108885-69-4Relevant articles and documents
Hydrolysis reactions of the taccalonolides reveal structure-activity relationships
Li, Jing,Peng, Jiangnan,Risinger, April L.,Mooberry, Susan L.
, p. 1369 - 1375 (2013)
The taccalonolides are microtubule stabilizers isolated from plants of the genus Tacca that show potent in vivo antitumor activity and the ability to overcome multiple mechanisms of drug resistance. The most potent taccalonolide identified to date, AJ, is a semisynthetic product generated from the major plant metabolite taccalonolide A in a two-step reaction. The first step involves hydrolysis of taccalonolide A to generate taccalonolide B, and then this product is oxidized to generate an epoxide group at C-22-C-23. To generate sufficient taccalonolide AJ for in vivo antitumor efficacy studies, the hydrolysis conditions for the conversion of taccalonolide A to B were optimized. During purification of the hydrolysis products, we identified the new taccalonolide AO (1) along with taccalonolide I. When the same hydrolysis reaction was performed on a taccalonolide E-enriched fraction, four new taccalonolides, assigned as AK, AL, AM, and AN (2-5), were obtained in addition to the expected product taccalonolide N. Biological assays were performed on each of the purified taccalonolides, which allowed for increased refinement of the structure-activity relationship of this class of compounds.
Identification and biological activities of new taccalonolide microtubule stabilizers
Peng, Jiangnan,Risinger, April L.,Fest, Gary A.,Jackson, Evelyn M.,Helms, Gregory,Polin, Lisa A.,Mooberry, Susan L.
, p. 6117 - 6124 (2011)
The taccalonolides are a unique class of microtubule stabilizers that do not bind directly to tubulin. Three new taccalonolides, Z, AA, and AB, along with two known compounds, taccalonolides R and T, were isolated from Tacca chantrieri and Tacca integrifolia. Taccalonolide structures were determined by 1D and 2D NMR methods. The biological activities of the new taccalonolides, as well as taccalonolides A, B, E, N, R, and T, were evaluated. All nine taccalonolides display microtubule stabilizing activity, but profound differences in antiproliferative potencies were noted, with IC50 values ranging from the low nanomolar range for taccalonolide AA (32 nM) to the low micromolar range for taccalonolide R (13 μM). These studies demonstrate that diverse taccalonolides possess microtubule stabilizing properties and that significant structure-activity relationships exist. In vivo antitumor evaluations of taccalonolides A, E, and N show that each of these molecules has in vivo antitumor activity.
Taccalonolide Microtubule Stabilizers Generated Using Semisynthesis Define the Effects of Mono Acyloxy Moieties at C-7 or C-15 and Disubstitutions at C-7 and C-25
Ola, Antonius R. B.,Risinger, April L.,Du, Lin,Zammiello, Cynthia L.,Peng, Jiangnan,Cichewicz, Robert H.,Mooberry, Susan L.
, p. 579 - 593 (2018)
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 semisynthesized 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 semisynthetic 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.
TACCALONOLIDE MICROTUBULE STABILIZERS
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Paragraph 00385, (2018/07/05)
The present disclosure relates to the fields of medicine and pharmaceuticals. In particular, the invention relates to the identification of epoxytaccalonolide microtubule stabilizers for use in inhibiting cell proliferation and disrupting normal cellular microtubule processes leading to cell death. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
NEW TACCALONOLIDE MICROTUBULE STABILIZERS
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Page/Page column 53-54, (2013/02/27)
The invention provides epoxytaccalonolide microtubule stabilizers and their use as anti-proliferative microtubule stabilizing agents.
