SYNTHESES AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF THE 2ND-GENERATION ANTITUMOR TAXOIDS - EXCEPTIONAL ACTIVITY AGAINST DRUG-RESISTANT CANCER-CELLS

A series of new 3'-(2-methyl-1-propenyl) and 3'-(2-methylpropyl) taxoi ds with modifications at C-10 was synthesized by means of the beta-lac tam synthon method using 10-modified 7-(triethylsilyl)-10-deacetylbacc atin III derivatives. The new taxoids thus synthesized show excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines. All but one of t hese new taxoids possess better activity than paclitaxel and docetaxel in the same assay, i.e., the IC50 values of almost all the taxoids ar e in the subnanomolar level. It is found that a variety of modificatio ns at C-10 is tolerated for the activity against normal cancer cell li nes, but the activity against a drug-resistant human breast cancer cel l line expressing MDR phenotype (MCF7-R) is highly dependent on the st ructure of the C-10 modifier. A number of the new taxoids exhibit rema rkable activity (IC50 = 2.1-9.1 nM) against MCF7-R. Among these, three new taxoids, SB-T-1213 (4a), SB-T-1214 (4b), and SB-T-1102 (5a), are found to be exceptionally potent, possessing 2 orders of magnitude bet ter activity than paclitaxel and docetaxel. The observed exceptional a ctivity of these taxoids may well be ascribed to an effective inhibiti on of P-glycoprotein binding by the modified C-10 moieties. The new ta xoid SB-T-1213 (4a) shows an excellent activity (T/C = 0% at 12.4 and 7.7 mg/kg/dose, log(10) cell kill = 2.3 and 2.0, respectively) against B16 melanoma in B6D2F(1) mice via intravenous administration.