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Synthesis, biological profiling and determination of the tubulin-bound conformation of 12-Aza-epothilones (azathilones)

AutorJantsch, Andrea; Nieto, Lidia ; Gertsch, Jürg; Rodríguez-Salarichs, Javier; Matesanz, Ruth ; Jiménez-Barbero, Jesús ; Díaz, José Fernando ; Canales, Ángeles ; Altmann, Karl-Heinz
Palabras claveAnticancer
Azathilones
Conformation
Drug discovery
Epothilones
Natural product
SAR
STD
Synthesis
Tubulin
Fecha de publicación3-ago-2016
EditorMolecular Diversity Preservation International
CitaciónMolecules 21:1010 (2016)
Resumen12-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 / -tubulin heterodimers was determined based on TR-NOE measurements and a model for the posture of the compound in its binding site on -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.
Descripción26 p.-6 fig.2 tab.
Versión del editorhttp://dx.doi.org/ 10.3390/molecules21081010
URIhttp://hdl.handle.net/10261/137691
DOI10.3390/molecules21081010
ISSN1420-3049
E-ISSN1420-3049
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