Cytoxic Activities Of Harmine Monomer Derivatives And 3 Sesquiterpene Lactones

Nowadays, Cancer is one of the major diseases with a strong threat to body health and life quality of human beings all over the world. Screening the leads with potent anti-tumor activity from the natural resource of the product library, and structure optimization with efficacy group modification based on the skeleton template, is one of the important route to to develop efficient and safe anticancer agents.The present experimental research has two parts ongoing work:(1) Three sesquiterpene lactones including Ivalin, Telekin and Carabrone, which are typical sesquiterpene lactones of Carpesium macrocephalum Franch. et Sav. separated by our group in recent years, were used to investigate thier effect on the tumor cell apoptosis by the morphology, Flow cytometry and other methods. (2) Based on the harmine skeleton template, a series derivatives were to synthesized by the strucutre modification in positon N2and position N9 with alkyl groups and substituted benzyl groups. Their anti tumor cell activities were also to be investigated, with the structure-funcion relationship analysis. these will provide clues to develope more efficient antitumor agents.According to our present results, the results were as the follows.1、Effects of Three sesquiterpene lactones including Ivalin, Telekin and Carabrone on the tumor cell apoptosisSesquiterpene lactones have anti-tumor,anti-ulcer, anti-inflammatory, anti-fungal, cell toxicity and neurotoxicity. Ivalin, telekin and carabrone of the lowest effective concentration of apoptosis of L1210 were respectively 2×10-6mol/L, 1×10-5mol/L, 1×10-5mol/L. Study on primedinsitulabeling and flow cytometry showed that apoptosis effect of Ivalin on was best and LNCaP cell was sensitive. The results of IC50 showed that the effect of Telekin was most active on cell L1210 and MCF-7 and that the effect of Ivalin was most active on cell PC-3 and LNCaP, of which half lethal concentration were 25μmol. L-1,14.0μ mol. L-1,30.4 μ mol. L-1 and 33.5 μ mol. L-1, respectively2、Synthesis of harmine mono alkaloid derivatives and theis cytotoxityβ-carboline alkaloids are a class of widely distributed in nature by the indole ring and pyridine ring consisting of alkaloids, with broad spectrum and significant of biological activity, such as anti -tumor, anti-anxiety, antidepressant, sedative, anti- parasites, some as a acknowledged neurotoxin involved in the development of neurodegenerative diseases. Thereforeβ- carboline alkaloids are paid widespread attention. In this paper, first, fragmentation pathways of three alkaloids, harmaline, harmine and vasicinone were investigated by electrospray ionization multi-stage tandem mass spectrometry. secondly, a novel sensing system based on the β-carboline core has been designed and synthesized for Hg2+ detection in water. The result anti-tumor activity and the mechanism of harmine derivatives were studied:(1)Fragmentation pathways of three alkaloids, harmaline, harmine and vasicinone were investigated by electrospray ionization multi-stage tandem mass spectrometry。ESI (positive) mass spectrometry showed that three β-carboline alkaloids of quasi-molecular peaks were produced and three alkaloids under electrospray ionized mode were all [M+H]+ through its first order mass spectrum. multi-stage mass spectrometry by 35% bombardmentenergy showed that fragment ion were rich with similar fragmentation pattern and some interesting neutral losses were found. methyl free radical were draw off through the second order MS and CO were draw off through the third order MS.(2) A novel sensing system based on the β-carboline core has been designed and synthesized for Hg2+ detection in water. We have demonstrated that a straight forward methodology can provide rapid, sensitive and selective recognition (cross-contamination experiments) for Hg2+ over a wide pH range.The vivid fluorescence change from blue to colorless can be clearly discriminated by the naked eye.Furthermore, there is a good negative correlation between the fluorescent intensity and the concentration of Hg2+ in the range 1.0 ×10-6 M to 7.0 ×10-6 M. β-Carboline as a fluorophore synthesized via this route also provides a new strategy for the design of novel fluorescence probes and fluorochromes.(3) Tree series derivatives with chemical reaction on the different sites of N9 and N2 of harmine as precursor compound. The activity of compounds obtained were tested using antitumor activity in vitro, and structure-function relationship was analyzed. We designed and synthesized 44 derivatives of harmine, of which 38 compounds were the first time to report. Their structures were characterized by ESI-MS,1H-NMR,13C-NMR. These compounds have more ability to induce cancer cell (SGC-7901,HL-60,A-549) apoptosis under the test cell apoptosis under the concentration of 10 μM.In conclusion, The results above demonstrated that the apoptosis effect of sesquiterpene lactones on cell L1210 PC-3 and LNCaP was compared and evaluated, which is meaningful for further study on the mechanisms within.Fragmentation pathways of three alkaloids by electrospray ionization multi-stage tandem mass spectrometry summarized the identification of these compounds by electrospray ionization mass spectrometry method. A water-soluble fluorescence probe have been developed by incorporating a β-carboline fragment with a dithioacetal.β-carboline as a fluorophore has potential for the design of novel fluorescence probes.The position N2 and position N9 on th eβ-carboline core structure modificated with alkyl groups and substituted benzyl groups are important active sites of the compounds of this kind. The optimal active derivatives could be obtained through this modification.