Absolute configuration of acremoxanthone C, a potent calmodulin inhibitor from purpureocillium lilacinum
Por:
Madariaga-Mazón A., González-Andrade M., Gonzalez, MDC, Glenn A.E., Cerda-García-Rojas C.M., Mata R.
Publicada:
1 ago 2013
Resumen:
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. © 2013 The American Chemical Society and American Society of Pharmacognosy.
Filiaciones:
Madariaga-Mazón A.:
Univ Nacl Autonoma Mexico, Fac Quim, Mexico City 04510, DF, Mexico
Facultad de Química, Universidad Nacional Autónoma de México, México D.F., 04510, Mexico
González-Andrade M.:
Instituto Nacional de Medicina Genómica, Secretaría de Salud, México, D.F., 14610, Mexico
Gonzalez, MDC:
Univ Nacl Autonoma Mexico, Inst Biol, Mexico City 04510, DF, Mexico
Glenn A.E.:
Toxicology and Mycotoxin Research Unit, USDA-ARS, Russell Research Center, 950 College Station Road, Athens, GA 30605, United States
Cerda-García-Rojas C.M.:
Departamento de Química, Centro de Investigación y de Estudios Avanzados Del Instituto Politécnico Nacional, Apartado 14-740, México D.F., 07000, Mexico
Mata R.:
Univ Nacl Autonoma Mexico, Fac Quim, Mexico City 04510, DF, Mexico
Facultad de Química, Universidad Nacional Autónoma de México, México D.F., 04510, Mexico
Instituto de Biología, Universidad Nacional Autónoma de México, México D.F., 04510, Mexico
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