Cytochalasans and Their Impact on Actin Filament Remodeling

Abstract

The eukaryotic actin cytoskeleton comprises the protein itself in its monomeric and filamentous forms, G- and F-actin, as well as multiple interaction partners (actin-binding proteins, ABPs). This gives rise to a temporally and spatially controlled, dynamic network, eliciting a plethora of motility-associated processes. To interfere with the complex inter- and intracellular interactions the actin cytoskeleton confers, small molecular inhibitors have been used, foremost of all to study the relevance of actin filaments and their turnover for various cellular processes. The most prominent inhibitors act by, e.g., sequestering monomers or by interfering with the polymerization of new filaments and the elongation of existing filaments. Among these inhibitors used as tool compounds are the cytochalasans, fungal secondary metabolites known for decades and exploited for their F-actin polymerization inhibitory capabilities. In spite of their application as tool compounds for decades, comprehensive data are lacking that explain (i) how the structural deviances of the more than 400 cytochalasans described to date influence their bioactivity mechanistically and (ii) how the intricate network of ABPs reacts (or adapts) to cytochalasan binding. This review thus aims to summarize the information available concerning the structural features of cytochalasans and their influence on the described activities on cell morphology and actin cytoskeleton organization in eukaryotic cells.

Comprehensive cell biological investigation of cytochalasin B derivatives with distinct activities on the actin network

“…27 Notwithstanding this, no decomposition of CB1 was observed (See Figure S5 in the Supplementary Information), so we assume that the cellular effects of CB1 are inherent to the compound. The reduced actin disruption activity of C-7 O-acetylated cytochalasans has been described before, 4,28,29 whereas the antiproliferative, long-lasting cytostatic activity of CB1 observed here deserves further investigations. For instance, CB1 might interfere with actin-independent targets such as summarized by Lambert et al (2023).…”

“…The successful N-methylation at position N-2 was proven by the presence of a singlet with an integral corresponding to 3 hydrogen atoms at 2.83 ppm in the 1 H-NMR spectrum of CB2 (see Figure S20 in the Supplementary information) and the respective N-methyl carbon in the 13 C-NMR spectrum of CB2 at 28.52 ppm, exhibiting a heteronuclear multiple bond correlation (HMBC) long-range 4 Furthermore, the deshielding of C-20 proton (5.49-5.52 ppm, m, 1H)) compared to the C-7 OH proton (3.88 ppm, d, 1H) was taken as proof for O-acetylation of the hydroxy function at C-20. Additionally, further analytical evidence for O-acetylation of the hydroxyl function at C-20 was provided by a heteronuclear multiple bond correlation (HMBC) long-range 4 J-coupling between the proton at C-20 and the methyl carbon of the introduced acetyl group (5.51 (5.49-5.52) ppm/20.97 ppm, see Figure S34 in the Supplementary Information).…”

“…3 The most prominent activity of cytochalasans however is the disruption of the actin cytoskeleton, resulting in impairment of cell shape and behavior. 4 Actin plays a crucial role in most if not all motile processes of eukaryotic cells, including changes of cell shape, cell migration, vesicular trafficking, and cytokinesis. 5 Actin undergoes dynamic cycles of polymerization and depolymerization.…”

“…This goal will require an in depth understanding of how distinct chemical moieties affect the activity of a given cytochalasan. A variety of structure activity relationship (SAR) studies have been published over the past decades, 4 attempting to shed light on the complexity of cytochalasan activity and diversity. Conclusions drawn from previous SAR studies include a pivotal role of the C-7 hydroxy group, while the amino acid incorporated in the isoindolone core will likely not affect activity.…”

Synthesis and migrastatic activity of cytochalasin analogues lacking a macrocyclic moiety

“…1). 7,8 The most important characteristic of cytochalasans is their binding to the barbed end of actin microfilaments, resulting in the inhibition of actin polymerization. 9,10 Among cytochalasans, cytochalasin B (CytB, 1 ) 11–14 and cytochalasin D (CytD, 2 ) 15–17 have been subjected to extensive investigation of their mechanism of action and antitumor activity.…”