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Publications - Bioorganic Chemistry

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Publications

Heinke, R.; Arnold, N.; Wessjohann, L.; Schmidt, J.; Negative ion tandem mass spectrometry of prenylated fungal metabolites and their derivatives Anal. Bioanal. Chem. 405, 177-189, (2013) DOI: 10.1007/s00216-012-6498-1

Liquid chromatography negative ion electrospray ionisation tandem mass spectrometry has been used for characterisation of naturally occurring prenylated fungal metabolites and synthetic derivatives. The fragmentation studies allow an elucidation of the decomposition pathways for these compounds. It could be shown, that the prenyl side chain is degraded by successive radical losses of C5 units. Both the benzoquinones and the phenolic derivatives display significant key ions comprising the aromatic ring. In some cases, the formation of significant oxygen-free key ions could be evidenced by high-resolution MS/MS measurements. Furthermore, the different types of basic skeletons, benzoquinones and phenol type as well as cyclic prenylated compounds, can be differentiated by their MS/MS behaviour.
Publications

Güttler, B. H.-O.; Cynis, H.; Seifert, F.; Ludwig, H.-H.; Porzel, A.; Schilling, S.; A quantitative analysis of spontaneous isoaspartate formation from N-terminal asparaginyl and aspartyl residues Amino Acids 44, 1205-1214, (2013) DOI: 10.1007/s00726-012-1454-0

The formation of isoaspartate (isoAsp) from asparaginyl or aspartyl residues is a spontaneous post-translational modification of peptides and proteins. Due to isopeptide bond formation, the structure and possibly function of peptides and proteins is altered. IsoAsp modifications within the peptide chain have been reported for many cytosolic proteins. Amyloid peptides (Aβ) deposited in Alzheimer’s disease may carry an N-terminal isoAsp-modification. Here, we describe a quantitative investigation of isoAsp-formation from N-terminal Asn and Asp using model peptides similar to the Aβ N-terminus. The study is based on a newly developed separation of peptides using capillary electrophoresis (CE). 1H NMR was employed to validate the basic finding of N-terminal isoAsp-formation from Asp and Asn. Thereby, the isomerization of Asn at neutral pH (0.6 day−1, peptide NGEF) is approximately six times faster than that within the peptide chain (AANGEF). The difference in velocity between Asn and Asp isomerization is approximately 50-fold. In contrast to N-terminal Asn, Asp isomerization is significantly accelerated at acidic pH. The kinetic solvent isotope (kD2O/kH2O) effect of 2.46 suggests a rate-limiting proton transfer in isoAsp-formation. The proton inventory is consistent with transfer of one proton in the transition state, supporting the previous notion of rate-limiting deprotonation of the peptide backbone amide during succinimide-intermediate formation. The study provides evidence for a spontaneous N-terminal isoAsp-formation within peptides and might explain the accumulation of N-terminal isoAsp in amyloid deposits.
Publications

Günnewich, N.; Higashi, Y.; Feng, X.; Choi, K.-B.; Schmidt, J.; Kutchan, T. M.; A diterpene synthase from the clary sage Salvia sclarea catalyzes the cyclization of geranylgeranyl diphosphate to (8R)-hydroxy-copalyl diphosphate Phytochemistry 91, 93-99, (2013) DOI: 10.1016/j.phytochem.2012.07.019

The bicyclic diterpene (−)-sclareol is accumulated in glandular trichomes in Salvia sclarea (Schmiderer et al., 2008), and is a major terpenoid component of this plant species. It is used as the starting material for Ambrox synthesis, a synthetic ambergris analog used in the flavor and fragrance industry. In order to investigate the formation of sclareol, cDNA prepared from secretory cells of glandular trichomes from S. sclarea inflorescence were randomly sequenced. A putative copalyl diphosphate synthase encoding EST, SscTPS1, was functionally expressed in Escherichia coli. Whereas reaction of geranylgeranyl diphosphate with the putative copalyl diphosphate synthase followed by hydrolysis with alkaline phosphatase yielded a diastereomeric mixture of (13R)- and (13S)-manoyl oxide, HCl hydrolysis yielded (−)-sclareol (1) and 13-epi-sclareol as products. The product of the reaction of SscTPS1 with geranylgeranyl diphosphate was subjected to analysis by LC-negative ion ESI-MS/MS without prior hydrolysis. EPI scans were consistent with copalyl diphosphate to which 18 mass units had added (m/z 467 [M+H]−). The enzymatic reaction was also carried out in the presence of 60% H218O. LC-negative ion ESI-MS/MS analysis established an additional reaction product consistent with the incorporation of 18O. Incubation in the presence of 60% 2H2O resulted in the incorporation of one deuterium atom. These results suggest water capture of the carbocation intermediate, which is known to occur in reactions catalyzed by monoterpene synthases, but has been described only several times for diterpene synthases.
Publications

