Isolation, crystal structure, absolute configuration and molecular docking of butyrolactone I as a potential inhibitor of topoisomerase II

Abstract

Butyrolactone I is a natural butenolide that has been isolated from the culture broth of the thermophilic fungus Aspergillus terreus TM8. Its structure was determined by HR-ESI-MS as well as NMR spectroscopic data. The crystal structure and absolute configuration of butyrolactone I are reported herein for the first time based on single crystal X-ray diffraction. Butyrolactone I is known as a highly selective inhibitor of cyclin-dependent protein kinases which inhibits cell cycle progression at the G1/S and G2/M transitions. Through this study, we investigate the action of butyrolactone I against the human topoisomerase II (topo II) and vascular endothelial growth factor receptor2 (VEGFR2) kinase. The molecular docking results introduced butyrolactone I either as a catalytic inhibitor against topo IIα or a poison to topo IIβ while the first mechanism is the most likely to take place. Contrarily to topo II, butyrolactone I displayed a low affinity toward VEGFR2 kinase. In the light of the molecular docking investigation, butyrolactone I, in synchronizing to a catalytic inhibitor and poison control, was subjected to the in vitro topo IIα relaxation assay. The results revealed the capability of butyrolactone I to suppress the relaxation of the supercoiled DNA plasmid in a concentration-dependent manner, with IC50 value of 6.64 μM. Interestingly, this IC50 was more comparable to the catalytic inhibitor (staurosporine) rather than the poison one (doxorubicin).