| Selective anticancer therapy based on specific antigen differences between tumorand normal cells is an amazing approach. Currently, some study for therapeuticpurposes. The ideal situation is linking these antibodies to cytotoxic agents, naturaltoxins to form targeting drugs. Unfortunately, the clinical testing of these targetingagents is not successful. The reason is a poor uptake of the antibody connected to thetoxic agent and a limiting factor that some malignant cells in the tumor tissue areantigen-negative.Therefore, these cells would not be destroyed. Antibody-directedenzyme prodrug therapy(ADEPT) is designed to overcome both problems. Anantibody directed against a tumor-associated antigen is linked to an enzyme and givenfirst. After antibodies bind to the antigens expressed on the surface of tumor cells andthe antibody-enzyme conjugates accumulate in the tumor , a prodrug is given, whichis converted to an high active cytotoxic drug by the enzyme to kill tumor cells. Thestudy for ADEPT was not reported in China.Toxoflavin was a natural antibotic compound. Recently, toxoflavin and itsanalogs were identified that they might novel anticancer agents. However, there arestill several limitations for its clinical use because of high toxicity and poor solubility.As glycosylation usually increases the solubility and changes the activities of thecompounds, therefore it is possible to overcome these drawbacks. Eight novel6-demethyl toxoflavin glycosides, which are potential prodrug in antibody directedenzyme prodrug therapy(ADEPT),were synthesized. We carry out the enzymologyand anticancer in vitro research. The prodrugs for ADEPT were screened out by thisway.The main results obtained from this work are as fellows:1.Eight novel toxoflavin glycosides, which are potential prodrug in antibodydirected enzyme prodrug therapy(ADEPT),were synthesized and namedGDT,GXT,LDT,LXT,GYET,GYST,LYET,LYST. Eight aldehyde glycosides werefirstly prepared using Koenigers-Knorr method by phase-transfer catalysis ,and thenthe aldehyde glycosides coupled with 3-methyl-6-(1`-methylhydrazino)-uracil inacetic acid to from imines, which reacted with sodium nitrite to form the ring oftoxoflavins.The final products of above reactions are the mixtures of 6-demethyltoxoflavins and 4-oxide 6-demethyl toxoflavins which were transformed to6-demethyl toxoflavins by reduction using hyposulphite. The synthesized 6-demethyltoxoflavin glycosides were treated with sodium methoxide in methanol to removeprotected gruop. Eight 6-demethyl Toxoflavin glycosides were proved to behomogeneous after being checked by HPLC,and their structure were identified byNMR,IR,and UV.2.Glycosides GDT,GXT were hydrolyzed byβ-Glucosidase to give aglyconesand monosaccharides, while glycosides GYST,GYET,LYST,LYET,LDT,LXT werequite stable treating in same conditions. This results showed that β-Glucosidasehave a high optic selectivity.The structure of GDT and GXT were similar , GYET andLYST were similar. The 6-demethyl Toxoflavin glycosides GDT and GXT can behydrolyzed byβ-Glucosidase, but GYET and LYST can be not. This results showedthat the stucture of aglycons was important for β-Glucosidase, meanwhile,the speedof GDT was quick than GXT byβ-Glucosidase hydrolysis.3.The anticancer activites of Eight 6-demethyl toxoflavin glycoside wereanalysis by cancer HCT-15 cell line in vitro,the results indicated that cancer HCT-15cell can not be inhibited . 6-demethyl toxoflavin glycoside GXT was IC50=4.6ug/mlfor cancer Hep-G2 cell line in vitro byβ-Glucosidase hydrolysis. GDT wasIC50=6.7ug/ml for cancer Hela cell line in vitro byβ-Glucosidase hydrolysis.
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