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
2013 Journal of natural products  
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, 3 J
more » ... cific rotation, 3 J C,H , and 3 J H,H values. Compounds 1 and 2 bind to the human calmodulin (hCaM) biosensor hCaM M124C-mBBr, with dissociation constants (K d ) of 18.25 and 19.40 nM, respectively, 70fold higher than that of chlorpromazine (K d = 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.
doi:10.1021/np4002477 pmid:23876004 fatcat:xq5k7is4dfb3lcbtdg6uhlfmgm