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Publications - Bioorganic Chemistry

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Publications

Paudel, G.; Bilova, T.; Schmidt, R.; Greifenhagen, U.; Berger, R.; Tarakhovskaya, E.; Stöckhardt, S.; Balcke, G. U.; Humbeck, K.; Brandt, W.; Sinz, A.; Vogt, T.; Birkemeyer, C.; Wessjohann, L.; Frolov, A.; Osmotic stress is accompanied by protein glycation in Arabidopsis thaliana J. Exp. Bot. 67, 6283-6295, (2016) DOI: 10.1093/jxb/erw395

Among the environmental alterations accompanying oncoming climate changes, drought is the most important factor influencing crop plant productivity. In plants, water deficit ultimately results in the development of oxidative stress and accumulation of osmolytes (e.g. amino acids and carbohydrates) in all tissues. Up-regulation of sugar biosynthesis in parallel to the increasing overproduction of reactive oxygen species (ROS) might enhance protein glycation, i.e. interaction of carbonyl compounds, reducing sugars and α-dicarbonyls with lysyl and arginyl side-chains yielding early (Amadori and Heyns compounds) and advanced glycation end-products (AGEs). Although the constitutive plant protein glycation patterns were characterized recently, the effects of environmental stress on AGE formation are unknown so far. To fill this gap, we present here a comprehensive in-depth study of the changes in Arabidopsis thaliana advanced glycated proteome related to osmotic stress. A 3 d application of osmotic stress revealed 31 stress-specifically and 12 differentially AGE-modified proteins, representing altogether 56 advanced glycation sites. Based on proteomic and metabolomic results, in combination with biochemical, enzymatic and gene expression analysis, we propose monosaccharide autoxidation as the main stress-related glycation mechanism, and glyoxal as the major glycation agent in plants subjected to drought.
Books and chapters

Bilova, T.; Greifenhagen, U.; Paudel, G.; Lukasheva, E.; Brauch, D.; Osmolovskaya, N.; Tarakhovskaya, E.; Balcke, G. U.; Tissier, A.; Vogt, T.; Milkowski, C.; Birkemeyer, C.; Wessjohann, L.; Frolov, A.; Glycation of Plant Proteins under Environmental Stress — Methodological Approaches, Potential Mechanisms and Biological Role (Shanker, A. K. & Shanker, C., eds.). 295-316, (2016) DOI: 10.5772/61860

Environmental stress is one of the major factors reducing crop productivity. Due to the oncoming climate changes, the effects of drought and high light on plants play an increasing role in modern agriculture. These changes are accompanied with a progressing contamination of soils with heavy metals. Independent of their nature, environmental alterations result in development of oxidative stress, i.e. increase of reactive oxygen species (ROS) contents, and metabolic adjustment, i.e. accumulation of soluble primary metabolites (amino acids and sugars). However, a simultaneous increase of ROS and sugar concentrations ultimately results in protein glycation, i.e. non-enzymatic interaction of reducing sugars or their degradation products (α-dicarbonyls) with proteins. The eventually resulting advanced glycation end-products (AGEs) are known to be toxic and pro-inflammatory in mammals. Recently, their presence was unambiguously demonstrated in vivo in stressed Arabidopsis thaliana plants. Currently, information on protein targets, modification sites therein, mediators and mechanisms of plant glycation are being intensively studied. In this chapter, we comprehensively review the methodological approaches for plant glycation research and discuss potential mechanisms of AGE formation under stress conditions. On the basis of these patterns and additional in vitro experiments, the pathways and mechanisms of plant glycation can be proposed.
Publications

Tanemossu Fobofou, S. A.; Franke, K.; Sanna, G.; Porzel, A.; Bullita, E.; La Colla, P.; Wessjohann, L. A.; Isolation and anticancer, anthelminthic, and antiviral (HIV) activity of acylphloroglucinols, and regioselective synthesis of empetrifranzinans from Hypericum roeperianum Bioorg. Med. Chem. 23, 6327-6334, (2015) DOI: 10.1016/j.bmc.2015.08.028

