Metachelins, Mannosylated and N‑Oxidized Coprogen-Type Siderophores from <i>Metarhizium robertsii</i>

Under iron-depleted culture conditions, the entomopathogenic fungus <i>Metarhizium robertsii</i> (Bischoff, Humber, and Rehner) (= <i>M. anisopliae</i>) produces a complex of extracellular siderophores including novel O-glycosylated and N-oxidized coprogen-type compounds as well as the known fungal siderophores <i>N</i>^α-dimethylcoprogen (NADC) and dimerumic acid (DA). Metachelin A (<b>1</b>), the most abundant component in the <i>M. robertsii</i> siderophore mixture, was characterized as a 1094 Da analogue of NADC that is O-glycosylated by β-mannose at both terminal hydroxyl groups and N-oxidized at the dimethylated α-nitrogen. The mixture also contained a 1078 Da analogue, metachelin B (<b>2</b>), which lacks the <i>N</i>-oxide modification. Also characterized were the aglycone of <b>1</b>, i.e., the <i>N</i>-oxide of NADC (<b>3</b>), and the monomannoside of DA (<b>6</b>). <i>N</i>-Oxide and <i>O</i>-glycosyl substituents are unprecedented among microbial siderophores. At high ESIMS source energy and at room temperature in DMSO, <b>1</b> underwent Cope elimination, resulting in loss of the <i>N</i>^α-dimethyl group and dehydration of the α–β bond. High-resolution ESIMS data confirmed that all tri- and dihydroxamate siderophores (<b>1</b>–<b>6</b>) complex with trivalent Fe, Al, and Ga. In a chrome azurol S assay, all of the <i>M. robertsii</i> siderophores showed iron-binding activity roughly equivalent to that of desferrioxamine B

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

<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