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Publications - Bioorganic Chemistry

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Publications

Otto, A., Porzel, A., Westermann, B., Brandt, W., Wessjohann, L. & Arnold, N. Structural and stereochemical elucidation of new hygrophorones from Hygrophorus abieticola (Basidiomycetes) Tetrahedron 73, 1682-1690, (2017) DOI: http://dx.doi.org/10.1016/j.tet.2017.02.013

Four new hygrophorones (1–4) together with the known hygrophorone B12 (5) have been isolated from fruiting bodies of the basidiomycete Hygrophorus abieticola Krieglst. ex Gröger & Bresinsky. Their structures were assigned on the basis of extensive one and two dimensional NMR spectroscopic analyses as well as ESI-HRMS measurements. Among these compounds, two previously undescribed hygrophorone types, named hygrophorone H12 (3) and 2,3-dihydrohygrophorone H12 (4), were identified. The absolute configuration of hygrophorone E12 (2) is suggested based on quantum chemical CD calculations, while a semisynthetic approach in conjunction with computational studies and analysis of NOE interactions allowed the stereochemical assignment of compounds 3 and 4. Additionally, semisynthetic derivatives of hygrophorone B12 (5) were generated by acetylation of the hydroxyl groups. The biological activity of the natural and semisynthetic hygrophorones was evaluated against phytopathogenic organisms, revealing that the α,β-unsaturated carbonyl functionality is likely to be an essential structural feature. Hygrophorone B12 (5) was identified as the most active compound, acting against both ascomycetous fungi and oomycetes.

Publications

Heller, L., Kahnt, M., Loesche, A., Grabandt, P., Schwarz, S., Brandt, W. & Csuk, R. Amino derivatives of platanic acid act as selective and potent inhibitors of butyrylcholinesterase Eur J Med Chem 126, 652-668, (2017) DOI: /10.1016/j.ejmech.2016.11.056

A set of thirtyfive 30-norlupan derivatives (2–36) was prepared from the natural triterpenoid platanic acid (PA), and the hydroxyl group at C-3, the carboxyl group at C-17 and the carbonyl group at C-20 were modified. These derivatives were tested for their inhibitory activity for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum) using Ellman's assay. Extra enzyme kinetic studies were performed. The most active compound was (3β, 20R)-3-acetyloxy-20-amino-30-norlupan-28-oate (32) showing a Ki value of 0.01 ± 0.003 μM for BChE. This compound proved to be a selective (FB = 851), mixed-type inhibitor for BChE.

Publications

Rissel, D., Heym, P., Thor, K., Brandt, W., Wessjohann, L. & Peiter, E. No silver bullet - Canonical Poly(ADP-Ribose) Polymerases (PARPs) are no universal factors of abiotic and biotic stress resistance of Arabidopsis thaliana Front Plant Sci. 8, 59, (2017) DOI: 10.3389/fpls.2017.00059

Abiotic and biotic stress can have a detrimental impact on plant growth and productivity. Hence, there is a substantial demand for key factors of stress responses to improve yield stability of crops. Members of the poly(ADP-ribose)polymerase (PARP) protein family, which post-translationally modify (PARylate) nuclear proteins, have been suggested as such universal determinants of plant stress responses. A role under abiotic stress has been inferred from studies in which a genetic or, more commonly, pharmacological inhibition of PARP activity improved the performance of stressed plants. To further elucidate the role of PARP proteins under stress, T-DNA knockout mutants for the three Arabidopsis thaliana PARP genes were subjected to drought, osmotic, salt, and oxidative stress. To exclude a functional redundancy, which was indicated by a transcriptional upregulation of the remaining parp genes, a parp triple mutant was generated. Surprisingly, parp mutant plants did not differ from wild type plants in any of these stress experiments, independent from the number of PARP genes mutated. The parp triple mutant was also analyzed for callose formation in response to the pathogenassociated molecular pattern flg22. Unexpectedly, callose formation was unaltered in the mutant, albeit pharmacological PARP inhibition robustly blocked this immune response, confirming previous reports. Evidently, pharmacological inhibition appears to be more robust than the abolition of all PARP genes, indicating the presence of so-far undescribed proteins with PARP activity. This was supported by the finding that protein PARylation was not absent, but even increased in the parp triple mutant. Candidates for novel PARP-inhibitor targets may be found in the SRO protein family. These proteins harbor a catalytic PARP-like domain and are centrally involved in stress responses. Molecular modeling analyses, employing animal PARPs as templates, indeed indicated a capability of the SRO proteins RCD1 and SRO1 to bind nicotinamide-derived inhibitors. Collectively, the results of our study suggest that the stress-related phenotypes of parp mutants are highly conditional, and they call for a reconsideration of PARP inhibitor studies. In the context of this study, we also propose a unifying nomenclature of PARP genes and parp mutants, which is currently highly inconsistent and redundant.