From the ethno-medicinally used leaves of Hypericum roeperianum we isolated a new tricyclic acylphloroglucinol (1), a new tetracyclic acylphloroglucinol (2), and a new prenylated bicyclic acylphloroglucinol (3) together with four known prenylated (4–7) and three known tetracyclic acylphloroglucinol derivatives (8–10). Structure elucidation was based on UV, IR, [α]D25, 1D- and 2D-NMR experiments. Furthermore, empetrifranzinans A (8) and C (9) were synthesized regioselectively in only two steps. The isolated compounds were evaluated for their cytotoxicity against PC-3 and HT-29 cancer cell lines as well as antibacterial and anthelmintic activities. They were also tested in cell-based assays for cytotoxicity against MT-4 cells and for anti-HIV activity in infected MT-4 cells. Significant anthelmintic activity against Caenorhabditis elegans was exhibited by compound 7 (3-geranyl-1-(2′-methylbutanoyl)-phloroglucinol), which might provide a new lead.
Publications

Farag, M. A.; Al-Mahdy, D. A.; Salah El Dine, R.; Fahmy, S.; Yassin, A.; Porzel, A.; Brandt, W.; Structure-Activity Relationships of Antimicrobial Gallic Acid Derivatives from Pomegranate and Acacia Fruit Extracts against Potato Bacterial Wilt Pathogen Chem. Biodivers. 12, 955-962, (2015) DOI: 10.1002/cbdv.201400194

Bacterial wilts of potato, tomato, pepper, and or eggplant caused by Ralstonia solanacearum are among the most serious plant diseases worldwide. In this study, the issue of developing bactericidal agents from natural sources against R. solanacearum derived from plant extracts was addressed. Extracts prepared from 25 plant species with antiseptic relevance in Egyptian folk medicine were screened for their antimicrobial properties against the potato pathogen R. solancearum by using the disc‐zone inhibition assay and microtitre plate dilution method. Plants exhibiting notable antimicrobial activities against the tested pathogen include extracts from Acacia arabica and Punica granatum. Bioactivity‐guided fractionation of A. arabica and P. granatum resulted in the isolation of bioactive compounds 3,5‐dihydroxy‐4‐methoxybenzoic acid and gallic acid, in addition to epicatechin. All isolates displayed significant antimicrobial activities against R. solanacearum (MIC values 0.5–9 mg/ml), with 3,5‐dihydroxy‐4‐methoxybenzoic acid being the most effective one with a MIC value of 0.47 mg/ml. We further performed a structure–activity relationship (SAR) study for the inhibition of R. solanacearum growth by ten natural, structurally related benzoic acids.
Books and chapters

Wessjohann, L.; Dippe, M.; Tengg, M.; Gruber-Khadjawi, M.; Methyltransferases in Biocatalysis (Riva, S. & Fessner, W. D., eds.). 393-426, (2014) ISBN: 9783527682492 DOI: 10.1002/9783527682492.ch18

The methyl group is one of the most widespread functionalities and decorates more than 67% of the top‐selling drugs of 2011.Although significant advances in synthetic chemistry have been achieved allowing the direct methylation, the need for environmentally benign alternatives is growing. As methylation is one of the most common chemical modifications in living cells, a variety of enzymes catalyzing the introduction of methyl groups has been evolved by nature. The enzymes are called methyltransferases (MTs) and are cofactor‐dependent. S‐adenosyl‐L‐methionine (SAM) is by far the most predominant natural source of methyl groups. Since MTs are involved in many cellular processes, their acceptor substrates are diverse, ranging from large biopolymers to small molecules.Their broad substrate spectrum would allow the use of MTs as catalysts for a wide range of biocatalytic methylation and as shown recently for also other alkylation reactions. The technological exploitation is under intensive investigation. As long as an effective recycling system for SAM is lacking, predominantly in vivo applications (cascade reactions using synthetic biology approaches) will emerge.
Books and chapters

Obst, K.; Sung, T. V.; Anh, N. T.; Trai, N. V.; Porzel, A.; Mundt, S.; Paetz, S.; Reichelt, N. V.; Engel, K.-H.; Ley, J. P.; Wessjohann, L.; Isolation and characterization of sweet-tasting Dammaran-type glycosides from Mycetia balansae (Hofmann, T., et al., eds.). 283-287, (2014)

