Study On The Synthesis And Pharmacological Evaluation Of 8-alkyl-palmatine Derivatives

Palmatine belongs to the isoquinoline alkaloids, and it is an important active component of Common Fibraurea Stem and Rhizoma Coptidis. Palmatine have broad spectrum of biological activity, such as anticancer, antivirus, antioxidation, analgesic, anti-inflammatory, fall blood pressure etc.Because of rich biological activity and safety non-toxic side effects, Palmatine, As a leading compounds, has been often research in structure-activity research structure in recent years.To increase the pharmaceutica activity of palmatine 8-alkyl-palmatine homologues with seriate different lipophilic property were synthesized in our laboratory by introducing different length alkyl at C8 position,some pharmacological effects of 8-alkyl-palmatine homologues were studied including the antimicrobial activity, lipid-modulating effect,and toxicity. The methods and results are as follows:1. The synthesis and molecular structure identification of 8-alkyl-palmatine homologuesPalmatine as raw material, a series of different alkyl chain long 8-alkyl palmatine derivatives were synthesized through three steps, and the different reaction conditions (temperature, solvent) on the influence of synthetic production rate intermediates were research to optimize the synthetic process. The structure of 8-alkyl-palmatine homologues synthesized was affirmed with element analysis, Ultraviolet spectrum, Infrared spectrum,1H NMR and 13C NMR. 2. Antimicrobial activities of 8-alkylpalmatine and the mechanism of the interactionsAntimicrobial activities of 8-alkyl palmatine on 5 patheogenic microorga-nisms are studied with the methods of agar well diffusion and 2-fold serial dilution test.5 patheogenic microorganisms used for the antimicrobial assay are Gram-positive (G+) bacteria viz. Bacillus subtilis, Staphylococcus aureus, Gram-negative (G-) bacteria viz. Proteus vulgaris, Escherichia coli and a fungus viz. Candida albicans, respectively. The result showed that G+ bacteria were more sensitive than G bacteria and fungus. The antimicrobial activity increased as the length of aliphatic chain elongated and then decreased gradually when the alkyl chain exceeded 8 carbon atoms. 8-octyl palmatine derivative show the highest antimicrobial activity.For this the inner antibacterial mechanism, The mechanism of the interactions of palmatine analogues with bacterial protein were determined by fluorescence spectrum analytical method.The results show that palmatine derivatives of membrane protein to help the endogenous fluorescent bacteria produced strong destroy function, through the hydrophobic action to make protein conformation change, and exert its bacteriostasis.3.The lipid-modulating effect of 8-alkyl-palmatine homologues in vivoWith experimental quail as animal model, the Lipid-modulating effects of 8-alkyl-palmatine homologues are studied.30 days after feeding drugs to quail, observe the drug group serum TC, TG rats, LDL-C, HDL-C changes.Results showed that TC, TG, LDL-C of quail serum are improved after the treatment of drugs. Indicated palmatine derivatives can improve TC, TG, LDL-C level of quail serum to a certain extent.5. Preliminary study on toxicity of 8-alkyl-palmatine homologues in vivoWith kuming mouse or SD rats as animal model, the LD50 of 8-alkyl-palmatine homologues was determined according to modified karber's method,Result showed that the toxicity of 8-alkyl palmatine derivatives was stronger than that of palmatine. However, by elongating the aliphatic chain, toxicity decreased gradually.8-butyl-palmatine showed highest toxicity.8-dodecyl-berberine and palmatine have almost the same with toxic.