Synthesis And Biological Activity Of Some Bile Acid-based Camptothecin Analogues

16new Bile acid-based Camptothecin (CPT) Analogues were synthesized, the compounds with camptothecin as the cytotoxic warhead and bile acid as the tumor recognition moiety. The structures of16new camptothecin (CPT) analogues were identified by H1NMR, MS, IR.In an attempt to improve the stability of lactone E-ring of CPT in vivo and the selectivity to hepatoma and colon cancer cells and evaluate the effect of different link chains to the biological activity of the new analogues, based on our previous experiment,16bile acid-camptothecin analogues with four different link chains were prepared by facile nucleophic substitution, esterification or admiration with high yields, simple the after and short reaction time.The cytotoxicity activities were investigated by MTT assay in vitro. The result showed that the compounds introduced bile acid into20-hydroxyl of CPT were good inhibition against human colon cancer cells (HCT-116); strong inhibition that nearly equal activity of CPT against Human hepatoma cells (SMMC-7721), including the compound G4that is less4times than the IC50value of CPT; lower sensitivity on human breast cancer cells (MCF-7) compared with CPT. The inhibit activities of CPT against the tree tumor cells is very close and this show the selectivity of bile acid-based camptothecin to the cells. Moreover, the different link and bile acid have effect to the antitumor activity of the new analogues.The compound E2was selected for the fluorescence and phase contrast image experience, because the SMMC-7721IC50of it is less416times than the MCF-7IC50. The images indicated that E2does accumulate in the SMMC-7721cancer cells, and this suggested introducing bile acid to20-hydroxyl of CPT could greatly increase the activity of the new compound entering into SMMC-7721.The preliminary antitumor activity studies in vivo of these compounds were evaluated against mouse liver adenocarcinoma H22, compared with that of HCPT. The activities of compounds G4are better than HCPT. The toxicity of these compounds introduced bile acid to20-hydroxyl of CPT is lower than HCPT.The stability of active lactone was detected in rat blood serum. Compared with camptothecin, the stability of these derivatives was significant improved.Introduced bile acid groups in10or20-position of CPT can improve the stability of lactone E-ring of CPT in vivo. The introduction of bile acid in20-position of camptothecin could decrease the toxicity in vivo and improve the selectivity to hepatoma cells...