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Publikation

Ricardo, M. G.; Schwark, M.; Llanes, D.; Niedermeyer, T. H. J.; Westermann, B.; Total synthesis of Aetokthonotoxin, the cyanobacterial neurotoxin causing vacuolar myelinopathy Chem.-Eur. J. 27, 12032-12035, (2021) DOI: 10.1002/chem.202101848

Aetokthonotoxin has recently been identified as the cyanobacterial neurotoxin causing Vacuolar Myelinopathy, a fatal neurologic disease, spreading through a trophic cascade and affecting birds of prey such as the bald eagle in the USA. Here, we describe the total synthesis of this specialized metabolite. The complex, highly brominated 1,2’-biindole could be synthesized via a Somei-type Michael reaction as key step. The optimised sequence yielded the natural product in five steps with an overall yield of 29 %.
Publikation

Ditfe, T.; Bette, E.; N. Sultani, H.; Otto, A.; Wessjohann, L. A.; Arnold, N.; Westermann, B.; Synthesis and biological evaluation of highly potent fungicidal deoxy‐hygrophorones Eur. J. Org. Chem. 2021, 3827-3836, (2021) DOI: 10.1002/ejoc.202100729

Although stripped from hydroxyl-groups, deoxygenated hygrophorones remain highly active against severe phytopathogens. The synthesis to these natural product congeners is achieved in rearrangement sequences, with an optimized deprotection strategy avoiding retro-aldol reactions. The activities are comparable to fungicides used in agriculture. Based on naturally occurring hygrophorones, racemic di- and mono-hydroxylated cyclopentenones bearing an aliphatic side chain have been produced in short synthetic sequences starting from furfuryl aldehyde. For the series of dihydroxylated trans-configured derivatives, an Achmatowicz-rearrangement and a Caddick-ring contraction were employed, and for the series of trans-configured mono-hydroxylated derivatives a Piancatelli-rearrangement. All final products showed good to excellent fungicidal activities against the plant pathogens B. cinerea, S. tritici and P. infestans.
Publikation

Sultani, H. N.; Morgan, I.; Hussain, H.; Roos, A. H.; Haeri, H. H.; Kaluđerović, G. N.; Hinderberger, D.; Westermann, B.; Access to new cytotoxic triterpene and steroidal Acid-TEMPO Conjugates by ugi multicomponent-reactions Int. J. Mol. Sci. 22, 7125, (2021) DOI: 10.3390/ijms22137125

Multicomponent reactions, especially the Ugi-four component reaction (U-4CR), provide powerful protocols to efficiently access compounds having potent biological and pharmacological effects. Thus, a diverse library of betulinic acid (BA), fusidic acid (FA), cholic acid (CA) conjugates with TEMPO (nitroxide) have been prepared using this approach, which also makes them applicable in electron paramagnetic resonance (EPR) spectroscopy. Moreover, convertible amide modified spin-labelled fusidic acid derivatives were selected for post-Ugi modification utilizing a wide range of reaction conditions which kept the paramagnetic center intact. The nitroxide labelled betulinic acid analogue 6 possesses cytotoxic effects towards two investigated cell lines: prostate cancer PC3 (IC50 7.4 ± 0.7 μM) and colon cancer HT29 (IC50 9.0 ± 0.4 μM). Notably, spin-labelled fusidic acid derivative 8 acts strongly against these two cancer cell lines (PC3: IC50 6.0 ± 1.1 μM; HT29: IC50 7.4 ± 0.6 μM). Additionally, another fusidic acid analogue 9 was also found to be active towards HT29 with IC50 7.0 ± 0.3 μM (CV). Studies on the mode of action revealed that compound 8 increased the level of caspase-3 significantly which clearly indicates induction of apoptosis by activation of the caspase pathway. Furthermore, the exclusive mitochondria targeting of compound 18 was successfully achieved, since mitochondria are the major source of ROS generation.
Publikation

Méndez, Y.; Vasco, A. V.; Humpierre, A. R.; Westermann, B.; Isonitriles: Versatile handles for the bioorthogonal functionalization of proteins ACS Omega 5, 25505-25510, (2020) DOI: 10.1021/acsomega.0c03728

