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Publikationen - Natur- und Wirkstoffchemie

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Bücher und Buchkapitel

Chini, A., Monte, I., Zamarreño, A. M., Hamberg, M., Lassueur, S., Reymond, P., Weiss, S., Stintzi, A., Schaller, A., Porzel, A., García-Mina, J. M. & Solano, R. An OPR3-independent pathway uses 4,5-didehydrojasmonate for jasmonate synthesis. Nat Chem Biol 14, 171-178, (2018) DOI: 10.1038/nchembio.2540

Biosynthesis of the phytohormone jasmonoyl-isoleucine (JA-Ile) requires reduction of the JA precursor 12-oxo-phytodienoic acid (OPDA) by OPDA reductase 3 (OPR3). Previous analyses of the opr3-1 Arabidopsis mutant suggested an OPDA signaling role independent of JA-Ile and its receptor COI1; however, this hypothesis has been challenged because opr3-1 is a conditional allele not completely impaired in JA-Ile biosynthesis. To clarify the role of OPR3 and OPDA in JA-independent defenses, we isolated and characterized a loss-of-function opr3-3 allele. Strikingly, opr3-3 plants remained resistant to necrotrophic pathogens and insect feeding, and activated COI1-dependent JA-mediated gene expression. Analysis of OPDA derivatives identified 4,5-didehydro-JA in wounded wild-type and opr3-3 plants. OPR2 was found to reduce 4,5-didehydro-JA to JA, explaining the accumulation of JA-Ile and activation of JA-Ile-responses in opr3-3 mutants. Our results demonstrate that in the absence of OPR3, OPDA enters the β-oxidation pathway to produce 4,5-ddh-JA as a direct precursor of JA and JA-Ile, thus identifying an OPR3-independent pathway for JA biosynthesis.

Publikation

Edeler, D., Arlt, S., Petković, V., Ludwig, G., Drača, D., Maksimović-Ivanić, D., Mijatović, S. & Kaluđerović, G. N. Delivery of [Ru(η6-p-cymene)Cl2{Ph2P(CH2)3SPh-κP}] using unfunctionalized and mercapto functionalized SBA-15 mesoporous silica: Preparation, characterization and in vitro study. J Inorg Biochem. 180, 155-162, (2018) DOI: 10.1016/j.jinorgbio.2017.12.011

SBA-15 (Santa Barbara Amorphous 15) mesoporous silica and its functionalized form (with 3-mercaptopropyltriethoxysilane) SBA-15~SH were used as carriers for [Ru(η6-p-cymene)Cl2{Ph2P(CH2)3SPh-κP}] complex, denoted as [Ru]. Prepared mesoporous silica nanomaterials were characterized by traditional methods. Materials without [Ru] complex did not show any cytotoxic activity against melanoma B16 and B16-F10 cell lines. On the contrary, materials containing [Ru] such as SBA-15¦[Ru] and SBA-15~SH¦[Ru], exhibited very high activity against tested tumor cell lines, moreover with similar inhibitory potential. According to the loaded amount of the [Ru] in SBA-15¦[Ru] and SBA-15~SH¦[Ru] the IC50 values are 1–2 μM depending on the test used, thus in comparison to [Ru] alone the activity of nanomaterials containing [Ru] are elevated 3–6 times in vitro. However, the mechanism of apoptosis induction differs for these two mesoporous silica. Unlike reference [Ru] compound and SBA-15~SH¦[Ru], SBA-15¦[Ru] induces high caspase activation. Discrepancy in mechanism of drugs action at intracellular level points towards an influence of functionalization as well as availability of the drug. Moreover, both SBA-15¦[Ru] and SBA-15~SH¦[Ru] similarly to [Ru] are declining autophagy in B16 cell line.
Publikation

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 217 , 613-624, (2018) 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.
Publikation

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.

Publikationen in Druck

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.
Publikation

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.
Publikation

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).

Publikation

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.
Publikation

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. 
Publikationen in Druck

Smolikova, G., Kreslavski, V., Shiroglazova, O., Bilova, T., Sharova, E., Frolov, A. & Medvedev, S. Photochemical activity changes accompanying the embryogenesis of pea (Pisum sativum) with yellow and green cotyledon. Functional Plant Biol. 45, 228-235, (2017) DOI: 10.1071/FP16379

The pea seeds are photosynthetically active until the end of the maturation phase, when the embryonic chlorophylls degrade. However, in some cultivars, the underlying mechanisms are compromised, and the mature seeds preserve green colour. The residual chlorophylls can enhance oxidative degradation of reserve biomolecules, and affect thereby the quality, shelf life and nutritive value of seeds. Despite this, the formation, degradation, and physical properties of the seed chlorophylls are still not completely characterised. So here we address the dynamics of seed photochemical activity in the yellow- and green-seeded pea cultivars by the pulse amplitude modulation (PAM) fluorometric analysis. The experiments revealed the maximal photochemical activity at the early- and mid-cotyledon stages. Thereby, the active centres of PSII were saturated at the light intensity of 15–20 µmol photons m–2 s–1. Despite of their shielding from the light by the pod wall and seed coat, photochemical reactions can be registered in the seeds with green embryo. Importantly, even at the low light intensities, the photochemical activity in the coats and cotyledons could be detected. The fast transients of the chlorophyll a fluorescence revealed a higher photochemical activity in the coat of yellow-seeded cultivars in comparison to those with the green-seeded ones. However, it declined rapidly in all seeds at the late cotyledon stage, and was accompanied with the decrease of the seed water content. Thus, the termination of photosynthetic activity in seeds is triggered by their dehydration.
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