Printed publications

Ristok, C., Leppert, K. N., Franke, K., Scherer-Lorenzen, M., Niklaus, P. A., Wessjohann, L. A. & Bruelheide, H. Leaf litter diversity positively affects the decomposition of plant polyphenols. Plant Soil (2017) DOI: 10.1007/s11104-017-3340-8

Background and Aims
Leaf litter decomposition is closely linked to nutrient cycling and driven by environmental conditions, species-specific leaf chemistry, and here in particular by polyphenols composition. However, not much attention has been paid on the decomposition of polyphenols themselves. We hypothesized that phenolics and tannin decomposition rates are species-specific and positively affected by litter species richness.

Methods
Leaf litter of three Chinese tree species was exposed to field decomposition conditions, aggregated in mixtures of different species richness (1-, 2-, 3-species mixtures). We sampled litter five times over the course of 171 days, calculated species-specific total phenolics and total protein precipitable tannin decomposition rates, assessed changes in polyphenol composition using HPLC, and tentatively identified compounds by LC-ESI-MS/MS.

Results
Leaf litter richness effects on phenolics and tannin decomposition rates were positive, except for Sapindus-specific tannins, and differed between leaf litter species. Decomposition duration changed polyphenol compositions, and significantly interacted with leaf litter species richness with increasing effects of litter richness with time.

Conclusions
Litter diversity effects on polyphenol decomposition are crucial for whole leaf litter decomposition. The contrasting dependencies of phenolics and tannin decomposition rates on leaf litter richness may provide explanations for equivocal results in leaf litter mixture experiments.
Publications

Kaluđerović, N. G., Bulatović, M., Krajnović, T., Paschke, R., B. Zmejkovski, B., Maksimović-Ivanić, D. & Mijatović, S. (18-Crown-6)potassium(I) Trichlorido[28-acetyl-3-(tris-(hydroxylmethyl)amino-ethane)betulinic ester-κN]platinum(II): synthesis and in vitro antitumor activity. Inorganics 5, 56, (2017) DOI: 10.3390/inorganics5030056

Synthesis of platinum(II) conjugate with acetylated betulinic acid tris(hydroxymethyl)aminomethane ester (BATRIS) is presented (BATRISPt). HR-ESI-MS and multinuclear NMR spectroscopy, as well as elemental analysis were used for characterization of BATRISPt. Cytotoxicity (3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), crystal violet (CV), and sulforhodamine B (SRB) assays) of BA, BATRIS, BATRISPt, and cisplatin were assessed on seven different tumor cell lines: melanoma B16, colon HCT116 and DLD-1, adenocarcinoma HeLa, breast MCF-7, and anaplastic thyroid tumor 8505C and SW1736; as well as normal MRC-5 fibroblasts. Furthermore, the effect of the mentioned compounds on the apoptosis (Annexin V/PI assay) and autophagy induction (acridine orange (AO) assay) as well as caspase 3, 8, and 9 activation were investigated on the selected B16 melanoma cell line. BATRISPt showed lower activity than BA, BATRIS, or cisplatin. All tested compounds triggered apoptosis in B16 cells. Induction of autophagy was observed in B16 cells exposed only to BATRIS. On the other hand, new conjugate activates caspases 8 and 9 in B16 cells with higher impact than BATRIS or cisplatin alone.
Publications

