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. 2022 May 25;8(6):560.
doi: 10.3390/jof8060560.

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

Affiliations

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

Katherine Yasmin M Garcia et al. J Fungi (Basel). .

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.

Keywords: ECD–TDDFT; Sparticola triseptata; actin inhibitors; antiproliferative; cytotoxic; structure elucidation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Secondary metabolites 15 from Sparticola triseptata and cytochalasin D (6).
Figure 2
Figure 2
COSY and HMBC correlations in 1.
Figure 3
Figure 3
Low-energy conformers (>1%) of (3S,5S,7S,8aR, 9aR,13E,16R, 20R,21E)-1 optimized at B3LYP/6-31G(d) (PCM/MeOH).
Figure 4
Figure 4
Experimental ECD spectrum of triseptatin (1, black solid curve) compared with wB97XD/DGDZVP-calculated ECD spectra (red solid curve) for the B3LYP/6-31G(d)-optimized conformers of (3S,5S,7S,8aR, 9aR, 13E,16R,20R,21E)–1.
Figure 5
Figure 5
Overlay images of immobilized U2-OS cells treated with different concentrations of compounds 13 and 6 (1: (a,e,j), 2: (b,f,k), 3: (c,g,l), and 6: (d,h,m)) normalized against their cytotoxicity against L929 cells for one hour (IC50; low dose, 1 × IC50 (ad); high dose, 5 × IC50 (eh)) and the corresponding high-dose washout experiment after one hour recovery time (jm). Volume of the DMSO vehicle control was adjusted to the highest volume of DMSO used in the corresponding experiment (i,n). Cells were stained for their F-actin cytoskeleton using fluorescently coupled phalloidin (pseudocoloured in red) and nuclear DNA using DAPI (pseudocoloured in blue). Representative scale bar in image (a) correspond to 25 µm.
Figure 6
Figure 6
Overlay images of immobilized U2-OS cells treated with a gradually increasing concentration (0.03–30 µM) of compounds 2, 3, and 6 (2: (ag), 3: (io), and 3: (qw)) for one hour. IC50 values determined against L929 cells are denoted with arrows. Volume of the DMSO vehicle control was adjusted to the highest volume of DMSO used in the corresponding experiment (h,p,x). Cells were stained for their F-actin cytoskeleton using fluorescently coupled phalloidin (pseudocoloured in red) and nuclear DNA using DAPI (pseudocoloured in blue). Representative scale bar shown in image (a) represent 25 µm.

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