SYNTHESES AND STRUCTURE-ACTIVITY RELATION SHIP OF PODOPHYLLOTOXIN DERIVATIVES AS POTENTIAL ANTICANCER DRUGS

Thirteen new 4 beta-substituted podophyllotoxin derivatives 5-17 were synthesized and their structures were confirmed by IR, MS, H-1 NMR and ESR as well as elementary analysis. All new compounds were evaluated for their anticancer activity against mouse leukemia P388 and human st omach carcinoma SGC-7901 cells in vitro, Compounds 5, 7-10 exhibited a remarkable inhibition activity against both P388 and SGC-7901 cells, In a structure-activity comparison it was found that 4'-O-demethylpodo phyllotoxins 5, 10-13 showed a superior activity to the corresponding 4'-methoxy analogues 6, 14-17 lacking a free OH group at C-4'. The rep lacement of the ''-NH-'' bridge at C-4 with the ''-O-'' bridge resulte d in lowering of the anticancer activity. These results demonstrate th e possibility of considerable simplification in the sugar structure of VP-16 and the importance of 4'-phenolic hydroxyl group, and suggest f urther elaboration of 4 beta-nitrogen-containing substitutient to opti mize the structure of this class of anticancer compounds.