Next Article in Journal
Design, Synthesis and Biological Evaluation of Benzohydrazide Derivatives Containing Dihydropyrazoles as Potential EGFR Kinase Inhibitors
Previous Article in Journal
Struvite Precipitation as a Means of Recovering Nutrients and Mitigating Ammonia Toxicity in a Two-Stage Anaerobic Digester Treating Protein-Rich Feedstocks
Previous Article in Special Issue
Antiproliferative Fate of the Tetraploid Formed after Mitotic Slippage and Its Promotion; A Novel Target for Cancer Therapy Based on Microtubule Poisons
Article Menu
Issue 8 (August) cover image

Export Article

Open AccessArticle
Molecules 2016, 21(8), 1010; doi:10.3390/molecules21081010

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

1
Department of Chemistry and Applied Biosciences, Insitute of Pharmaceutical Sciences, ETH Zürich, CH-8093 Zürich, Switzerland
2
Department of Organic Chemistry I, Fac. C. C. Químicas, Universidad Complutense de Madrid, ES-28040 Madrid, Spain
3
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain
4
Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012 Bern, Switzerland
5
CIC bioGUNE, 48170 Derio, Spain
6
Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain
7
Department of Organic Chemistry II, Faculty of Science & Technology, University of the Basque Country, 48940 Leioa, Bizkaia, Spain
*
Author to whom correspondence should be addressed.
Academic Editors: Iwao Ojima and Derek J. McPhee
Received: 29 June 2016 / Revised: 24 July 2016 / Accepted: 27 July 2016 / Published: 3 August 2016
(This article belongs to the Special Issue New Generation of Microtubule-Interacting Anticancer Agents)
View Full-Text   |   Download PDF [2245 KB, uploaded 3 August 2016]   |  

Abstract

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. View Full-Text
Keywords: anticancer; azathilones; conformation; drug discovery; epothilones; natural product; SAR; STD; synthesis; tubulin anticancer; azathilones; conformation; drug discovery; epothilones; natural product; SAR; STD; synthesis; tubulin
Figures

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Jantsch, A.; Nieto, L.; Gertsch, J.; Rodríguez-Salarichs, J.; Matesanz, R.; Jiménez-Barbero, J.; Díaz, J.F.; Canales, Á.; Altmann, K.-H. Synthesis, Biological Profiling and Determination of the Tubulin-Bound Conformation of 12-Aza-Epothilones (Azathilones). Molecules 2016, 21, 1010.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]

Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top