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 1H– 1H 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 μM) and 4 (IC 50 = 5.62 μM) was comparable with that of chlorpromazine (CPZ; IC 50 = 7.26 μM), 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).
Highlights
The genus Emericella, one of the anamorphus of Aspergillus,[2] biosynthesizes a remarkable diversity of secondary metabolites with interesting biological properties representing potential leads for the developing of new pharmaceutical agents
E. quadrilineata has yielded some immunostimulant xanthones[10] and tremorgenic alkaloids, while E. aurantiobrunnea some variecolin analogues which compete with macrophage inflammatory protein (MIP)-1α for binding to human CCR5 in a scintillation proximity assay.[11]
Within the scope of a program aiming at the discovery of novel calmodulin (CaM)-inhibitors useful as pesticide or drug leads,[23, 24, 25] we report the structure elucidation and CaMinhibitor properties of two new tajixanthones analogs from a Emericella strain isolated from a coral species collected on the Mexican Pacific coast
Summary
The genus Emericella, one of the anamorphus of Aspergillus,[2] biosynthesizes a remarkable diversity of secondary metabolites with interesting biological properties representing potential leads for the developing of new pharmaceutical agents. Within the scope of a program aiming at the discovery of novel calmodulin (CaM)-inhibitors useful as pesticide or drug leads,[23, 24, 25] we report the structure elucidation and CaMinhibitor properties of two new tajixanthones analogs from a Emericella strain isolated from a coral species collected on the Mexican Pacific coast. Modulation of physiological targets of CaM by natural or synthetic compounds offers great possibilities for the discovery of new leads for the development of herbicide or therapeutically useful agents. Smooth muscle relaxants, α-adrenergic blocking, inmunostimulant and cytoprotective drugs, among others, inhibit CaM.[25]
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