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Books and chapters

Bojahr, J.; Obst, K.; Brockhoff, A.; Reichelt, K.; Brandt, W.; Pienkny, S.; Ley, J. P.; Wessjohann, L.; Meyerhof, W.; Interaction of novel sweeteners from Mycetia balansae with the human sweet taste receptor (Hofmann, T., et al., eds.). 253-257, (2014)

In times where overweight and diabetes are major health issues, the demand for taste–optimized low-calorie sweeteners and sweetness enhancers is increasing. The consumer’s preference for natural food ingredients has enforced the search for natural sweeteners. A potential source of such a natural non-nutritive sweetener is the Vietnamese plant Mycetia balansae, which is used for sweetening by locals. We have identified the sweet principle of Mycetia balansae using sensory-guided analysis and characterized its action on the human sweet taste receptor with an integrated approach combining homology modelling and cell-based functional receptor expression.
Books and chapters

Backes, M.; Vössing, T.; Aust, S.; Pienkny, S.; Brandt, W.; Wessjohann, L.; Ley, J. P.; Identification of nitrogen-containing flavonoids as a potent bitter masker supported by combined gustophore modeling and docking studies (Hofmann, T., et al., eds.). 29-34, (2014)

Combining (i) a pharmacophore model based on bitter masking actives related to homoeriodictyol and (ii) a homology model of the broadly tuned human bitter receptor hTAS2R10, some new scaffolds for bitter masking compounds based on neoisoflavonoids were deduced. The masking activities of the compounds were predicted via docking of their energy minimized conformers into the putative binding site and subsequent careful analysis of receptor distortion and the number of potential hydrogen bridge bonds. Whereas weak binding candidates showed no masking effect against 500 ppm caffeine, the neoisoflavonoids 3 and 4 and the azaneoisoflavonoids 6 and 7 were able to reduce the bitterness of caffeine by 14 to 34%. Moreover, the new maskers could effectively reduce the bitterness of 100 ppm naringine by about 40-50%.
Publications

Geissler, T.; Brandt, W.; Porzel, A.; Schlenzig, D.; Kehlen, A.; Wessjohann, L.; Arnold, N.; Acetylcholinesterase inhibitors from the toadstool Cortinarius infractus Bioorg. Med. Chem. 18, 2173-2177, (2010) DOI: 10.1016/j.bmc.2010.01.074

Inhibition of acetylcholinesterase (AChE) and therefore prevention of acetylcholine degradation is one of the most accepted therapy opportunities for Alzheimer´s disease (AD), today. Due to lack of selectivity of AChE inhibitor drugs on the market, AD-patients suffer from side effects like nausea or vomiting. In the present study the isolation of two alkaloids, infractopicrin (1) and 10-hydroxy-infractopicrin (2), from Cortinarius infractus Berk. (Cortinariaceae) is presented. Both compounds show AChE-inhibiting activity and possess a higher selectivity than galanthamine. Docking studies show that lacking π–π-interactions in butyrylcholinesterase (BChE) are responsible for selectivity. Studies on other AD pathology related targets show an inhibitory effect of both compounds on self-aggregation of Aβ-peptides but not on AChE induced Aβ-peptide aggregation. Low cytotoxicity as well as calculated pharmacokinetic data suggest that the natural products could be useful candidates for further drug development.
Publications

Teichert, A.; Schmidt, J.; Porzel, A.; Arnold, N.; Wessjohann, L.; N-Glucosyl-1H-indole Derivatives from Cortinarius brunneus (Basidiomycetes) Chem. Biodivers. 5, 664-669, (2008) DOI: 10.1002/cbdv.200890062

Two new N ‐glucosylated indole alkaloids were isolated from fruiting bodies of the basidiomycete Cortinarius brunneus (Pers .) Fr . The structures were elucidated by means of the spectroscopic data. Additionally, the very recently reported compounds N‐ 1‐β‐ glucopyranosyl‐3‐(carboxymethyl)‐1H ‐indole (3 ) and N‐ 1‐β‐ glucopyranosyl‐3‐(2‐methoxy‐2‐oxoethyl)‐1H ‐indole (4 ) could be detected. Compound 3 is the N ‐glucoside of the plant‐growth regulator 1H ‐indole‐3‐acetic acid (IAA), but, in contrast, it does not exhibit auxin‐like activity in an Arabidopsis thaliana tap root elongation assay.
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