Calmodulin inhibitors from the fungus Emericella sp.

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 con. guration at C-20 and C-25 was designated as S and R, respectively, by Mosher ester methodology. Thereafter, the con. guration at C-14 and C-15 of 2 was established as S and S, respectively by comparing the optical rotation and H-1-H-1 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 (IC50 = 5.54 mu M) and 4 (IC50 = 5.62 mu M) was comparable with that of chlorpromazine (CPZ; IC50 = 7.26 mu M), 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). (C) 2008 Elsevier Ltd. All rights reserved.