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, <i>Sparticola triseptata</i>. A new cytochalasan analog triseptatin (<b>1</b>), along with the previously described cytochalasans deoxaphomin B (<b>2</b>) and cytochalasin B (<b>3</b>), and polyketide derivatives <i>cis</i>-4-hydroxy-6-deoxyscytalone (<b>4</b>) and 6-hydroxymellein (<b>5</b>) were isolated from the rice culture of <i>S. triseptata</i>. The structure of <b>1</b> 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 <b>1</b> and <b>2</b> 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 <b>1</b> and <b>2</b> 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.