Antiproliferative and Cytotoxic Cytochalasins from Sparticola triseptata Inhibit Actin Polymerization and Aggregation

Abstract

Laying the groundwork on preliminary structure–activity relationship study relating to the disruptive activity of cytochalasan derivatives on mammalian cell actin cytoskeleton, we furthered our study on the cytochalasans of the Dothideomycetes fungus, Sparticola triseptata. A new cytochalasan analog triseptatin (1), along with the previously described cytochalasans deoxaphomin B (2) and cytochalasin B (3), and polyketide derivatives cis-4-hydroxy-6-deoxyscytalone (4) and 6-hydroxymellein (5) were isolated from the rice culture of S. triseptata. The structure of 1 was elucidated through NMR spectroscopic analysis and high-resolution mass spectrometry (HR-ESI-MS). The relative and absolute configurations were established through analysis of NOESY spectroscopic data and later correlated with experimental electronic circular dichroism and time-dependent density functional theory (ECD–TDDFT) computational analysis. Compounds 1 and 2 showed cytotoxic activities against seven mammalian cell lines (L929, KB3.1, MCF-7, A549, PC-3, SKOV-3, and A431) and antiproliferative effects against the myeloid leukemia K-562 cancer cell line. Both 1 and 2 were shown to possess properties inhibiting the F-actin network, prompting further hypotheses that should to be tested in the future to enable a well-resolved concept of the structural implications determining the bioactivity of the cytochalasin backbone against F-actin.

Polyoxygenated Cyclohexenes from Uvaria grandiflora with Multi-Enzyme Targeting Properties Relevant in Type 2 Diabetes and Obesity

“…USCF Chimera (version 1.13.1) was used to facilitate the removal of bound residues and minimization of structures. Dock-prepping of ligand and protein structures was done using Antechamber, and molecular docking was performed using the BFGS algorithm of AutoDock Vina (version 1.1.2) . Validation of the docking protocol was done via the redocking experiment of the co-crystallized ligands.…”

“…Dock-prepping of ligand and protein structures was done using Antechamber, and molecular docking was performed using the BFGS algorithm of AutoDock Vina (version 1.1.2). 23 Validation of the docking protocol was done via the redocking experiment of the co-crystallized ligands. The conformational protein–ligand structure was visualized and analyzed using Biovia Discovery Studios (version 4.1).…”

Cytochalasans and Their Impact on Actin Filament Remodeling

“…Additionally, following treatment with ChA ( 4 ), ChB ( 5 ), chaetoglobosin D (ChD, 61 ), ChJ ( 54 ), ChA monoacetate ( 60 ), and ChD diacetate ( 62 ), it was observed that cells are not able to spread again during a washout on the substratum after rounding, which was then shown to constitute a concentration-dependent effect. We encountered a similar phenomenon and attempted to estimate treatment conditions inferred from the extent of F-actin-disrupting effects [ 76 , 77 , 78 , 79 ]. Doing this, we observed that indeed there is a subset of compounds that tend to induce longer-lasting effects on F-actin networks, whereas other cytochalasans are again readily reversible.…”

“…Doing this, we observed that indeed there is a subset of compounds that tend to induce longer-lasting effects on F-actin networks, whereas other cytochalasans are again readily reversible. The physicochemical reasons for this behavior are unclear, but they seem to be linked to the modification of the macrocycle, which will be elaborated upon in a later passage [ 76 , 77 , 78 , 79 ].…”

How areN-methylcarbamates encapsulated by β-cyclodextrin: insight into the binding mechanism

“…In all cases, solvent effects have been included by employing the polarizable continuum model (PCM), which is often used in the ECD calculations. 47,50,51 Based on the excitation energies and rotational strengths obtained from TD-DFT, the theoretical ECD spectra were generated using the program Multiwfn. 52 2.2.2 QM/CSM calculations.…”