SYNTHESES AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF TAXOIDS DERIVED FROM 14-BETA-HYDROXY-10-DEACETYLBACCATIN-III

A series of new taxoids derived from 14 beta-hydroxy-10-deacetylbaccat in III was synthesized by means of the beta-lactam synthon method. Mos t of the new taxoids thus synthesized possess excellent cytotoxicity a gainst human ovarian (A121), non-small-cell lung (A549), colon (HT-29) , and breast (MCF-7) cancer cell Lines, and several of these taxoids s how subnanomolar IC50 values which are severalfold to 1 order of magni tude better than those of paclitaxel and docetaxel. Modifications at t he 3'- and 3'-N-positions exert marked effects on the activity. For th e substituents at C-3', the cytotoxicity decreases in the order 2-fury l similar to 2-methyl-1-propenyl greater than or equal to 2-methylprop yl > (E)-1-propenyl greater than or equal to n-propyl > phenyl much gr eater than 2,2-dimethylpropyl. For the 3'-N substituents, the activity decreases in the order t-BuOCO > Ph > n-hexanoyl. A significant incre ase in the cytotoxicity against the doxorubicin-resistant human breast cancer cell line MCF7-R that expresses the multidrug resistance (MDR) phenotype is observed by the proper modification of the substituent a t C-10. The observed remarkable effects of the substituents at C-10 on the activity against MCF7-R can be ascribed to the effective inhibiti on of the binding of these new taxoids to P-glycoprotein that is respo nsible for MDR.