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Studies on Designation and Synthesis of the Leading Compound Desmosdumotin C Derivatives

Author: HuChunMei
Tutor: WuJiuHong
School: PLA Military Academy of Medical Sciences
Course: Medicinal Chemistry
Keywords: Active lead compounds The hairy leaves false Yingzhaosu C Derivative synthesis Anti-tumor effects Biogenic doctrine
CLC: R914
Type: Master's thesis
Year: 2007
Downloads: 81
Quote: 1
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Abstract


Mao Ye fake Yingzhaosu C is from the the Annonaceae (Annonaceae) Desmos genus (Desmos Lour) leaves the Desmos root hair isolated a natural new skeleton compounds with anti-tumor activity. The compounds in vitro anti-tumor activity test showed that it has a variety of tumor cells was significantly inhibited. Therefore, we choose Ktze the false Yingzhaosu C its derivatives for the synthesis of lead compounds and some of these compounds in vitro anti-tumor activity test, the antitumor activity in vivo tests carried out on the the hair leaves false Yingzhaosu C. The research laid the foundation for the further synthesis of new derivatives and further research activity screening. The main research work and results, including the following aspects: 1. According to a preliminary study of the instructors, the lead compound selected of false Yingzhaosu C Ktze as subject, inverse synthetic analysis and literature through the compound to determine the derivatives of the synthetic route. 2. We choose the 2,4,6 - trihydroxyacetophenone as the starting material by chemical synthesis method is carried out on the the hair leaves false Yingzhaosu C total synthesis, structural modification and transformation, similar chalcone structure derivatives H1-1 ~ H1-9 and H2-1 ~ in H2-5. Flavonoids easy to get chalcone compound under acidic conditions, while the the hairy leaves false Yingzhaosu C structure similar to chalcone, so different acidic cyclization reaction, get their ring derivatives H3-1 -1, H3-1, H3-2-1, H3-3-1 and H3-?-2. More than a total of 19 synthetic compounds, application 1 HNMR analysis of all of the compounds, MS and elemental analysis method to confirm some of the compounds, confirmed the structure of the compound. 3. For the anti-tumor activity of the studied compounds, in vitro anti-tumor activity screening. MTT, observed pre-synthesized Compound 10 (H1-1, H1-2, H1-4, H1-5, H1-6, H2-2, H2-3, H2-4, H2-5 and H3 -2-1) tumor cells HL-60 (human leukemia cell line) and MOL-4 (human leukemia cell line) inhibition. The test results show that the majority of compounds of the two kinds of tumor cells are active, including H1-1, H1-2 and H1-4, H1-5 and H2-2, H2-3, H2,-4. H2-2 at a concentration of 10 -5 mol / L when the inhibition of HL-60 was 99.3%, the compound of the highest inhibition rate of HL-60 cells. H2-4 at a concentration of 10 -5 mol / L when the mol-4 cell inhibition rate was 83.0%, and the the highest compound MOL-4 inhibitory rate. Preliminary QSAR: bromine substituted benzene ring ends are the compound increased activity; the position of substitution of the fluorine on the benzene ring have a greater impact on the activity of the compounds; furan ring substitution on the benzene ring so that the compound decreased activity; compound after the cyclization activity. reduced. 4. Activity in vivo tests examine the observed false Yingzhaosu C Ktze in vivo S 180 solid tumor growth inhibition and toxicity of. The test results show that the hair leaves false Yingzhaosu C mice transplanted tumor S 180 inhibition and acute toxicity of small. In 2.5mg/kg, 5mg/kg and 10mg/kg three dose groups Ktze false Yingzhaosu C S 180 average inhibition rate of solid tumors were 30.18%, 43.16% and 47.02 %. The acute toxicity test shows of the compound LD 50 = 46.0 (39.8 - 53.1) mg / kg,. 5. The genus the plant flavonoids literature research Desmos, the genus flavonoids in the structure have the following common characteristics: B-ring unsubstituted A-ring wholly replace the (individual trisubstituted), contains more than half of A acyl group, and the presence of flavonoids, chalcone flavanone three forms. Biotransformation of flavonoids in the genus are discussed based on the research of the flavonoids students relationship, and biotransformation pathways of these compounds to form 6: flavanone 2'-hydroxy chalcone intermediates 8-substituted group interchangeable isomer; oxidized to form a β-hydroxy chalcone flavanone oxidase; the β-HYDROXYCHALCONE chalcone ring combined to form a 2 - hydroxy-flavanone; 2 - hydroxy-dihydro- flavonoids dehydrated to form flavonoids. The conversion of channels, including the case of most of the flavonoids in the plant. The other hand, the synthetic hair leaves false Yingzhaosu C ring derivative of the compound obtained is not designed compounds, due to the resulting product with the compound structure of the design has some similarities, therefore, the reaction mechanism also conducted discussed. On the basis of literature research, design and synthetic hair leaves the false Yingzhaosu C derivatives, 19: 10 compounds in vitro anti-tumor activity test, most of the compounds are active, the experimental design is reasonable; hair leaves preliminary study the false Yingzhaosu C vivo antitumor activity, further confirmed the value of the compound; students relationship of an idea for the synthesis of hairy leaves false Yingzhaosu C derivatives - get a class cyclized derivatives may provide wider screening for the study of the structure-activity relationship. The research laid the foundation for the further study of the synthesis of new derivatives and activity screening, to achieve the purpose of the experiment is expected to study basic.

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