Citrinin Derivatives From Penicillium Citrinum Y34 That Inhibit alpha-Glucosidase and ATP-Citrate Lyase

Two new citrinin dimers bearing a 6,6-spiroketal moiety (1 and 2) and four known analogues (3-6), together with 18 known citrinin monomers (7-24), were isolated from the culture of hydrothermal vent-associated fungus Penicillium citrinum Y34. Their structures were identified by extensive spectroscopic analyses, C-13 NMR calculation in combination with DP4+, linear correlation coefficient (R-2), and mean absolute error (MAE) values analyses, and electronic circular dichroism (ECD) calculation. The alpha-glucosidase and ATP-citrate lyase (ACL) inhibitory activities of isolated compounds were evaluated. Compounds 1, 3, and 12 displayed moderate alpha-glucosidase inhibitory activities with IC50 values of 239.8, 176.2, and 424.4 mu M, respectively. Enzyme kinetics investigations of 1 and 3 suggested their non-competitive inhibition of alpha-glucosidase with K-i values of 204.3 and 212.7 mu M, respectively. Meanwhile, compound 4 showed significant ACL inhibitory potential with an IC50 value of 17.4 mu M. Furthermore, the interactions of 1, 3, and 12 with alpha-glucosidase and 4 with ACL were investigated by molecular docking assay. This study demonstrates that citrinins, especially for their dimers, could be potential lead compounds for the development of new agents for the treatment of metabolic diseases.