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Title: (+)-Ascosalitoxin and vermelhotin, a calmodulin inhibitor, from an endophytic fungus isolated from Hintonia latiflora

Author
item LEYTE-LUGO, MARTHA - Universidad Nacional Autonoma De Mexico
item GONZALEZ-ANDRADE, MARTIN - Universidad Nacional Autonoma De Mexico
item GONZALEZ, MARIA, DEL CARMEN - Universidad Nacional Autonoma De Mexico
item Glenn, Anthony - Tony
item CERDA-GARCIA-ROJAS, CARLOS - National Polytechnic Institute
item MATA, RACHEL - Universidad Nacional Autonoma De Mexico

Submitted to: Journal of Natural Products
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/27/2012
Publication Date: 8/27/2012
Citation: Leyte-Lugo, M., Gonzalez-Andrade, M., Gonzalez, Maria, D., Glenn, A.E., Cerda-Garcia-Rojas, C.M., Mata, R. 2012. (+)-Ascosalitoxin and vermelhotin, a calmodulin inhibitor, from an endophytic fungus isolated from Hintonia latiflora. Journal of Natural Products. 75:1571-1577. DOI: 10.1021/np300327y

Interpretive Summary: Endophytic fungi were isolated from the plant Hintonia latiflora, which is a medicinal plant in Mexico used for treatment of diabetes. This unidentified fungus (strain 39140-2) was found to produce secondary metabolites, one of which was a new compound. The structure of the new compound was determined using NMR spectroscopy and molecular modeling. The ability of the compounds to act as inhibitors of the enzyme calmodulin was also examined.

Technical Abstract: Chemical investigation of the endophytic fungus 39140-2, isolated from the medicinal plant Hintonia latiflora, yielded the known polyketide vermelhotin (1) and a new salycilic aldehyde derivative, namely 9S,11R-(+)-ascosalitoxin (2). The structure and absolute configuration of the new compound was established through extensive NMR spectroscopy and molecular modeling calculations at the DFT B3LYP/DGDZVP level which included the comparison between theoretical and experimental optical rotation. In addition, chemical transformations of 2 yielded suitable derivatives for NOESY and 1H-1H NMR coupling constants analyses which reinforce the stereochemical assignment. The potential affinity of 1 and 2 with (Ca+2)4-hCaM in solution was also measured using the fluorescent biosensor hCaM M124C-mBBr. The results showed that only 1 bound to the protein with a dissociation constant (Kd) of 0.25 ± 0.04 uM, close to that of chlorpromazine (CPZ, Kd=0.64 ± 0.03 uM) a classical CaM inhibitor. The stoichiometry ratio for 1: CaM was 1 to 4 as for other well-known CaM-ligands.