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

Gaugaz, Fabienne Zdenka; Chicca, Andrea; Redondo-Horcajo, Mariano; Barasoain, Isabel; Díaz, J Fernando; Altmann, Karl-Heinz (2019). Synthesis, Microtubule-Binding Affinity, and Antiproliferative Activity of New Epothilone Analogs and of an EGFR-Targeted Epothilone-Peptide Conjugate. International journal of molecular sciences, 20(5) Molecular Diversity Preservation International MDPI 10.3390/ijms20051113

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Chicca, Andrea

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1661-6596

Publisher:

Molecular Diversity Preservation International MDPI

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

27 Sep 2019 12:37

Last Modified:

23 Oct 2019 05:04

Publisher DOI:

10.3390/ijms20051113

PubMed ID:

30841526

Uncontrolled Keywords:

cancer drug discovery epothilone medicinal chemistry microtubule-stabilizing agents prodrug total synthesis tumor-targeting

BORIS DOI:

10.7892/boris.133499

URI:

https://boris.unibe.ch/id/eprint/133499

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