Absolute Configuration of Acremoxanthone C, a Potent Calmodulin Inhibitor from Purpureocillium lilacinum

Bioassay guided fractionation of an extract from Purpureocillum lilacinum allowed the isolation of two calmodulin (CaM) inhibitors, acremoxanthone C (1, K _d= 18.25 nM) and acremonidin A (2, K _d= 19.40 nM). The planar structure of 1 was previously reported but the absolute configuration at the stereogenic centers was not unambiguously established. Herein, the absolute configuration of 1 was established as 2R, 3R, 1'S, 11'S, and 14'R through extensive NMR spectroscopy and molecular modeling calculations at the DFT B3LYP/DGDZVP level which included the comparison between theoretical and experimental optical rotation and ³ J _C,H and ³ J _H,H values. Docking analysis predicted that 1 and 2 bind to CaM in a similar site as the vinblastine derivative KAR-2 does, which is unusual.