Taccalonolide C-6 Analogues, Including Paclitaxel Hybrids, Demonstrate Improved Microtubule Polymerizing Activities
| Autor: | April L. Risinger, Shayne D. Hastings, Lin Du |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Taccalonolide
Paclitaxel Pharmaceutical Science macromolecular substances 01 natural sciences Article Analytical Chemistry chemistry.chemical_compound Structure-Activity Relationship Microtubule Tubulin Drug Discovery medicine Side chain Humans Pharmacology Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Tubulin Modulators 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Complementary and alternative medicine Mechanism of action Polymerization Docking (molecular) Covalent bond Biophysics Molecular Medicine Steroids medicine.symptom HeLa Cells |
| Zdroj: | J Nat Prod |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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