Calmodulin inhibitors from the fungus Emericella sp.

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Figueroa M, Gonzalez Mdel C, Rodriguez-Sotres R, Sosa-Peinado A, Gonzalez-Andrade M, Cerda-Garcia-Rojas CM, Mata R

Calmodulin inhibitors from the fungus Emericella sp.

Bioorg Med Chem. 2009 Mar 15;17(6):2167-74. doi: 10.1016/j.bmc.2008.10.079. Epub 2008 Nov 5.

PubMed ID

19013822 [ View in PubMed

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Abstract

Two new xanthones identified as 15-chlorotajixanthone hydrate (1) and 14-methoxytajixanthone (2) were isolated from an Emericella sp. strain 25379 along with shamixanthone (3) and tajixanthone hydrate (4). The stereostructures of 1 and 2 were elucidated by spectroscopic and molecular modeling methods. The absolute configuration at the stereogenic centers of 1 was established according to CD measurements. In the case of 2, however, the absolute configuration at C-20 and C-25 was designated as S and R, respectively, by Mosher ester methodology. Thereafter, the configuration at C-14 and C-15 of 2 was established as S and S, respectively by comparing the optical rotation and (1)H-(1)H coupling constant experimental values with those obtained through molecular modeling calculations at DFT B3LYP/DGDZVP level of theory for diasteroisomers 2a-2d. The activation of the calmodulin-sensitive cAMP phosphodiesterase (PDE1) was inhibited in the presence of 1-4 in a concentration-dependent manner. The effect of compounds 2 (IC(50)=5.54 microM) and 4 (IC(50)=5.62 microM) was comparable with that of chlorpromazine (CPZ; IC(50)=7.26 microM), a well known CaM inhibitor used as a positive control. The inhibition mechanism of both compounds was competitive with respect to CaM according to a kinetic study. A docking analysis with 2 and 4 using the AutoDock 4.0 program revealed that they interacted with CaM in the same pocket as trifluoropiperazine (TFP).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Chlorpromazine	Calmodulin	IC 50 (nM)	7260	N/A	N/A	Details
Chlorpromazine	Calmodulin	Ki (nM)	19280	N/A	N/A	Details