Metacridamides A and B, Macrocycles from Conidia of the Entomopathogenic Fungus <i>Metarhizium acridum</i>

Abstract

<i>Metarhizium acridum</i>, an entomopathogenic fungus, has been commercialized and used successfully for biocontrol of grasshopper pests in Africa and Australia. Its conidia produce two novel 17-membered macrocycles, metacridamides A (<b>1</b>) and B (<b>2</b>), which consist of a Phe unit condensed with a nonaketide. Planar structures were elucidated by a combination of mass spectrometric and NMR techniques. Following hydrolysis of <b>1</b>, chiral amino acid analysis assigned the l-configuration to the Phe unit. A crystal structure established the absolute configuration of the eight remaining stereogenic centers in <b>1</b>. Metacridamide A (<b>1</b>) showed cytotoxicity to three cancer lines with IC₅₀'s of 6.2, 11.0, and 10.8 μM against Caco-2 (epithelial colorectal adenocarcinoma), MCF-7 (breast cancer), and HepG2/C3A (hepatoma) cell lines, respectively. In addition, metacridamide B (<b>2</b>) had an IC₅₀ of 18.2 μM against HepG2/C3A, although it was inactive at 100 μM against Caco-2 and MCF-7. Neither analogue showed antimicrobial, phytotoxic, or insecticidal activity