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

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• 作者：Abraham Madariaga-Maz贸n ; Mart铆n Gonz谩lez-Andrade ; Mar铆a del Carmen Gonz谩lez ; Anthony E. Glenn ; Carlos M. Cerda-Garc铆a-Rojas ; Rachel Mata
• 刊名：Journal of Natural Products
• 出版年：2013
• 出版时间：August 23, 2013
• 年：2013
• 卷：76
• 期：8
• 页码：1454-1460
• 全文大小：401K
• 年卷期：v.76,no.8(August 23, 2013)
• ISSN：1520-6025

文摘

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鈥?i>S, 11鈥?i>S, and 14鈥?i>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 (K_d) of 18.25 and 19.40 nM, respectively, 70-fold higher than that of chlorpromazine (K_d = 1.24 渭M), 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鈥揳nthraquinone heterodimers in species of Paecilomyces or Purpureocillium genera.