Calmodulin inhibitors from the fungus Emericella sp.
- Bioorganic & Medicinal Chemistry, 17(6), p.2167-2174, 2009 .
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 (IC50 = 5.54 lM)and 4 (IC50 = 5.62 lM)was comparable with that of chlorpromazine (CPZ; IC50 = 7.26 lM), 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).