Absolute Configuration And Antitumor Activity Studies Of Annonaceous Acetogenins

Chemical derivatization were used to determined the absolute configuration of annonaceous acetogenins.Combining the chemical derivatization,structure-activity relationship of annonaceous acetogenins can be explored.The paper consisted of four chapters.They are review and basis,structure identification of annonaceous acetogenins,cytotoxic activity of annonaceous acetogenins,relationship of annonaceous acetogenins with multidrug-associated protein.Basing on the analysis of relevant literature,the research ideas and contents of this paper were drawn up.Section 1 review and basisThe section summarized that configuration determination plays an important role in natural product research and new drug development The theory and development of Mosher’s derivatization method has been briefly introduced,and described the relationship between Mosher’ method and ACGs structure identification combining with the structure characteristics of ACGs.Therefore,it’s completely necessary to conduct the study according to the present SAR situation of ACGs.Section 2 structure identification of annonaceous acetogeninsBy means of nuclear magnetic resonance spectrum and mass spectrometer,together with Mosher’s method,30 ACGs was identified.Eithteen compounds of ACGs were isolated and identitied from the ethylacetate extract of Annona squamosa L.in this study.In which,twelve ones are new comounds(seven of which were tested for configuration)and the other six are known.In addition,the AC of twelve other ACGs were identified including eleven compounds which have been reported without confirming AC.Into tally,this study has carried out the stereo-configurations of twenty ACGs.Section 3 cytotoxic activity of annonaceous acetogeninsThe cytotoxic activity of eighteen ACGs,including 12 new ones,was evaluated by administrating three multidrug-resistant tumor cells:SMMC-7721/ADR、MCF-7/ADR、A549/T.Compared with the positive drugs,tested compounds showed strong antitumor activity,and a few of them had good selectivity to diverse tumor cells.Vitro administration of normal cells and plate cloning experiments revealed that secondary alcohol carbon with S shows more cytotoxicity than configuration in a dose-dependent manner,but it also had a greater effect on the proliferation of normal cells.Section 4 relationship of annonaceous acetogenins with multi drug-resistant proteinThree pairs of isomeric ACGs were also used to consider the SAR by treating SMMC-7721/ADR cell line and measuring the expression of MDR1 or MRP2 protein.ACGs can inhibit the expression of drug-resistant protein in different degrees against control group.However,the relationship between configuration and the expression of protein is vague,which needs more compounds and cell lines to prove it.