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 (1) of the brevianamide series. The phytotoxin was given the trivial name of malbrancheamide (1). The structure of 1 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, 1 exists in one preferred conformation, which was optimized by DFT calculations. Compound 1. caused moderate inhibition of radicle growth of Amaranthus hypochondriacus (IC50 = 0.37 mu M) and inhibited the activation of the calmodulin-dependent enzyme PDE1 (IC50 = 3.65 +/- 0.74 mu M). This effect was comparable to that of chlorpromazine (IC50 = 2.75 +/- 0.87 mu M) a well characterized CaM antagonist. The inhibition mechanism of 1 was competitive with respect to CaM according to a kinetic analysis. (c) 2005 Elsevier Ltd. All rights reserved.