Martina Altemöller

Alternariol (AOH), a mycotoxin formed by Alternaria alternata, has been reported to possess genotoxic properties. However, the underlying mechanism of action is unclear. Here, we tested the hypothesis that interactions with DNA-topoisomerases play a role in the DNA-damaging properties of AOH. First we compared DNA-damaging properties of AOH with other Alternaria mycotoxins such as AOH monomethyl ether (AME), altenuene and isoaltenuene. AOH and AME significantly increased the rate of DNA strand breaks in human carcinoma cells (HT29, A431) at micromolar concentrations, whereas altenuene and isoaltenuene did not affect DNA integrity up to 100 microM. Next, we selected AOH as the most DNA-damaging Alternaria metabolite for further studies of interactions with DNA topoisomerases. In cell-free assays, AOH potently inhibited DNA relaxation and stimulated DNA cleavage activities of topoisomerase I, IIalpha and IIbeta. Stabilisation of covalent topoisomerase II-DNA intermediates by AOH was also detectable in cell culture, and here, the IIalpha isoform was preferentially targeted. AOH is thus characterised as a poison of topoisomerase I and II with a certain selectivity for the IIalpha isoform. Since topoisomerase poisoning and DNA strand breakage occurred within the same concentration range, poisoning of topoisomerase I and II might at least contribute to the genotoxic properties of AOH.

Abstract Total synthesis of altenuene and isoaltenuene, toxins produced by various alternaria fungi, were achieved for the first time in ten steps, starting with quinic acid and commercially available acetal‐protected phloroglucinic acid, with the longest linear sequence consisting of seven steps. The key reactions are palladium‐catalyzed Suzuki‐type couplings between an arene boronate and iodinated cyclohexenes. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Abstract Graphislactones A–H and the structurally related ulocladol are highly oxygenated resorcylic lactones produced by lichens and fungi. We present total syntheses of graphislactones A, C–F, H and of ulocladol. Graphislactones E, F, and H were synthesized for the first time. The spectra of graphislactones E and F synthesized as the originally proposed structures were not in agreement with published data. Consequently, revised structures for these compounds are proposed, whose correctness is unambiguously proven by total synthesis and comparison of the spectroscopic data. Key steps in all syntheses are Suzuki couplings for the construction of the central biaryl bond and Dakin reactions to supply further hydroxy groups required in these highly oxygenated substrates. Graphislactones A, C, and H, acylated graphislactone D and ulocladol were prepared in 8–11 steps with 7–20 % yield starting with purchasable compounds, where the longest linear sequence consists of 5–9 steps. The syntheses are thus significantly shorter than the previously published syntheses of graphislactones A–D and of ulocladol. Graphislactones E and F were synthesized in 8 steps, where the longest linear sequences consist of 6 and 5 steps, respectively. They were isolated as the respective acetylated compounds with 25 and 10 % yield.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)