Potent Taccalonolides, AF and AJ, Inform Significant Structure–Activity Relationships and Tubulin as the Binding Site of These Microtubule Stabilizers

Abstract

The taccalonolides are a class of microtubule stabilizing agents isolated from plants of the genus Tacca. In efforts to define their structure activity relationships, we isolated 5 new taccalonolides, AC-AF, and H2, from one fraction of an ethanol extract of Tacca plantaginea. The structures were elucidated using a combination of spectroscopic methods, including 1D and 2D NMR and HRESIMS. Taccalonolide AJ, an epoxidation product of taccalonolide B, was generated by semi-synthesis. Five of these taccalonolides demonstrated cellular microtubule stabilizing activities and antiproliferative actions against cancer cells, with taccalonolide AJ exhibiting the highest potency with an IC50 value of 4.2 nM. The range of potencies of these compounds, from 4.2 nM to greater than 50 µM, for the first time provides the opportunity to identify specific structural moieties crucial for potent biological activities as well as those that impede optimal cellular effects. In mechanistic assays taccalonolide AF and AJ stimulated the polymerization of purified tubulin, an activity that had not previously been observed for the taccalonolides A and B, providing the first evidence that this class of microtubule stabilizers can interact directly with tubulin/microtubules. Taccalonolides AF and AJ were able to enhance tubulin polymerization to the same extent as paclitaxel, but with a distinct kinetic profile, suggesting a distinct binding mode or the possibility of a new binding site. The potencies of taccalonolides AF and AJ, their direct interaction with tubulin, together with the previous excellent in vivo antitumor activity of this class reveal the potential of the taccalonolides as new anticancer agents.

Cytotoxic Taccalonolides and Withanolides from Tacca chantrieri

“…The chemical constituents of Tacca plants include taccalonolides, steroidal sapogenins, steroidal glycosides, and diarylheptanoids, of which taccalonolides are the most studied due to their microtubule-stabilizing activities [3][4][5][6][7][8][9][10]. As the characteristic constituents of the genus Tacca, taccalonolides represent a rare class of steroids possessing a highly oxygenated pentacyclic skeleton carrying a γ-or δ-lactone moiety.…”

Phytochemical and Pharmacological Studies of the <i>Genus Tacca</i>: A Review

“…Then Chen and his group first elucidated their complete structures with modern chemical techniques [14,15]. Extensive studies of the Genus Tacca have led to the identification of taccalonolides C-Z (3-26), AA-AJ (27)(28)(29)(30)(31)(32)(33) and H2 (34) ( Table 1, Fig 1) [8,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. All of them were new constituents and have antitumor activities.…”

“…The range of potencies of these compounds, from 4.2 nM to > 50 μM, for the first time provided an opportunity to identify specific structural moieties crucial for potent biological activities as well as those that impede optimal cellular effects. In mechanistic assays, taccalonolides AF (32) and AJ (33) could interact directly with tubulin/microtubules and were able to enhance tubulin polymerization to the same extent as paclitaxel but exhibited a distinct kinetic profile, suggesting a distinct binding mode or the possibility of a new binding site [12].…”

“…Then, much attention has been paid to Tacca species due to their cytotoxic, microtubule-stabilizing activities and as a starch source. The potency of taccalonolides, withanolides and their direct interaction with tubulin, together with their previous in vivo antitumor activities, reveal the potential of taccalonolides as new anticancer agents [8][9][10][11][12].…”

Plantagiolides K–N, three new withanolides and one withanolide glucoside from Tacca plantaginea

“…The chemical constituents of Taccaceae plants include steroids covering taccalonolides, withanolides, and spirostane glycosides, furostane glycosides, C-28 steroidal saponins, and diarylheptanoids as well as their glycosides [3]. What is more, recent studies have shown that the taccalonolides are a unique class of microtubule stabilizers, considerable antitumor efficacy in vivo but different mechanisms of taxol [4][5][6], which attracts many scholars.…”