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

  • Jantsch A Department of Chemistry and Applied Biosciences, Insitute of Pharmaceutical Sciences, ETH Zürich, CH-8093 Zürich, Switzerland. a.jantsch@hotmail.com.
  • Nieto L Department of Organic Chemistry I, Fac. C. C. Químicas, Universidad Complutense de Madrid, ES-28040 Madrid, Spain. linietog@gmail.com.
  • Gertsch J Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012 Bern, Switzerland. juerg.gertsch@ibmm.unibe.ch.
  • Rodríguez-Salarichs J Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain. javierr@cib.csic.es.
  • Matesanz R Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain. ruth.m.r@cib.csic.es.
  • Jiménez-Barbero J CIC bioGUNE, 48170 Derio, Spain. jjbarbero@cicbiogune.es.
  • Díaz JF Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain. fer@cib.csic.es.
  • Canales Á Department of Organic Chemistry I, Fac. C. C. Químicas, Universidad Complutense de Madrid, ES-28040 Madrid, Spain. angelescm@cib.csic.es.
  • Altmann KH Department of Chemistry and Applied Biosciences, Insitute of Pharmaceutical Sciences, ETH Zürich, CH-8093 Zürich, Switzerland. karl-heinz.altmann@pharma.ethz.ch.
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  • 2016-08-17
Published in:
  • Molecules (Basel, Switzerland). - 2016
SAR
STD
anticancer
azathilones
conformation
drug discovery
epothilones
natural product
synthesis
tubulin
A549 Cells
Antineoplastic Agents
Binding Sites
Cell Proliferation
Cell Survival
Cyclization
Drug Screening Assays, Antitumor
Epothilones
Hep G2 Cells
Humans
Models, Molecular
Molecular Structure
Protein Binding
Protein Conformation
Tubulin
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/201277
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