Design and Synthesis of Actin-Targeting 10-Phenoxy Cytochalasan Analogues: Balancing Cytotoxicity and Migrastatic Activity

TL;DR

Scientists designed new cytochalasan compounds that target actin to reduce cancer cell migration without causing cell death.

Contribution

A modular synthesis method introduces 10-phenoxy substituents to cytochalasans, balancing migrastatic and cytotoxic effects.

Findings

Several 7-hydroxy-10-phenoxycytochalasans inhibited actin polymerization and showed migrastatic effects.

Para-substituents modulated cytotoxicity without affecting migrastatic activity.

Lipophilic ortho-substituents failed to show migrastatic effects despite predicted actin binding.

Abstract

Cytochalasans are
actin polymerization inhibitors with potent migrastatic
activity, but their potential therapeutic use is limited by their
cytotoxicity. Here, we describe a modular late-stage approach that
introduces unprecedented 10-phenoxy substituents into the cytochalasan
scaffold via a Mitsunobu reaction. A series of ten 10-phenoxycytochalasan
analogues was synthesized and evaluated for actin polymerization inhibition,
migrastatic activity, and cytotoxicity (BLM, MRC-5, and HaCaT). At
10 μM concentration, several 7-hydroxy-10-phenoxycytochalasans
(12a,d–g) significantly inhibited
actin polymerization in vitro and showed migrastatic effects in a
spheroid invasion assay. Para-substituents of the phenoxy group modulated
cytotoxicity without compromising actin polymerization inhibition
or migrastatic activity. In contrast, lipophilic ortho-substituents
predicted by molecular docking to enhance actin binding failed to
manifest migrastatic activity, underscoring the limitations of the
molecular docking with this type of compounds. These findings demonstrate
that migrastatic and cytotoxic effects can be decoupled in cytochalasan
analogues and highlight 10-phenoxy substitution as a promising strategy
toward noncytotoxic migrastatic agents.

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