title: Absolute configuration of acremoxanthone C, a potent calmodulin inhibitor from Purpureocillium lilacinum.
abstract: 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, ³J(C,H), and ³J(H,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.
authors.affiliation: Facultad de Química, Universidad Nacional Autónoma de México , México D.F. 04510, Mexico.
authors.forename: Abraham
authors.initials: A
authors.lastname: Madariaga-Mazón
authors.forename: Martín
authors.initials: M
authors.lastname: González-Andrade
authors.forename: María Del Carmen
authors.initials: Mdel C
authors.lastname: González
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Glenn
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Cerda-García-Rojas
authors.forename: Rachel
authors.initials: R
authors.lastname: Mata
mesh_terms: D000465:Algorithms; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D006999:Hypocreales / Q000737:chemistry*; D008800:Mexico; D008956:Models, Chemical; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D044004:Xanthones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
chemical_list: D002147:Calmodulin; D006576:Heterocyclic Compounds, 4 or More Rings; D044004:Xanthones; C584591:acremoxanthone C