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 Show more
Permanent link
https://doi.org/10.3929/ethz-b-000331757Publication status
publishedExternal links
Journal / series
International Journal of Molecular SciencesVolume
Pages / Article No.
Publisher
MDPI Molecular diversity preservation internationalSubject
cancer; drug discovery; epothilone; medicinal chemistry; microtubule-stabilizing agents; prodrug; total synthesis; tumor-targetingOrganisational unit
03647 - Altmann, Karl-Heinz (emeritus) / Altmann, Karl-Heinz (emeritus)
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