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Publikationen - Natur- und Wirkstoffchemie

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Fredericks, W. J.; McGarvey, T.; Wang, H.; Lal, P.; Puthiyaveettil, R.; Tomaszewski, J.; Sepulveda, J.; Labelle, E.; Weiss, J. S.; Nickerson, M. L.; Kruth, H. S.; Brandt, W.; Wessjohann, L. A.; Malkowicz, S. B. The Bladder Tumor Suppressor Protein TERE1 (UBIAD1) Modulates Cell Cholesterol: Implications for Tumor Progression DNA Cell Biol 30, 851-864, (2011) DOI: 10.1089/dna.2011.1315

Convergent evidence implicates the TERE1 protein in human bladder tumor progression and lipid metabolism. Previously, reduced TERE1 expression was found in invasive urologic cancers and inhibited cell growth upon re-expression. A role in lipid metabolism was suggested by TERE1 binding to APOE, a cholesterol carrier, and to TBL2, a candidate protein in triglyceride disorders. Natural TERE1 mutations associate with Schnyder's corneal dystrophy, characterized by lipid accumulation. TERE1 catalyzes menaquinone synthesis, known to affect cholesterol homeostasis. To explore this relationship, we altered TERE1 and TBL2 dosage via ectopic expression and interfering RNA and measured cholesterol by Amplex red. Protein interactions of wild-type and mutant TERE1 with GST-APOE were evaluated by binding assays and molecular modeling. We conducted a bladder tumor microarray TERE1 expression analysis and assayed tumorigenicity of J82 cells ectopically expressing TERE1. TERE1 expression was reduced in a third of invasive specimens. Ectopic TERE1 expression in J82 bladder cancer cells dramatically inhibited nude mouse tumorigenesis. TERE1 and TBL2 proteins inversely modulated cellular cholesterol in HEK293 and bladder cancer cells from 20% to 50%. TERE1 point mutations affected APOE interactions, and resulted in cholesterol levels that differed from wild type. Elevated tumor cell cholesterol is known to affect apoptosis and growth signaling; thus, loss of TERE1 in invasive bladder cancer may represent a defect in menaquinone-mediated cholesterol homeostasis that contributes to progression.

Bakthir, H.; Awadh Ali, N. A.; Arnold, N.; Teichert, A.; Wessjohann, L. Anticholinesterase activity of endemic plant extracts from Soqotra Afr J Tradit Complement Altern Med 8, 296-299, (2011) DOI: 10.4314/ajtcam.v8i3.65292

A total of 30 chloroform and methanol extracts from the following endemic Soqotran plants Acridocarpus socotranus Olive, Boswellia socotranao Balf.fil, Boswellia elongata Balf. fil., Caralluma socotrana N. Br, Cephalocroton socotranus Balf.f, Croton socotranus Balf. fil.., Dendrosicycos socotrana Balf.f., Dorstenia gigas Schweinf. ex Balf. fil., Eureiandra balfourii Cogn. & Balf. fil., Kalanchoe farinaceae Balf.f, Limonium sokotranum (Vierh) Radcl. Sm), Oldenlandia pulvinata, Pulicaria diversifolia( Balf. and Pulicaria stephanocarpa Balf. were screened for their acetylcholinesterase inhibitory activity by using in vitro Ellman method at 50 and 200 μg/ml concentrations. Chloroform extracts of Croton socotranus, Boswellia socotrana, Dorstenia gigas, and Pulicaria stephanocarpa as well as methanol extracts of Eureiandra balfourii exhibited inhibitory activities higher than 50 % at concentration of 200 μg. At a concentrations of 50 μg, the chloroform extract of Croton socotranus exhibited an inhibition of 40.6 %.
Bücher und Buchkapitel

Wessjohann, L. A.; Nin Brauer, M. C.; Brand, K. Chalcogen-Based Organocatalysis (Mahrwald, R., ed.). 209-314, (2011) ISBN: 978-90-481-3865-4 DOI: 10.1007/978-90-481-3865-4_7

Most current organocatalysts are based on nitrogen (or phosphorus) as reactive atom, including also most processes depending on proton acidity and/or Lewis basicity. Only few organocatalytic systems use organochalcogens, although such reactions are of great importance in nature, especially evident in hydrolases with serine or cysteine as catalytic hotspot, or in oxidoreductases with cysteine or selenocysteine as key players. Catalytic processes in nature commonly rely on the nucleophilic or redox properties of chalcogen atoms. Accordingly early attempts in chemical catalysis using organochalcogens concentrate either on systems reminiscent of catalytic diads and triads of enzymes with catalysts consisting of a hydroxyl or sulfhydryl group that is activated as nucleophile by a neighboring base (catalytic diads and triads). Other “traditional” uses of chalcogen-based catalysts comprise chiral dioxiranes and oxaziranes for epoxidations, and sulfur redox catalysts, the latter especially in the application of sulfur ylides covered by the predominant work of Aggarwal et al. Since the advent of “Organocatalysis” as a distinct subfield of catalysis, not only these traditional organochalcogen catalyst systems excelled; also new applications are more systematically studied now, including not only oxygen and sulfur but increasingly selenium – and to a smaller extent – even tellurium based catalysis [372]. If nature and its several thousand years of selection of catalysis modes serve as a reference, group VI-based catalysis is yet very much below its real potential in chemical organocatalysis. This contribution thus aims at giving the reader an entry into this so much underutilized field, which offers ample room especially for those who like to try new paths and who not only wish expand on existing processes of well ­established nitrogen-based catalysts.
Bücher und Buchkapitel