Nguyen,T. H. A., Nguyen, V. T., Dao, D. T., Tran, D. Q., Nguyen, T. T., Giang, T. K. L., Franke, K., Trinh, T. T. & Tran, V. S. Chemical Constituents of Chirita drakei. Nat Prod Commun 12 , 563-566, (2017)

Chirita drakei Burtt (now accepted as Primulina drakei (B.L.Burtt)
Mich.Möller & A.Weber) is growing on limestone mountain slopes of Ha Long Bay
islands in Vietnam. The chemical investigation of the aerial parts of C. drakei led to the
isolation and structural elucidation of two new compounds named chiridrakoside A (1)
and chiridrakoside B (2) besides twelve known compounds comprising five
phenylethanoid glycosides (3–7), two lignans (8, 9), a phenyl propanoid (10), an
anthraquinone (11), a furan derivative (12) and two triterpenes (13, 14). All described
compounds, except 4, 5 and 11, were obtained for the first time from the genera Chirita
or Primulina. The cytotoxic activity of the isolated compounds was evaluated against the
four human cancer cell lines KB (mouth epidermal carcinoma), HepG2 (hepatocellular
carcinoma), Lu (lung carcinoma) and MCF7 (breast carcinoma). Epoxyconiferyl alcohol
(10) exhibited cytotoxic activity against the tested cell lines (IC50 from 46 to 128 μM).

Printed publications

Mot, A. C., Prell, E., Klecker, M., Naumann, C., Faden, F., Westermann, B. & Dissmeyer, N. Real-time detection of PROTEOLYSIS1 (PRT1)-mediated ubiquitination via fluorescently labeled substrate probes New Phytolog (2017) DOI: 10.1111/nph.14497

The N-end rule pathway has emerged as a major system for regulating protein functions by controlling their turnover in medical, animal and plant sciences as well as agriculture. Although novel functions and enzymes of the pathway have been discovered, the ubiquitination mechanism and substrate specificity of N-end rule pathway E3 ubiquitin ligases have remained elusive. Taking the first discovered bona fide plant N-end rule E3 ligase PROTEOLYSIS1 (PRT1) as a model, we used a novel tool to molecularly characterize polyubiquitination live, in real time.
We gained mechanistic insights into PRT1 substrate preference and activation by monitoring live ubiquitination using a fluorescent chemical probe coupled to artificial substrate reporters. Ubiquitination was measured by rapid in-gel fluorescence scanning as well as in real time by fluorescence polarization.
The enzymatic activity, substrate specificity, mechanisms and reaction optimization of PRT1-mediated ubiquitination were investigated ad hoc instantaneously and with significantly reduced reagent consumption.
We demonstrated that PRT1 is indeed an E3 ligase, which has been hypothesized for over two decades. These results demonstrate that PRT1 has the potential to be involved in polyubiquitination of various substrates and therefore pave the way to understanding recently discovered phenotypes of prt1 mutants.
Printed publications

Bilova, T., Paudel, G., Shilyaev, N., Schmidt, R., Brauch, D., Tarakhovskaya, E., Milrud, S., Smolikova, G., Tissier, A., Vogt, T., Sinz, A., Brandt, W., Birkemeyer, C., Wessjohann, L. A. & Frolov, A. Global proteomic analysis of advanced glycation end products in the Arabidopsis proteome provides evidence for age-related glycation hotspots. J Biol Chem. (2017) DOI: 10.1074/jbc.M117.794537

