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Absolute configuration of acremoxanthone C, a potent calmodulin inhibitor from Purpureocillium lilacinum

Abraham Madariaga-Mazón, Martín González-Andrade, María del Carmen González, Anthony E. Glenn, Carlos M. Cerda-García-Rojas, Rachel Mata
Journal of Natural Products 2013 v.76 no. pp. 1454-1460
Paecilomyces, binding capacity, biosensors, calmodulin, chlorpromazine, culture media, dissociation, fractionation, molecular conformation, mycelium, nuclear magnetic resonance spectroscopy
Bioassay-guided fractionation of an extract prepared from the culture medium and mycelium of Purpureocillium lilacinum allowed the isolation of two calmodulin(CaM) inhibitors, namely, acremoxanthone C (1) and acremonidin A (2). 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 specific rotation, 3JC,H,and 3JH,H values. Compounds 1 and 2 bind to the human calmodulin (hCaM) biosensor hCaM M124C-mBBr, with dissociation constants (Kd) of 18.25 and 19.40 nM, respectively, 70-fold higher than that of chlorpromazine (Kd = 1.24 μM), used as positive control. Docking analysis using AutoDock 4.2 predicted that 1 and 2 bind to CaM at a similar site to that which KAR-2 binds, which is unusual. Furthermore, a novel, sensible, and specific fluorescent biosensor of hCaM, i.e., hCaM T110C-mBBr, was constructed; this device is labeled at a site where classical inhibitors do not interact and was successfully applied to measure the interaction of 1 with CaM. This is the first report of xanthone−anthraquinone heterodimers in species of Paecilomyces or Purpureocillium genera.