Taccalonolide microtubule stabilizers

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 18; pp. 5091 - 5096
• Main Authors: Li, Jing, Risinger, April L., Mooberry, Susan L.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.09.2014
• Subjects: Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Humans; Laulimalide; Microtubule; Microtubule stabilizer; Microtubules - drug effects; Microtubules - metabolism; Models, Molecular; Molecular Conformation; Paclitaxel; Steroids - chemistry; Steroids - isolation & purification; Steroids - pharmacology; Structure-Activity Relationship; Tacca; Taccalonolide; Taxol; Tubulin; Tubulin Modulators - chemistry; Tubulin Modulators - isolation & purification; Tubulin Modulators - pharmacology; Microtubule stabilizer; Tubulin; Taxol; Paclitaxel; Tacca; Laulimalide; Microtubule; Taccalonolide
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.01.012

This review focuses on a relatively new class of microtubule stabilizers, the taccalonolides. The taccalonolides are highly oxygenated pentacyclic steroids isolated from plants of the genus Tacca. Originally identified in a cell-based phenotypic screen, the taccalonolides have many properties similar to other microtubule stabilizers. They increase the density of interphase microtubules, causing microtubule bundling, and form abnormal multi-polar mitotic spindles leading to mitotic arrest and, ultimately, apoptosis. However, the taccalonolides differ from other microtubule stabilizers in that they retain efficacy in taxane resistant cell lines and in vivo models. Binding studies with the newly identified, potent taccalonolide AJ demonstrated covalent binding to β-tubulin at or near the luminal and/or pore taxane binding site(s) which stabilizes microtubule protofilaments in a unique manner as compared to other microtubule stabilizers. The isolation and semi-synthesis of 21 taccalonolides helped to identify key structure activity relationships and the importance of multiple regions across the taccalonolide skeleton for optimal biological potency.