Taccalonolide Microtubule Stabilizers Generated Using Semi-Synthesis Define the Effects of Mono Acyloxy Moieties at C-7 or C-15 and Disubstitutions at C-7 and C-25

摘要

The taccalonolides are a unique class of microtubule stabilizers isolated from Tacca spp. that have efficacy against drug-resistant tumors. Our previous studies have demonstrated that a C-15 acetoxy taccalonolide, AF, has superior in vivo antitumor efficacy compared to AJ, which bears a C-15 hydroxy group. With the goal of further improving the in vivo efficacy of this class of compounds, we semi-synthesized and tested the biological activities of 28 new taccalonolides with monosubstitutions at C-7 or C-15 or disubstitutions at C-7 and C-25, covering a comprehensive range of substituents from formic acid to anthraquinone-2-carbonyl chloride. The resulting taccalonolide analogues with diverse C-7/C-15/C-25 modifications exhibited IC50 values from 2.4 nM to >20 μM, allowing for extensive in vitro structure-activity evaluations. This semi-synthetic strategy was unable to provide a taccalonolide with improved therapeutic window due to hydrolysis of substituents at C-7 or C-15 regardless of size or steric bulk. However, two of the most potent new taccalonolides, bearing isovalerate modifications at C-7 or C-15, demonstrated potent and highly persistent antitumor activity in a drug-resistant xenograft model when administered intratumorally. This study demonstrates that targeted delivery of the taccalonolides to the tumor could be an effective, long-lasting approach to treat drug-resistant tumors.