Synthesis And In Vitro Antitumor Activity Of β-carboline-3-carboxylic Acid Dimmers

Researchs have shown that the β-carboline alkaloid dimers which connected in different ways have good biological activity, such as inhibition of tumor proliferation, anti-malarial, inhibition of Ache/Bache, and so on. Some β-carboline dimers have a good affinity for DNA, so its anti-cancer activity was mach better than β-carboline derivatives. In addition, the study suggested that introducing suitable N9-substituent could improve its anti-tumor activity, and the aralkyl was better than tallow alkyl. In this study, We synthesized β-carboline dimers combined with N9-aralkyl modified, and tested their in vitro antitumor activity, discussed structure-activity relationships, provided the basis for further mechanism research. The results are as follows:1. With L-tryptophan as a starting material, after three steps reaction, we got β-carboline-3-carboxylate. Then it reacted with benzyl bromide, o-methyl benzyl chloride, p-methyl benzyl chloride, o-fluorine benzyl chloride respectively, we got four N9-substituted β-carboline-3-carboxylate(including three new compounds); After hydrolysis, they reacted with six dibromo compound respectively, generated 24 β-carboline-3-carboxylic acid dimer(including twenty-one new compounds). We test the physical properties of all the compounds, identified their structure by 1H NMR, 13 C NMR, ESI-MS.2. We test all dimers’ inhibition rate to human gastric cancer(SGC-7901) and human hepatoma cells(SMMC-7721) at concentration of 10 μM by MTT assay, as well as the N9-substituted intermediate compounds to SGC-7901. Then we selected compounds who’s rate above 50% for assaying IC50 values. We discovered 6 dimers(Q-1-0, Q-1-2, Q-2-0, Q-3-4, Q-4-2, Q-4-4) who have good activity to SGC-7901, their IC50 values were: 7.729 μM, 7.720 μM, 10.72 μM, 7.182 μM, 5.824 μM, 8.961 μM. We also discovered 9 dimers(Q-1-1, Q-1-2, Q-1-3, Q-2-1, Q-2-2, Q-2-3, Q-3-5, Q-4-3, Q-4-4) who have good activity to SMMC-7721, their IC50 values were: 5.53μ M, 7.153 μM, 3.496 μM, 4.718 μM, 4.228 μM, 6.681 μM, 9.844 μM, 4.659 μM, 4.587 μM. Compounds Q-1-2, Q-4-4 have excellent activity to two tumor cell, with IC50 values below 10 μM.3. Primary structure-activity relationships indicated: Most β-carboline-3-carboxylic acid dimers have better active than the corresponding monomer derivatives to SGC-7901, and N9-o-fluorobenzyl have better active than other substituents compounds; The dimers who connected with carbon chain of 3,5 carbon atoms have better activity than which connected with 4,6,8 carbon atoms; When dimers connected with even carbon, their activity to SGC-7901 were gradually reduced with the carbon chains longer. Most dimers had activity to SMMC-7721, the dimers who linked with carbon chains of 4,5,6 carbon atoms have better activity; Each dimmer series of SMMC-7721 activity were presented first enhanced and then weakening trend. The dimer which linked with carbon chains of 5 carbon atoms have a very good activity to two tumor cells, yet the dimer which linked with para-xylene almost have the lowest activity to two tumor cells.These studies indicated that β-carboline dimers have a good inhibition of tumor cell activity, some dimer have better active than monomer derivative, having great research value.