Synthesis, Microtubule-Binding Affinity, and Antiproliferative Activity of New Epothilone Analogs and of an EGFR-Targeted Epothilone-Peptide Conjugate

Abstract

A new simplified, epoxide-free epothilone analog was prepared incorporating an N-(2-hydroxyethyl)-benzimidazole side chain, which binds to microtubules with high affinity and inhibits cancer cell growth in vitro with nM potency. Building on this scaffold, a disulfide-linked conjugate with the purported EGFR-binding (EGFR, epidermal growth factor receptor) peptide GE11 was then prepared. The conjugate retained significant microtubule-binding affinity, in spite of the size of the peptide attached to the benzimidazole side chain. The antiproliferative activity of the conjugate was significantly lower than for the parent scaffold and, surprisingly, was independent of the EGFR expression status of cells. Our data indicate that the disulfide-based conjugation with the GE11 peptide is not a viable approach for effective tumor-targeting of highly potent epothilones and probably not for other cytotoxics.

Mitotic Poisons in Research and Medicine

“…Then, this highly potent conjugate with a peptide targeting the epidermal growth factor receptor (EGFR) was prepared. Interestingly, this conjugate retained the tubulin-binding activity despite the sterically very large interference into its structure, but its anticancer activity was significantly lower than that of the free epothilone derivative [ 133 ].…”

Synthesis, Profiling, and Bioactive Conformation of trans‐Cyclopropyl Epothilones

“…In order to overcome these limitations, we have instead investigated the more water-soluble epothilone analog 46 ( Figure 5), which we have prepared in the context of studies on tumor-targeted conjugates of epothilones. [53] The interactions of 46 with both α/β tubulin heterodimers [54] as well as cross-linked microtubules were studied by two-dimensional transferred nuclear Overhauser effect spectroscopy (TR-NOESY), to derive the tubulin-bound conformation of 46, and by saturation transfer difference nuclear magnetic resonance (STD-NMR), to identify the sites of interaction with the protein in the binding pocket. Strong negative TR-NOE cross-peaks where detected for 46 in both systems; in addition, clear STD signals were evident (again in both systems), with the highest STD intensities being observed for the protons of the benzimidazole ring and the cyclopropane moiety.…”