The property of the isonitrile group to enable the simultaneous α-addition of a strong electrophile and a nucleophile has always attracted the attention of organic chemists. Its versatility is augmented when recognizing that its high structural compactness, the inertia to most of the naturally occurring functional groups, and relatively prolonged physiological and metabolical stability, convert it into the smallest bioorthogonal group. The discovery and optimization of the isonitrile-tetrazine [4+1] cycloaddition as an alternative tool for the development of ligation and decaging strategies and the recently reported reaction of isonitriles with chlorooximes bring new opportunities for the utilization of this functional group in biological systems. Although several approaches have been reported for the synthesis of isonitrile-modified carbohydrates and polysaccharides, its incorporation in proteins has been barely explored. Besides compiling the reported methods for the assembly of isonitrile-modified proteins, this Mini-Review aims at calling attention to the real potential of this modification for protein ligation, decaging, immobilization, imaging, and many other applications at a low structural and functional cost.
Publikation

Ravanello, B. B.; Seixas, N.; Rodrigues, O. E. D.; da Silva, R. S.; Villetti, M. A.; Frolov, A.; Rivera, D. G.; Westermann, B.; Diversity Driven Decoration and Ligation of Fullerene by Ugi and Passerini Multicomponent Reactions Chem.-Eur. J. 24, 9788-9793, (2018) DOI: 10.1002/chem.201802414

Aiming at providing an efficient and versatile method for the diversity‐oriented decoration and ligation of fullerenes, we report the first C60 derivatization strategy based on isocyanide‐multicomponent reactions (I‐MCRs). The approach comprises the use of Passerini and Ugi reactions for assembling pseudo‐peptidic scaffolds (i.e., N‐alkylated and depsipeptides, peptoids) on carboxylic acid‐functionalized fullerenes. The method showed wide substrate scope for the oxo and isocyanide components, albeit the Ugi reaction proved efficient only for aromatic amines. The approach was successfully employed for the ligation of oligopeptides and polyethyleneglycol chains (PEG) to C60, as well as for the construction of bis‐antennary as well as PEG‐tethered dimeric fullerenes. The quantum yields for the formation of 1O2 was remarkable for the selected compounds analyzed.
Publikation

Nawaz, S. A.; Ayaz, M.; Brandt, W.; Wessjohann, L. A.; Westermann, B.; Cation–π and π–π stacking interactions allow selective inhibition of butyrylcholinesterase by modified quinine and cinchonidine alkaloids Biochem. Biophys. Res. Commun. 404, 935-940, (2011) DOI: 10.1016/j.bbrc.2010.12.084

Scaffold varied quaternized quinine and cinchonidine alkaloid derivatives were evaluated for their selective butyrylcholinesterase (BChE) inhibitory potential. Ki values were between 0.4–260.5 μM (non-competitive inhibition) while corresponding Kivalues to acetylcholinesterase (AChE) ranged from 7.0–400 μM exhibiting a 250-fold selectivity for BChE.Docking arrangements (GOLD, PLANT) revealed that the extended aromatic moieties and the quaternized nitrogen of the inhibitors were responsible for specific π–π stacking and π–cation interactions with the choline binding site and the peripheral anionic site of BChE’s active site.
Publikation

Eschen-Lippold, L.; Draeger, T.; Teichert, A.; Wessjohann, L.; Westermann, B.; Rosahl, S.; Arnold, N.; Antioomycete Activity of γ-Oxocrotonate Fatty Acids against P. infestans J. Agr. Food Chem. 57, 9607-9612, (2009) DOI: 10.1021/jf902067k

Infections with Phytophthora infestans, the causal agent of potato and tomato late blight disease, are difficult to control and can lead to considerable agricultural losses. Thus, the development of new effective agents against the pathogen is of great interest. In previous work, (E)-4-oxohexadec-2-enoic acid (3) was isolated from Hygrophorus eburneus, which exhibited fungicidal activity against Cladosporium cucumerinum. Here, the inhibitory effect of 3 on P. infestans spore germination and mycelium growth in vitro is demonstrated. The in vivo effect on infections of whole potato plants was investigated by spraying plants with the sodium salt of 3, sodium (2E)-4-oxohexadec-2-enoic acid (4), prior to P. infestans inoculation. Additionally, the influence of 3 on mycelium growth of Colletotrichum coccodes, the causal agent of potato black dot disease, was analyzed. In all approaches, a significant inhibition of pathogen development was achieved. Importantly, the unsaturated fatty acid exerted no toxic effect when sprayed on plants, a prerequisite for its commercial use.

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