.on the basis of the early stage of the research work.We synthesized three series derivatives with chemical reaction on the different sites of N9,k7,and N2.The activity of compounds obtained were evaluated using antitumor activity in vitro,and structure-function relationship was analyzed as well.The mechanisms of inducing cancer cell apoptosis of those compounds were assessed,which provided the necessary data to support the development and utilization of these compounds.1.105 derivatives were designed and synthesized by a multiple step synthetic procedures,of which 80 compounds were the first time to report.Their structures were characterized by ESI-MS,1H-NMR,13C-NMR.X-ray single crystal analysis is used to confirm the structure of three compounds.2.The cytotoxic activities of all the synthesized compounds in the concentration of 10 ?M were evaluated against to MCF-7,SGC-7901,SMMC-7721,Hela,HL-60 and A-549 by the MTT assay.Sensitive cells were selected for IC50 value concentration test.We succeeded to find several kinds of compounds with outstanding activity,which are much better than positive control agent taxol.These compounds have further researched value and potential application prospect.Compounds of D48,D52,D91 and D108 showed excellent activity to HL-60 with the IC50 value as followings:5.38 ?M,5.39 ?M,1.35 ?M and 0.93 ?M,while taxol was 3.01 ?M.Compounds of D37,D51,D52,D57,D77,D81,D82,D91,D96,D103,D106 and D108 showed excellent activity to A-549 with the IC50 value as followings:4.65 ?M,4.53pM,5.39?M,9.71 ?M,5.94 ?M,3.47 ?M,2.18 ?M,3.23 ?M,3.86 ?M,0.084 ?M,0.84 ?M and 1.94?M,while taxol was 2.46 ?M.D76 showed excellent activity to SGC-7901 with the IC50 value of 7.54?M,while taxol was 3.01 ?M.3.Study on structure-activity relationship,2-pot and 9-pot are important active sites of this kind of compounds.Better active derivatives could be obtained through modification which is 4 C atoms,benzyl or 8 C atoms in the link section,with a strong activity.4.These compounds have certain ability to induce cancer cell apoptosis under the test cell apoptosis.Compounds of D4,D42,D65 and D95 at the concentration of 5?M showing activity to SGC-7901 for cell apoptosis rate after 48 h as following:16.87%,13.66%,7.36%and 6.09%.And cell cycle was blocked in the S or G2/M phasesThe results showed that it was an effective method for developing and synthesizing the dimer derivatives compounds for ?-carboline alkaloids compounds as a template.And this kind of derivatives can induce tumor cell apoptosis,and cell cycle retardation occurred in S phase and G2/M phase.Therefore,dimerization of ?-carbolines is an effective methods to develop these compounds.