Syntheses and Structure−Activity Relationships of the Second-Generation Antitumor Taxoids:  Exceptional Activity against Drug-Resistant Cancer Cells

A series of new 3‘-(2-methyl-1-propenyl) and 3‘-(2-methylpropyl) taxoids with modifications at C-10 was synthesized by means of the β-lactam synthon method using 10-modified 7-(triethylsilyl)-10-deacetylbaccatin 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 these new taxoids possess better activity than paclitaxel and docetaxel in the same assay, i.e., the IC₅₀ values of almost all the taxoids are in the subnanomolar level. It is found that a variety of modifications at C-10 is tolerated for the activity against normal cancer cell lines, but the activity against a drug-resistant human breast cancer cell line expressing MDR phenotype (MCF7-R) is highly dependent on the structure of the C-10 modifier. A number of the new taxoids exhibit remarkable activity (IC₅₀ = 2.1−9.1 nM) against MCF7-R. Among these, three new taxoids, SB-T-1213 (<b>4a</b>), SB-T-1214 (<b>4b</b>), and SB-T-1102 (<b>5a</b>), are found to be exceptionally potent, possessing 2 orders of magnitude better activity than paclitaxel and docetaxel. The observed exceptional activity of these taxoids may well be ascribed to an effective inhibition of P-glycoprotein binding by the modified C-10 moieties. The new taxoid SB-T-1213 (<b>4a</b>) shows an excellent activity (T/C = 0% at 12.4 and 7.7 mg/kg/dose, log₁₀ cell kill = 2.3 and 2.0, respectively) against B16 melanoma in B6D2F₁ mice via intravenous administration.