Gulyas-Fekete, G.; Boluda, C. J.; Westermann, B.; Wessjohann, L. A.; Anti-Friedel-Crafts-Type Substitution To Form Biaryl Linkages Synthesis 45, 3038-3043, (2013) DOI: 10.1055/s-0033-1339682

The ipso-substitution of one (or two) hydroxy groups of phloroglucinol with arene nucleophiles (e.g., o-xylene, tetralin, biphenyl) can be achieved easily under Friedel–Crafts-type conditions with or without the use of organic solvents affording a variety of 3,5-dihydroxybiphenyls (57–89% yields). The new method has significant practical advantages compared to classical biaryl-­coupling routes.
Publications

Frick, S.; Nagel, R.; Schmidt, A.; Bodemann, R. R.; Rahfeld, P.; Pauls, G.; Brandt, W.; Gershenzon, J.; Boland, W.; Burse, A.; Metal ions control product specificity of isoprenyl diphosphate synthases in the insect terpenoid pathway Proc. Natl. Acad. Sci. U.S.A. 110, 4194-4199, (2013) DOI: 10.1073/pnas.1221489110

Isoprenyl diphosphate synthases (IDSs) produce the ubiquitous branched-chain diphosphates of different lengths that are precursors of all major classes of terpenes. Typically, individual short-chain IDSs (scIDSs) make the C10, C15, and C20 isoprenyl diphosphates separately. Here, we report that the product length synthesized by a single scIDS shifts depending on the divalent metal cofactor present. This previously undescribed mechanism of carbon chain-length determination was discovered for a scIDS from juvenile horseradish leaf beetles, Phaedon cochleariae. The recombinant enzyme P. cochleariae isoprenyl diphosphate synthase 1 (PcIDS1) yields 96% C10-geranyl diphosphate (GDP) and only 4% C15-farnesyl diphosphate (FDP) in the presence of Co2+ or Mn2+ as a cofactor, whereas it yields only 18% C10 GDP but 82% C15 FDP in the presence of Mg2+. In reaction with Co2+, PcIDS1 has a Km of 11.6 μM for dimethylallyl diphosphate as a cosubstrate and 24.3 μM for GDP. However, with Mg2+, PcIDS1 has a Km of 1.18 μM for GDP, suggesting that this substrate is favored by the enzyme under such conditions. RNAi targeting PcIDS1 revealed the participation of this enzyme in the de novo synthesis of defensive monoterpenoids in the beetle larvae. As an FDP synthase, PcIDS1 could be associated with the formation of sesquiterpenes, such as juvenile hormones. Detection of Co2+, Mn2+, or Mg2+ in the beetle larvae suggests flux control into C10 vs. C15 isoprenoids could be accomplished by these ions in vivo. The dependence of product chain length of scIDSs on metal cofactor identity introduces an additional regulation for these branch point enzymes of terpene metabolism.
Publications

Farag, M. A.; Weigend, M.; Luebert, F.; Brokamp, G.; Wessjohann, L. A.; Phytochemical, phylogenetic, and anti-inflammatory evaluation of 43 Urtica accessions (stinging nettle) based on UPLC–Q-TOF-MS metabolomic profiles Phytochemistry 96, 170-183, (2013) DOI: 10.1016/j.phytochem.2013.09.016

Several species of the genus Urtica (especially Urtica dioica, Urticaceae), are used medicinally to treat a variety of ailments. To better understand the chemical diversity of the genus and to compare different accessions and different taxa of Urtica, 63 leaf samples representing a broad geographical, taxonomical and morphological diversity were evaluated under controlled conditions. A molecular phylogeny for all taxa investigated was prepared to compare phytochemical similarity with phylogenetic relatedness. Metabolites were analyzed via UPLC–PDA–MS and multivariate data analyses. In total, 43 metabolites were identified, with phenolic compounds and hydroxy fatty acids as the dominant substance groups. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) provides a first structured chemotaxonomy of the genus. The molecular data present a highly resolved phylogeny with well-supported clades and subclades. U. dioica is retrieved as both para- and polyphyletic. European members of the U. dioica group and the North American subspecies share a rather similar metabolite profile and were largely retrieved as one, nearly exclusive cluster by metabolite data. This latter cluster also includes – remotely related – Urtica urens, which is pharmaceutically used in the same way as U. dioica. However, most highly supported phylogenetic clades were not retrieved in the metabolite cluster analyses. Overall, metabolite profiles indicate considerable phytochemical diversity in the genus, which largely falls into a group characterized by high contents of hydroxy fatty acids (e.g., most Andean-American taxa) and another group characterized by high contents of phenolic acids (especially the U. dioica-clade). Anti-inflammatory in vitro COX1 enzyme inhibition assays suggest that bioactivity may be predicted by gross metabolic profiling in Urtica.
Publications

Farag, M. A.; El-Ahmady, S. H.; Elian, F. S.; Wessjohann, L. A.; Metabolomics driven analysis of artichoke leaf and its commercial products via UHPLC–q-TOF-MS and chemometrics Phytochemistry 95, 177-187, (2013) DOI: 10.1016/j.phytochem.2013.07.003

