Studies On Designation And Synthesis Of The Leading Compound Desmosdumotin C Derivatives

Desmosdumotin C, isolated from Desmos dumosus (Annonaceae) , is a novel compound with unique structure, which shows significant and selective cytotoxicity in vitro. It can inhibit several tumor cells' growth. So we selected Desmosdumotin C as the leading compound and synthesized some derivatives of this compound. To evaluate the activity of these compounds, anti-tumor effect of 10 derivitives on two cell lines (HL-60 and MOL-4) in vitro was investigated by the methold of MTT. On the other hand, anti-tumor effect of Desmosdumotin C in vivo was also studied. This is a good foundation for the further synthesis of Desmosdumotin C derivatives and anti-tumor activity screening.The paper includes five parts illustrated below:1. Based on the previous research done by the advisor in this subject and comprehensive analysis of the literature, Desmosdumotin C is selected as the leading compound. Analysises of the inverse synthetic compounds are made to identify the synthetic route for Desmosdumotin C derivatives.2. According to the study of this subject in these years, Desmosdumotin C and its derivatives are synthesized by a chemical method. In this way, 2,4,6-trihydroxyaceto-phenone is used as starting material. Because Desmosdumotin C is similar to chalcones in structure, which can be translated into flavone in acid condition, some derivatives with closed ring C can also be synthesized in acid condition. Totally, we get 19 compounds, which are H1-1 to H1-9 , H2-1 to H2-5, H3-1-1, H3-1, H3-2-1, H3-3-1å’ŒH3-3-2 .The structures of these compounds are established mainly by 1H NMR, MS.3. To study the activity of these compounds, the anti-tumor effect of 10 derivitives on two cell lines (HL-60 and MOL-4) in vitro is investigated by the methold of MTT. The result shows that most of these compounds (H1-1, H1 -2, H1-4, H1-5, H2-2, H2-3, H2-4, H2-5) have inhibitive effect on two cell lines. When the density of H2-2 is 10^5-mol/L, its inhibition ratio on cell HL-60 is 99.3%, which is the most effective one among these compounds. On the other hand, H2-4 is the most effective one on cell MOL-4 and its inhibition ratio on cell MOL-4 is 83.0%.We can get some conclusion by the basic study of the structure and activity relationship, that is the activity of compound substituted by bromine in benzene ring increases, the situation of fluorine in benzene ring has an effect on the activity, benzene ring substituted by furan down cut down the activity and compounds with closed ring C have lower activity.4. At the same time, we made some study on anti-tumor effect of Desmosdumotin C in vivo. The result shows that Desmosdumotin C has inhibitive effect on S₁₈₀ solid tumor and has low acute toxicity. Average inhibition ratio on dose of 2.5mg/kg, 5mg/kg and 10mg/kg are respectively 30.18%, 43.16% and 47.02%. Acute toxic experiment shows that LD50 is equal to 46.0 (39.8⁵3.1) mg/kg.5 Finally, the bio-relationship about the flavonoid from Desmos is discussed based on the study of these compounds, because there are some common characteristics among them, that is most of these compounds have an unsubstituted B ring and a completely substituted A ring, several compounds contain an aldehyde group on the A ring, which is quite rare in natural products. According to the bio-relationship study of the flavonoid, we get some conclusions about biotransformation of flavonoid from Desmos. Flavanone can form 6,8-substituent group exchanged isomers with 2'- hydroxy chalcone as intermediates. Flavanone can be oxidated intoβ-hydroxy chalcone in the role of oxidase.β-hydroxy chalcone can form cyclized 2-hydroxy flavanone and 2-hydroxy flavanone dehydrated into flavone. This biotransformation includes most of the flavonoid from Desmos. According to the bio-relationship study of the flavonoid, we also synthesized some compounds with closed ring C which are not those have been designed, but these synthetic compounds and designed compounds still have some common characteristics. So we discussed the bio-relationship of these compounds and discussed the mechamism of the reaction. Maybe this discussion can provide some evidences for the further research.In conclusion, we have designed and synthesized 19 derivatives of Desmosdumotin C and some of them can inhibite cells growth in vitro, which demonstrate that the designation for the experiment is sensible. The study on anti-tumor effect of Desmosdumotin C in vivo confirms the value of study on the research. The discussion about bio-relationship of flavonoid provides an idea on synthesis of derivatives of Desmosdumotin C, which can get some derivatives with closed ring C. These compounds can provide a broader scope of screening for the study of structure-activity relationship.