Next Article in Journal
Nomegestrol Acetate Suppresses Human Endometrial Cancer RL95-2 Cells Proliferation In Vitro and In Vivo Possibly Related to Upregulating Expression of SUFU and Wnt7a
Next Article in Special Issue
An Emerging Role for Tubulin Isotypes in Modulating Cancer Biology and Chemotherapy Resistance
Previous Article in Journal
Associations of Drug Lipophilicity and Extent of Metabolism with Drug-Induced Liver Injury
Previous Article in Special Issue
Centrosomal Protein 70 Is a Mediator of Paclitaxel Sensitivity
Article Menu
Issue 7 (July) cover image

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2017, 18(7), 1336; doi:10.3390/ijms18071336

Quinolin-6-Yloxyacetamides Are Microtubule Destabilizing Agents That Bind to the Colchicine Site of Tubulin

1
Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, CH-5232 Villigen, Switzerland
2
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain
3
Chemical Research, Syngenta Crop Protection AG, Schaffhauserstrasse 101, CH-4332 Stein, Switzerland
*
Authors to whom correspondence should be addressed.
Received: 26 April 2017 / Revised: 9 June 2017 / Accepted: 18 June 2017 / Published: 22 June 2017
(This article belongs to the Special Issue Microtubule-Targeting Agents)
View Full-Text   |   Download PDF [3223 KB, uploaded 22 June 2017]   |  

Abstract

Quinolin-6-yloxyacetamides (QAs) are a chemical class of tubulin polymerization inhibitors that were initially identified as fungicides. Here, we report that QAs are potent anti-proliferative agents against human cancer cells including ones that are drug-resistant. QAs act by disrupting the microtubule cytoskeleton and by causing severe mitotic defects. We further demonstrate that QAs inhibit tubulin polymerization in vitro. The high resolution crystal structure of the tubulin-QA complex revealed that QAs bind to the colchicine site on tubulin, which is targeted by microtubule-destabilizing agents such as colchicine and nocodazole. Together, our data establish QAs as colchicine-site ligands and explain the molecular mechanism of microtubule destabilization by this class of compounds. They further extend our structural knowledge on antitubulin agents and thus should aid in the development of new strategies for the rational design of ligands against multidrug-resistant cancer cells. View Full-Text
Keywords: microtubules; microtubule targeting agents; quinolin-6-yloxyacetamides; multidrug resistance microtubules; microtubule targeting agents; quinolin-6-yloxyacetamides; multidrug resistance
Figures

Figure 1

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

Sharma, A.; Sáez-Calvo, G.; Olieric, N.; de Asís Balaguer, F.; Barasoain, I.; Lamberth, C.; Díaz, J.F.; Steinmetz, M.O. Quinolin-6-Yloxyacetamides Are Microtubule Destabilizing Agents That Bind to the Colchicine Site of Tubulin. Int. J. Mol. Sci. 2017, 18, 1336.

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]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top