Re-evaluation of the Fijianolide/Laulimalide Chemotype Suggests an Alternate Mechanism of Action for C-15/C-20 Analogs.

Herein, we report on naturally derived microtubule stabilizers with activity against triple negative breast cancer (TNBC) cell lines, including paclitaxel, fijianolide B/laulimalide (), fijianolide B di-acetate (), and two new semisynthetic analogs of , which include fijianolide J () and fijianolide L (). Similar to paclitaxel, compound demonstrated classic microtubule stabilizing activity with potent (GI = 0.7-17 nM) antiproliferative efficacy among the five molecularly distinct TNBC cell lines. Alternatively, compounds or , generated from oxidation of C-20 or C-15 and C-20 respectively, resulted in a unique profile with reduced potency (GI = 4-9 μM), but improved efficacy in some lines, suggesting a distinct mechanism of action. The C-15, C-20 di-acetate, and dioxo modifications on and resulted in compounds devoid of classic microtubule stabilizing activity in biochemical assays. While also had no detectable effect on cellular microtubules, promoted a reorganization of the cytoskeleton resulting in an accumulation of microtubules at the cell periphery. Compound , with a single C-20 oxo substitution, displayed a mixed phenotype, sharing properties of and . These results demonstrate the importance of the C-15/C-20 chiral centers, which appear to be required for the potent microtubule stabilizing activity of this chemotype and that oxidation of these sites promotes unanticipated cytoskeletal alterations that are distinct from classic microtubule stabilization, likely through a distinct mechanism of action.