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 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).
Figueroa
Mario
M
Facultad de Química, Universidad Nacional Autónoma de México, México DF 04510, Mexico.
González
María del Carmen
Mdel C
Rodríguez-Sotres
Rogelio
R
Sosa-Peinado
Alejandro
A
González-Andrade
Martín
M
Cerda-García-Rojas
Carlos M
CM
Mata
Rachel
R
D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002942:Circular Dichroism; D004591:Electrophoresis, Polyacrylamide Gel; D032842:Emericella / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D021241:Spectrometry, Mass, Electrospray Ionization; D016339:Spectrometry, Mass, Fast Atom Bombardment; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology*
C541042:14-methoxytajixanthone; C541041:15-chlorotajixanthone; D002147:Calmodulin; D044004:Xanthones