Wessjohann, L. A.; Ostrowski, S.; Bakulev, V.; Berseneva, V.; Bogdanov, A. V.; Romanova, I. P.; Mironov, V. F.; Larionova, O. A.; Shaikhutdinova, G. R.; Sinyashin, O. G.; Baibulatova, N. Z.; Dokichev, V. A.; Fedorova, O. V.; Ovchinnikova, I. G.; Rusinov, G. L.; Titova, J. A.; Nasonova, A.; Kim, D.-J.; Kim, K.-S.; Jang, Y. M.; Kim, S. J.; Nasonova, A.; Kim, D.-J.; Kim, K.-S.; Rakhimova, E. B.; Minnebaev, A. B.; Akhmetova, V. R.; Qin, C.; Zhang, R.; Wang, Q.; Ren, J.; Tian, L.; Mironov, M. A.; Demina, T. S.; Tcoy, A. M.; Akopova, T. A.; Markvicheva, E. A.; Chernyshenko, A. O.; Zelenetski, A. N.; Pandit, S. S. Multi-Component Reactions in Supramolecular Chemistry and Material Science (Mironov, M. A., ed.). Adv Exp Med Biol 699, 173-201, (2011) ISBN: 978-1-4419-7270-5 DOI: 10.1007/978-1-4419-7270-5_6

Multi-component reactions of building blocks with more than one MCR-reactive group will give rise to oligomeric MCR products. The proper choice of at least two bifunctional building blocks will give either a polymeric or a cyclic product. Apart from polymerization, repetitive or consecutive Ugi reactions have been used to produce linear MCR-heterooligomers with such building blocks.

Rodríguez-Díaz, M.; Delporte, C.; Cartagena, C.; Cassels, B. K.; González, P.; Silva, X.; León, F.; Wessjohann, L. A. Topical anti-inflammatory activity of quillaic acid from Quillaja saponaria Mol. and some derivatives J Pharm Pharmacol 63, 718-724, (2011) DOI: 10.1111/j.2042-7158.2011.01263.x

Objectives Quillaic acid is the major aglycone of the widely studied saponins of the Chilean indigenous tree Quillaja saponaria Mol. The industrial availability of quillaja saponins and the extensive functionalisation of this triterpenoid provide unique opportunities for structural modification and pose a challenge from the standpoint of selectivity in regard to one or the other secondary alcohol group, the aldehyde, and the carboxylic acid functions. The anti‐inflammatory activity of this sapogenin has not been studied previously and it has never been used to obtain potential anti‐inflammatory derivatives.Methods A series of quillaic acid derivatives were prepared and subjected to topical assays for the inhibition of inflammation induced by arachidonic acid or phorbol ester.Key findings Quillaic acid exhibited strong topical anti‐inflammatory activity in both models. Most of its derivatives were less potent, but the hydrazone 8 showed similar potency to quillaic acid in the TPA assay.Conclusions The structural modifications performed and the biological results suggest that the aldehyde and carboxyl groups are relevant to the anti‐inflammatory activity in these models.

Yeboah, S. O.; Mitei, Y. C.; Ngila, J. C.; Wessjohann, L.; Schmidt, J. Compositional and Structural Studies of the Major and Minor Components in Three Cameroonian Seed Oils by GC–MS, ESI-FTICR-MS and HPLC J Am Oil Chem Soc 88, 1539-1549, (2011) DOI: 10.1007/s11746-011-1832-x

