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Identification of C-6 as a New Site for Linker Conjugation to the Taccalonolide Microtubule Stabilizers.

Lin DuApril L RisingerSamantha S YeeAntonius R B OlaCynthia L ZammielloRobert H CichewiczSusan L Mooberry
Published in: Journal of natural products (2019)
The taccalonolides are a class of microtubule stabilizers that circumvent clinically relevant forms of drug resistance due to their unique mechanism of microtubule stabilization imparted by the covalent binding of the C-22-C-23 epoxide moiety to tubulin. A taccalonolide (8) with a fluorescein group attached with a linker at C-6 was generated, and biochemical and cell-based assays showed that it bound directly to tubulin and stabilized microtubules. This pharmacological probe has allowed, for the first time, a direct visualization of a taccalonolide binding to microtubules, verifying their cellular binding site. This C-6-modified taccalonolide showed potency comparable to the untagged compound in biochemical experiments; however, its potency was lower in cellular assays, presumably due to decreased cellular permeability. These studies provide a valuable tool to facilitate the further understanding of taccalonolide pharmacology and demonstrate that C-6 is a promising site for a linker to be added to this novel class of microtubule stabilizers for targeted drug delivery.
Keyphrases
  • drug delivery
  • high throughput
  • cancer therapy
  • single cell
  • living cells
  • dna binding