Synthesis, Biological Profiling and Determination of the Tubulin-Bound Conformation of 12-Aza-Epothilones (Azathilones).

Jantsch, Andrea; Nieto, Lidia; Gertsch, Jürg; Rodríguez-Salarichs, Javier; Matesanz, Ruth; Jiménez-Barbero, Jesús; Díaz, J Fernando; Canales, Ángeles; Altmann, Karl-Heinz (2016). Synthesis, Biological Profiling and Determination of the Tubulin-Bound Conformation of 12-Aza-Epothilones (Azathilones). Molecules, 21(8) Molecular Diversity Preservation International MDPI 10.3390/molecules21081010

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12-Aza-epothilones (azathilones) incorporating quinoline side chains and bearing different N12-substituents have been synthesized via highly efficient RCM-based macrocyclizations. Quinoline-based azathilones with the side chain N-atom in the meta-position to the C15 atom in the macrocycle are highly potent inhibitors of cancer cell growth in vitro. In contrast, shifting the quinoline nitrogen to the position para to C15 leads to a ca. 1000-fold loss in potency. Likewise, the desaturation of the C9-C10 bond in the macrocycle to an E double bond produces a substantial reduction in antiproliferative activity. This is in stark contrast to the effect exerted by the same modification in the natural epothilone macrocycle. The conformation of a representative azathilone bound to α/β-tubulin heterodimers was determined based on TR-NOE measurements and a model for the posture of the compound in its binding site on β-tubulin was deduced through a combination of STD measurements and CORCEMA-ST calculations. The tubulin-bound, bioactive conformation of azathilones was found to be overall similar to that of epothilones A and B.

Item Type:

Journal Article (Original Article)


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

UniBE Contributor:

Gertsch, Jürg


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




Molecular Diversity Preservation International MDPI




Barbara Järmann-Bangerter

Date Deposited:

19 Apr 2017 13:46

Last Modified:

28 Sep 2021 03:02

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

SAR; STD; anticancer; azathilones; conformation; drug discovery; epothilones; natural product; synthesis; tubulin




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