The lipid components of three Cameroonian seed oils, ke tchock (Aframomum arundinaceum), njangsa (Ricinodendron heudelotii) and calabash nutmeg (Monodora myristica), have been investigated. Gas chromatography (GC)–mass spectrometry (MS) fatty acid (FA) analysis showed M. myristica seed oil to be dominated by linoleic (49.29%) and oleic (37.17%) acids; R. heudelotii was mainly linoleic (58.73%), followed by stearic (15.00%) and oleic (14.21%) acids; A. arundinaceum was predominantly oleic (65.76%) and palmitic (20.36%) acids. Electrospray ionization (ESI)-Fourier transform ion cyclotron resonance (FTICR)-MS analysis showed seven major triacylglycerol (TAG) classes for M. myristica, with C54:5, C54:4 and C54:6 dominating. R. heudelotii had eight major TAG classes with C54:8, C54:7 and C54:6 being most abundant. A. arundinaceum also had eight major TAG classes with C52:2, C54:3 and C50:2 dominating. 13C nuclear magnetic resonance (NMR) analysis of the TAGs showed that both sn-1,3 and sn-2 positions were predominantly occupied by linoleoyl and oleoyl chains. High-performance liquid chromatography (HPLC) fluorescence detector (FLD) analysis showed that M. myristica contained only α- and β-tocopherols (195.40 and 73.95 µg/g, respectively), R. heudelotii contained mainly γ-tocopherol (289.40 µg/g), and A. arundinaceum had mainly γ- and β-tocopherols (236.78 and 124.93 µg/g, respectively). GC–MS analysis of the unsaponifiable matter showed that β-sitosterol was the most abundant phytosterol in all three seed oils. The absolute amounts of 4-desmethylsterols were 196.15, 608.71 and 362.15 µg/g for M. myristica, R. heudelotii and A. arundinaceum seed oils, respectively. These compositional and structural studies provide justification for the use of all three seed oils in food products.

Kopycki, J.; Schmidt, J.; Abel, S.; Grubb, C. D. Chemoenzymatic synthesis of diverse thiohydroximates from glucosinolate-utilizing enzymes from Helix pomatia and Caldicellulosiruptor saccharolyticus Biotechnol Lett 33, 1039-1046, (2011) DOI: 10.1007/s10529-011-0530-y

Thiohydroximates comprise a diverse class of compounds important in both biological and industrial chemistry. Their syntheses are generally limited to simple alkyl and aryl compounds with few stereocenters and a narrow range of functional groups. We hypothesized that sequential action of two recombinant enzymes, a sulfatase from Helix pomatia and a β-O-glucosidase from Caldicellulosiruptor saccharolyticus, on glucosinolates would allow synthesis of thiohydroximates from a structurally broad array of abundant precursors. We report successful synthesis of thiohydroximates of varied chemical classes, including from homochiral compounds of demonstrated biological activity. The chemoenzymatic synthetic route reported here should allow access to many, if not all, of the thiohydroximate core structures of the ~200 known naturally occurring glucosinolates. The enrichment of this group for compounds with possible pharmacological potential is discussed.

Welsch, S. J.; Umkehrer, M.; Ross, G.; Kolb, J.; Burdack, C.; Wessjohann, L. A. PdII/IV catalyzed oxidative cyclization of 1,6-enynes derived by Ugi-4-component reaction Tetrahedron Lett 52, 6295-6297, (2011) DOI: 10.1016/j.tetlet.2011.09.094

A variety of 1,6-enynes were synthesized by an Ugi-reaction and further elaborated by a PdII/IV catalyzed oxidative cyclization to produce N-substituted 3-aza-bicyclo[3.1.0]hexan-2-ones. Different substitution patterns were tested to examine the scope and limitations of the amide tethered substrates.

Geissler, T.; Wessjohann, L. A. A Whole-Plant Microtiter Plate Assay for Drought Stress Tolerance-Inducing Effects J Plant Growth Regul 30, 504-511, (2011) DOI: 10.1007/s00344-011-9212-1

The frequency and intensity of extreme weather events and global temperature are rising, which poses a potential threat to life, specifically crops, and therefore food and bioenergy supply. Reduced water availability has the most severe impact on potential grain yield. Negative effects of transient drought stress (dry spells) can be countered by drought tolerance-inducing chemicals. In search for useful compounds, biochemical assays are fast but limited in scope, whereas whole-plant assays are slow, require large amounts of compounds, and are usually not concentration-related. Here we report the development of a fast, concentration-dependent whole-plant assay using the fast growing duckweed Lemna minor L. 4-Amino-1,8-naphthalimide (1) and the imidacloprid metabolite 6-chloronicotinic acid (2) were affirmed as drought stress tolerance enhancers. Both also reduce oxidative stress-induced cell death in Arabidopsis thaliana (L.) Heynh. cell suspension culture but show differences in their mode of action.

Lee, D.-U.; Park, J. H.; Wessjohann, L.; Schmidt, J. Alkaloids from Papaver coreanum Nat Prod Commun 6, 1593-1594, (2011) DOI: 10.1177/1934578X1100601109

The alkaloid pattern of the endemic plant Papaver coreanum Nakai (Papaveraceae) was determined for the first time. Eight alkaloids could be identified by LC/ESIMS/MS and high-resolution mass spectrometry. Among them, protopine and allocryptopine represent the main components. Besides norsanguinarine, sanguinarine, dihydrosanguinarine, oxysanguinarine, lincangenine, and cryptopine, some other trace alkaloids were found whose structures remain unknown.
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