Malbrancheamide, a new calmodulin inhibitor from the fungus Malbranchea aurantiaca

Bioassay-directed fractionation of an ethyl acetate extract (mycelia and broth) of the fungus Malbranchea aurantiaca led to the isolation of the novel phytotoxic alkaloid (5aS,12aS,13aS)-8,9-dichloro-12,12-dimethyl-2,3,11,12,12a,13-hexahydro-1H,6H-5a,13a (epiminomethano)indolizino[7,6b]carbazol-14-one () of the brevianamide series. The phytotoxin was given the trivial name of malbrancheamide (). The structure of was unequivocally established by UV, NMR, MS and X-ray studies. The absolute configuration was established by X-ray analysis according to the method of Flack. According to the conformational studies using molecular mechanics analyses, exists in one preferred conformation, which was optimized by DFT calculations. Compound caused moderate inhibition of radicle growth of Amaranthus hypochondriacus (IC50=0.37 μM) and inhibited the activation of the calmodulin-dependent enzyme PDE1 (IC50=3.65±0.74 μM). This effect was comparable to that of chlorpromazine (IC50=2.75±0.87 μM) a well characterized CaM antagonist. The inhibition mechanism of was competitive with respect to CaM according to a kinetic analysis.