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The total synthesis of destruxin E (1) has been achieved for the first time, and the stereochemistry of its chiral center at the epoxide has been determined to be (S). The cyclization precursor 3a was synthesized by solid-phase peptide synthesis. Macrolactonization of 3a utilizing MNBA-DMAPO, followed by formation of the epoxide, then furnished destruxin E. Its diastereomer, epi-destruxin E (2), was also synthesized in the same manner. Furthermore, the biological evaluation indicated that destruxin E exhibits V-ATPase inhibitory activity 10-fold greater than that of epi-destruxin E.

Destruxins are of current interest as bioactive agents. They are cyclic hexadepsipeptides produced by fungi, the most common destruxins, A, B and E, differing in the structure of a side chain. Before they can be widely used, the potential risk of destruxins and their metabolites entering the human food chain must to be assessed; thus, knowledge of the structures of their degradation products is essential. Here we report a study aimed at identifying, by tandem mass spectrometry and accurate mass analysis, the products resulting from thermally and temporally induced degradation of destruxin E. The degradation products fell into two groups: those with relatively simple modifications of the side chain and those involving much more complex rearrangements. The structures of most of the degradation products were deduced from the MS data, with the major product being destruxin E diol: significantly, this compound had previously been reported to have only been produced as a metabolic product of enzyme action rather than as a simple degradation product as demonstrated here. Copyright © 2004 John Wiley & Sons, Ltd.

The toxicity of destruxin E for nymphs of Empoasca vitis (Gothe) was assessed in the laboratory using various administrative routes: 10 ml of a given concentration of the toxin (30, 100, 300 and 1000 ppm) were sprayed either on potato leaves or directly onto the insects, and 1 μl of a 100 ppm concentration of toxin was applied onto the nota of the insects. Checks were made daily for 4 days and mortality in E. vitis was recorded. Natural mortality was less than 5%. Nymphs of E. vitis were susceptible to the insecticidal activity of destruxin E in all three treatments. Mortality was concentration-dependent in nymphs exposed to treated leaves and in nymphs sprayed directly. The potency of destruxin E was reflected in the low LC50 values obtained: 46.4 ppm for insects exposed to treated leaves and 38.2 ppm for insects sprayed directly. The LT50 values were 3.2 days (at 30 ppm) and 0.2 days (1000 ppm) for nymphs sprayed directly, and slightly higher for nymphs exposed to treated leaves. Analysis of data (100 ppm) showed that there was no significant difference in mortality due to either of the three bioassay procedures. Mortality rates were 87.5% in nymphs sprayed directly, 93.8% in nymphs exposed to treated leaves, and 78.1% in nymphs in the topical application test. The LT50 value in the latter test (at 100 ppm) was 1.3 days. Contact insecticidal activity of destruxin E is demonstrated here for the first time. Zusammenfassung Kontaktwirkung des Myzotoxins Destruxin E auf Empoasca vitis (Gothe) (Hom., Cicadellidae) Die Toxizitat von Destruxin E gegenuber Nymphen von Empoasca vitis wurde im Labor unter verschiedenen Applikationsbedingungen untersucht. Es wurden jeweils 10 ml der getesteten Konzentrationen (30, 100, 300 und 1000 ppm) auf Kartoffelblatter bzw. direkt auf die Insekten gespritzt und 1 μl einer 100 ppm Konzentration wurde den Insekten topikal appliziert. Die Versuche wurden wahrend 4 Tagen taglich kontrolliert, und die Mortalitat von E. vitis wurde registriert. Die naturliche Mortalitat lag unter 5%. Bei alien drei Applikationsbedingungen erwiesen sich E. vitis-Nymphen als empfindlich gegenuber Detruxin E. Bei der Behandlung der Blatter und der direkten Bespruhung der Nymphen konnte eine konzentrationsabhangige Mortalitat nachgewiesen werden. Die LC50 betrug bei Behandlung der Blatter 46,4 ppm, bei Behandlung der Nymphen 38,2 ppm. Die Lt50-Werte bei direkter Behandlung der Nymphen betrugen 3,2 Tage (30 ppm) und 0,2 Tage (1000 ppm); die Werte lagen etwas hoher, wenn die Applikation uber die Behandlung der Blatter erfolgte. Die statistische Analyse der Daten bei einer Konzentration von 100 ppm ergab, das kein signifikanter Mortalitatsunterschied zwischen den drei Applikationsmethoden besteht. Die Mortalitatsraten betrugen 87,5% (direkte Behandlung der Nymphen), 93,8% (Behandlung der Blatter) und 78,1% (Topikalapplikation). Der Lt50-Wert betrug bei 100 ppm 1,3 Tage. In den vorliegenden Versuchen konnte erstmalig eine Kontaktwirkung von Destruxin E nachgewiesen werden.

In the course of our screening efforts to discover small molecules as selective inhibitors of vacuolar-type H + -ATPase of Saccharomyces cerevisiae, we have identified eight active destruxins, 1-8, from the fungus Metarhizium anisopliae. The structures were elucidated by extensive 1D- and 2D-NMR spectroscopy, and MS spectrometry. One of these compounds, 8, a regioisomer of chlorohydrin destruxin E (7), is a new destruxin.

Chemical investigation of the cytotoxic and anti-tuberculosis active butanone extract obtained from the growth media of the marine-derived fungus Beauveria felina led to the isolation of two new destruxins, [beta-Me-Pro] destruxin E chlorohydrin (1) and pseudodestruxin C (3), along with five known cyclic depsipeptides. The structures of the new destruxin derivatives were established by analysis of spectroscopic data, while the absolute configuration of the common amino acid residues was established by Marfey's analysis. The absolute configuration of the 2(R),4(S)-5-chloro-2,4-dihydroxypentanoic acid residue in 1 could be established by application of a J-based configuration method followed by derivatization with R-MPA-Cl and NMR analysis.

R. Dornetshuber-Fleiss, P. Heffeter, T. Mohr, P. Hazemi, K. Kryeziu, C. Seger, W. Berger, R. Lemmens-Gruber. University of Vienna and Medical University of Vienna, Institute of Pharmacology and Toxicology and the Institute of Cancer Research Department of Medicine I and Comprehensive Cancer Center of the Medical University, Vienna, Austria; Medical University of Vienna, Institute of Cancer Research Department of Medicine I and Comprehensive Cancer Center of the Medical University, Vienna, Austria; University of Vienna, Department of Pharmacology and Toxicology, Vienna, Austria; Medical University of Vienna, Institute of Cancer Research Department of Medicine I and Comprehensive Cancer Center of the Medical University, Vienna, Austria; Leopold-Franzens University Innsbruck, Institute of Pharmacy Department of Pharmacognosy, Vienna, Austria