Glycation is a post-translational modification resulting from the interaction of protein amino and guanidino groups with carbonyl compounds. Initially, amino groups react with reducing carbohydrates, yielding Amadori and Heyns compounds. Their further degradation results in formation of advanced glycation end products (AGEs), also originating from α-dicarbonyl products of monosaccharide autoxidation and primary metabolism. In mammals, AGEs are continuously formed during the life of the organism, and accumulate in tissues, being well-known markers of ageing, impacting age-related tissue stiffing and atherosclerotic changes. However, the role of AGEs in age-related molecular alterations in plants is still unknown. To fill this gap, we present here a comprehensive study of the age-related changes in the Arabidopsis thaliana glycated proteome, including the proteins affected and specific glycation sites therein. We also consider the qualitative and quantitative changes in glycation patterns in terms of the general metabolic background, pathways of AGE formation, and the status of plant anti-oxidative/anti-glycative defense. Although the patterns of glycated proteins were only minimally influenced by plant age, the abundances of 96 AGE sites in 71 proteins were significantly affected in an age-dependent manner and clearly indicated the existence of age-related glycation hotspots in the plant proteome. Homology modeling revealed glutamyl and aspartyl residues in close proximity (less than 5 Å) to these sites in 3 ageing-specific and 8 differentially glycated proteins, four of which were modified in catalytic domains. Thus, the sites of glycation hotspots might be defined by protein structure that indicates, at least partly, site-specific character of glycation. Data are available via ProteomeXchange with identifier PXD006434 
Publications

Loesche, A., Wiese, J., Sommerwerk, S., Simon, V., Brandt, W. & Csuk, R. Repurposing N,N '-bis-(arylamidino)-1,4-piperazinedicarboxamidines: An unexpected class of potent inhibitors of cholinesterases. Eur J Med Chem 125, 430-434, (2017) DOI: org/10.1016/j.ejmech.2016.09.051

Drug repurposing (=drug repositioning) is an effective way to cut costs for the development of new therapeutics and to reduce the time-to-market time-span. Following this concept a small library of compounds was screened for their ability to act as inhibitors of acetyl- and butyrylcholinesterase. Picloxydine, an established antiseptic, was shown to be an inhibitor for both enzymes. Systematic variation of the aryl substituents led to analogs possessing almost the same good properties as gold standard galantamine hydrobromide.
Publications

Melaku, Y., Worku, T., Mekonnen, Y., Schmidt, J., Arnold. N. & Dagne, E. Antiplasmodial Compounds from Leaves of Dodonaea angustifolia Curr Bioactive Comp 13, 268-273, (2017) DOI: org/10.2174/1573407213666170403121222

Background: Dodonaea angustifolia is used in Ethiopian traditional medicine to treat malaria. The objective of this work was to conduct bioassay guided fractionation of the leaves of D. angustifolia using Plasmodium berghei infected mice. Methods: The antiplasmodial activity of the extracts and pure compounds were evaluated using the standard Peter’s four-day suppressive method. The structures of isolated compounds were elucidated using chemical and spectroscopic methods. Results: In this study the ethyl acetate soluble portion of the 80% aqueous MeOH extract of the leaves significantly suppressed parasitaemia in Plasmodium berghei infected mice (80.28% at 150 mg/kg). Three active compounds which exhibited significant percent suppression of parasitaemia by 81% at 40 mg/kg, 80% at 50 mg/kg and 70% at 40 mg/kg, respectively were identified. These are the flavanone pinocembrin (1), the flavanol santin (2) and the clerodane diterpene 2-hydroxy-15,16-epoxyceloda-3,13(16),14-trien-18-oic acid (3). Under similar conditions chloroquine suppressed parasitaemia by 100% at 25 mg/kg. Chemical study of the ethanol extract of the leaves yielded 5,7,4'-trihydroxy-3,6-dimethoxyflavone (4), ent-16-hydroxy-labdan-3α,8β-dihydroxy,13(14)-en-15,16-olide (5) and 5,6,7-trihydroxy-3,4'-dimethoxyflavone (6). Compound 6 has not been reported before as a natural product. Conclusion: From the leaves of D. angustifolia three compounds with significant antiplasmodial activities were isolated and characterized, with pinocembrin as the most active compound. 
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