Taccalonolide C-6 Analogues, Including Paclitaxel Hybrids, Demonstrate Improved Microtubule Polymerizing Activities.

Journal of Natural Products
April L RisingerLin Du

Abstract

The C-22,23-epoxy taccalonolides are microtubule stabilizers that bind covalently to β-tubulin with a high degree of specificity. We semisynthesized and performed biochemical and cellular evaluations on 20 taccalonolide analogues designed to improve target engagement. Most notably, modification of C-6 on the taccalonolide backbone with the C-13 N-acyl-β-phenylisoserine side chain of paclitaxel provided compounds with 10-fold improved potency for biochemical tubulin polymerization as compared to that of the unmodified epoxy taccalonolide AJ. Covalent docking demonstrated that the C-13 paclitaxel side chain occupied a binding pocket adjacent to the core taccalonolide pocket near the M-loop of β-tubulin. Although paclitaxel-taccalonolide hybrids demonstrated improved in vitro biochemical potency, they retained features of the taccalonolide chemotype, including a lag in tubulin polymerization and high degree of cellular persistence after drug washout associated with covalent binding. Together, these data demonstrate that C-6 modifications can improve the target engagement of this covalent class of microtubule drugs without substantively changing their mechanism of action.

References

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May 21, 2011·Cell Cycle·April L Risinger, Susan L Mooberry
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Jan 24, 2017·Journal of Natural Products·April L RisingerSusan L Mooberry
Jun 7, 2017·Nature Communications·Yuxi WangJinliang Yang
Mar 10, 2018·Journal of Natural Products·Celine NadaradjaneHayley M McDaid
Mar 23, 2019·International Journal of Molecular Sciences·Francisco de Asís BalaguerJ Fernando Díaz
Jun 4, 2019·Journal of Computer-aided Molecular Design·Pedro A Sánchez-MurciaFederico Gago
Dec 12, 2020·Progress in the Chemistry of Organic Natural Products·Samantha S YeeApril L Risinger

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