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Burkholdines are cyclic lipopeptides with unusual antifungal potency, making them promising leads as a new class of antifungal agents. However, a recent report using knockout mutagenesis indicates that these and related compounds, such as occidiofungins, xylocandins, and cepacidines, may also be synonymous with the long-known hemolytic virulence factors found in diverse Burkholderia isolates. Because of their possible roles in causing Burkholderia infections or curing fungal infections, it is important to fully define their structures and biological activities using pure compounds. Here, we report the structures of three further burkholdines, Bk-1119, Bk-1213, and Bk-1215, which were elucidated using spectroscopic methods. The absolute configuration of this compound class was determined for the first time using a combination of spectroscopy and chemical degradation techniques. Antifungal and hemolytic activities were assessed for five pure burkholdines, representative of the structural diversity of this lipopeptide class. All of the burkholdines were potent antifungal and hemolytic agents, validating their probable role in virulence. However, one of the burkholdines (Bk-1119) exhibited a >30-fold selectivity for fungi versus sheep erythrocytes and was more than 25-fold more potent than amphotericin against some fungal strains. Therefore, burkholdines have potential to selectively target fungal infections.

Potent antifungal cyclic lipopeptides, burkholdines (Bk), were isolated from a culture of Burkholderia ambifaria 2.2N. Bk-1229 (1) and Bk-1097 (2) are octapeptides comprised of nonproteinogenic amino acids, including beta-hydroxytyrosine, beta-hydroxyasparagine, and a new fatty acyl amino acid. 1 and 2 are fungicidal against a panel of fungi with potencies 2-60-fold better than amphotericin B control.

The photochemistry, photophysics, and photosensitization (Type I and II) of indomethacin (IN) (N-[p-chlorobenzoyl]-5-methoxy-2-methylindole-3-acetic acid) has been studied in a variety of solvents using NMR, high performance liquid chromatography-mass spectroscopy, transient spectroscopy, electron paramagnetic resonance in conjunction with the spin trapping technique, and the direct detection of singlet molecular oxygen (1O2) luminescence. Photodecomposition of IN (lambda ex > 330 nm) in degassed or air-saturated benzene proceeds rapidly to yield a major (2; N-[p-chlorobenzyl]-5-methoxy-2-methyl-3-methylene-indoline) and a minor (3; N-[p-chlorobenzoyl]-5-methoxy-2,3-dimethyl-indole) decarboxylated product and a minor indoline (5; 1-en-5-methoxy-2-methyl-3- methylene-indoline), which is formed by loss of the p-chlorobenzoyl moiety. In air-saturated solvents two minor oxidized products 4 (N-[p-chlorobenzoyl]-5-methoxy-2-methyl-indole-3-aldehyde) and 6 (5-methoxy-2-methyl-indole-3-aldehyde) are also formed. When photolysis was carried out in 18O2-saturated benzene, the oxidized products 4 and 6 contained 18O, indicating that oxidation was mediated by dissolved oxygen in the solvent. In more polar solvents such as acetonitrile or ethanol, photodecomposition is extremely slow and inefficient. Phosphorescence of IN at 77 K shows strong solvent dependence and its emission is greatly reduced as polarity of solvent is increased. Flash excitation of In in degassed ethanol or acetonitrile products no transients. A weak transient is observed at 375 nm in degassed benzene, which is not quenched by oxygen.(ABSTRACT TRUNCATED AT 250 WORDS)

The chemical structures of AT2433-A1 (2), AT2433-A2 (3), AT2433-B1 (4) and AT2433-B2 (5) were elucidated by degradation and spectroscopic studies. Compounds 2-5 are disaccharides closely related to rebeccamycin. The aglycone in 2 and 3 was determined to be 6-N-methyl-11-chloro-5H-indolo[2,3-a]pyrolo[3,4-c]carbazole and in 4 and 5 it was determined to be 6-N-methyl-5H-indolo[2,3-a]pyrolo[3,4-c]carbazole. Compounds 2 and 4 are 4-N"-methyl analogs of 3 and 5.

A rapid, integrated biological-physicochemical system for the identification of six major classes of antitumor compounds in fermentation broths is described. The system relies upon preliminary fractionation of the fermentation broth by liquid-solid extraction, gradient high-performance liquid chromatography with diode-array spectrophotometric detection of the compounds and automated bioassay. The previously stored UV-VIS spectra of the biologically active peaks are used for identification. Confirmation of compound identity is by thermospray liquid chromatography-mass spectrometry. The method has been applied to representatives of the bleomycin, streptonigrin, echinomycin, chromomycin, actinomycin and anthracycline groups.