Issue 15, 2018

Iriomoteolides: novel chemical tools to study actin dynamics

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

Supplementary files

Article information

Article type
Edge Article
Submitted
02 okt 2017
Accepted
10 mar 2018
First published
03 apr 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2018,9, 3793-3802

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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