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

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.

Drugs That Changed Society: Microtubule-Targeting Agents Belonging to Taxanoids, Macrolides and Non-Ribosomal Peptides

“…Taccalonolide AJ is a semisynthetic product prepared by epoxidation of taccalonolide B [ 104 ]. In early publications, the C-22-C-23 epoxide was α-disposed; later publications suggest a β-disposed epoxide [ 101 , 105 ].…”

Microtubule-Interfering Drugs: Current and Future Roles in Epithelial Ovarian Cancer Treatment

“…Taccalonolides are pentacyclic steroids discovered in 1963 as isolates from Tacca plantaginerea Andrea [ 97 ]. These compounds appear not to share cross-resistance with paclitaxel and stabilize microtubules via a unique mechanism with defective -tubulin spindles and interphase microtubule bundling yielding G2/M arrest [ 98 ]. Cyclostreptin (FR182877, Fujisawa Pharmaceutical Co, Tokyo, Japan) was generated from Streptomyces in 1998 and is particularly effective at stabilizing microtubules at low temperatures, and may additionally promote tubulin polymerization [ 96 , 97 , 99 , 100 ].…”