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Issue 15, 2018
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Iriomoteolides: novel chemical tools to study actin dynamics

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Abstract

Despite its promising biological profile, the cellular targets of iriomoteolide-3a, a novel 15-membered macrolide isolated from Amphidinium sp., have remained unknown. A small library of non-natural iriomoteolide-3a analogues is presented here as a result of a novel, highly convergent, catalysis-based scaffold-diversification campaign, which revealed the suitable sites for chemical editing in the original core. We provide compelling experimental evidence for actin as one of iriomoteolides' primary cellular targets, establishing the ability of these secondary metabolites to inhibit cell migration, induce severe morphological changes in cells and cause a reversible cytoplasmic retraction and reduction of F-actin fibers in a time and dose dependent manner. These results are interpreted in light of the ability of iriomoteolides to stabilize F-actin filaments. Molecular dynamics simulations provide evidence for iriomoteolide-3a binding to the barbed end of G-actin. These results showcase iriomoteolides as novel and easily tunable chemical probes for the in vitro study of actin dynamics in the context of cell motility processes including cell invasion and division.

Graphical abstract: Iriomoteolides: novel chemical tools to study actin dynamics

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Publication details

The article was received on 02 Oct 2017, accepted on 10 Mar 2018 and first published on 03 Apr 2018


Article type: Edge Article
DOI: 10.1039/C7SC04286H
Citation: Chem. Sci., 2018,9, 3793-3802
  • Open access: Creative Commons BY-NC license
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    Iriomoteolides: novel chemical tools to study actin dynamics

    A. Unzue, R. Cribiú, M. M. Hoffman, T. Knehans, K. Lafleur, A. Caflisch and C. Nevado, Chem. Sci., 2018, 9, 3793
    DOI: 10.1039/C7SC04286H

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