Synthesis, Antibacterial And Anti-tumor Activity Evaluation Of Matrine Derivatives

The development of new antibacterial and anticancer therapeutic agents is one of thefundanmental goals in medicinal chemistry. In the efforts to develop the better antibacterialand anticancer drugs, some scientists focus their interest on the modification andtransformation of the structure of natural products, which was important to the research anddevelopment of new drugs now.Matrine is one of the Chinese herbal medicine, it possesses a wide range of biologicalactivity. In China, matrine injection has been used for the treatment of hepatitis and matrinesuppository cures naginitis and cervicitic. In this article, we opened the D ring of matrine, andgot matrinic acid, we modified matrinic acid at the12-position and on the carboxyl group.Nine new matrinic acid derivatives (5a–5i) were synthesized using commercially availablematrine as a starting material in a four–step reaction. The structures of all synthesizedcompounds were confirmed by mass spectrometry,1H-nuclear magnetic resonance (NMR)spectroscopy, and13C-NMR spectroscopy. The resulting spectra showed identical signals forthe functional proton groups of the prepared compounds.Minimum inhibitory concentrations (MIC) detected antibacterial activity agaistGram-positive bacterials (Staphyloccocus aureus, Pseudomonas aeruginosa) andGram-negative bacterials (Escherichia coli, Bacillus subtilis). Among these derivatives,matrinic acid didn’t exhibit an increased antibaterial,12-benzyl-matrinic acid butyl ester (5e)was found to exert the best antibacterial activity, with the MIC value of125or250μg/mL.Other derivatives showed better antibacterial than matrine.The anti-tumor activities of these derivatives were investigated by3-(4,5-dimethylthiazol-2-diphenyl-tetrazolium) bromide (MTT) assay against humanmalignant melanoma (A375), human lung adenocarcinoma (A549), human cervical carcinoma(HeLa) and human hepatocellular carcinoma (HepG2) cells. The results demonstrated that (i)the amide bond on the carboxyl group may be required for anticancer activity,(ii)introductionof cyclic amine substituents to the carboxyl group can significantly enhance anticanceractivity,(iii) conversion of the carboxyl group to its ester derivatives can also improve anticancer activity, and (iv) increasing the lipophilicity of matrinic acid esters can enhanceanticancer activities against the four cancer cell lines tested. Among the derivatives,5e and5iexhibited the highest activities against the four cancer cell lines，with the IC50value of37.0~78.9and59.3~89.2μg/mL.We deduced that the amide bond of matrine have an impact on its antibacterial andanti-tumor activity. However, the inscreasing of the alkyl chain of matrinic acid ester canimprove their antibacterial and anti-tumor activity. So5e will be a potential antibacterial andanti-tumor agent.