The demand to develop efficient and reliable analytical methods for the quality control of herbal medicines and nutraceuticals is on the rise, together with an increase in the legal requirements for safe and consistent levels of active principles. Here, we describe an ultra-high performance liquid chromatography method (UHPLC) coupled with quadrupole high resolution time of flight mass spectrometry (qTOF-MS) analysis for the comprehensive measurement of metabolites from three Cynara scolymus (artichoke) cultivars: American Green Globe, French Hyrious, and Egyptian Baladi. Under optimized conditions, 50 metabolites were simultaneously quantified and identified including: eight caffeic acid derivatives, six saponins, 12 flavonoids and 10 fatty acids. Principal component analysis (PCA) was used to define both similarities and differences among the three artichoke leaf cultivars. In addition, batches from seven commercially available artichoke market products were analysed and showed variable quality, particularly in caffeic acid derivatives, flavonoid and fatty acid contents. PCA analysis was able to discriminate between various preparations, including differentiation between various batches from the same supplier. To the best of our knowledge, this study provides the first approach utilizing UHPLC–MS based metabolite fingerprinting to reveal secondary metabolite compositional differences in artichoke leaf extracts.
Publications

Farag, M. A.; Wessjohann, L. A.; Cytotoxic effect of commercial Humulus lupulus L. (hop) preparations – In comparison to its metabolomic fingerprint J. Adv. Res. 4, 417-421, (2013) DOI: 10.1016/j.jare.2012.07.006

Hops (Humulus lupulus L. Cannabaceae) is an economically important crop, that has drawn more attention in recent years due to its potential pharmaceutical applications. Bitter acids (prenylated polyketides) and prenylflavonoids are the primary phytochemical components that account for hops resins medicinal value. We have previously reported on utilizing untargeted NMR and MS metabolomics for analysis of 13 hops cultivars, revealing for differences in α- versus β-bitter acids composition in derived resins. In this study, effect of ratios of bitter α- to β-acids in hop resins to cytotoxicity of hop resins was investigated. In vitro cell culture assays revealed that β-acids were more effective than α-acids in growth inhibition of PC3 and HT29 cancer cell lines. Nevertheless, hop resins enriched in β-acids showed comparable growth inhibition patterns to α-enriched resins and suggesting that bioactivity may not be easily predicted by metabolomics and/or gross metabolic profiling in hops.
Publications

Chaudhuri, S. R.; Kaluđerović, G. N.; Bette, M.; Schmidt, J.; Schmidt, H.; Paschke, R.; Steinborn, D.; Synthesis, characterization and cytotoxicity studies of platinum(II) complexes with amino acid ligands in various coordination modes Inorg. Chim. Acta 394, 472-480, (2013) DOI: 10.1016/j.ica.2012.08.034

Reactions of [Pt(CO3)(PPh3)2]·CH2Cl2 (1) with non-substituted and alkyl substituted amino acids, NH(R)CH(R′)CO2H (R/R′ = H/Me, L1; H/iPr, L2; H/CH2CHMe2, L3; Me/H, L4; Et/H, L5), in the presence of Tl[PF6] in methanol afforded with liberation of CO2 the formation of platinum(II) complexes of the type [Pt(PPh3)2{NHR–CHR′–C(O)O-κN,κO}][PF6] (R/R′ = H/Me, 2; H/iPr, 3; H/CH2CHMe2, 4; Me/H, 5; Et/H, 6). Single-crystal X-ray diffraction analysis of complex 4 exhibited a square-planar coordination of the platinum atom having coordinated two triphenylphosphane ligands and a deprotonated κN,κO-coordinated leucine ligand (L3−H). On varying the pKa value of the amino group, platinum(II) complexes with different coordination modes of amino acid ligands were obtained. Thus, treatment of complex 1 with N-acetyl l-alanine (L6), possessing a comparatively highly acidic NH proton, in 1:1 ratio in methanol resulted in the formation of [Pt(PPh3)2{N(COMe)–CHMe–C(O)O-κN,κO}] (7), while reacting N-phenyl glycine (L7) having a moderately acidic NH proton with complex 1 afforded a mixture of complexes [Pt(PPh3)2{NPh–CH2–C(O)O-κN,κO}] (8) and [Pt(PPh3)2{NHPh–CH2–C(O)O-κO}2] (10). Treatment of complex 1 with two equivalents of L6/L7 in dichloromethane resulted in the formation of [Pt(PPh3)2{NHR–CHR′–C(O)O-κO}2] (R/R′ = COMe/Me, 9; Ph/H, 10). An analogous reactivity was observed for l-lactic acid on treating with complex 1 in 1:1 and 2:1 ratio resulting in [Pt(PPh3)2{O–CHMe–C(O)O-κO,κO′}] (11) and [Pt(PPh3)2{HO–CHMe–C(O)O-κO}2] (12). The identities of all complexes have been proven by NMR (1H, 13C, 31P) spectroscopic and high-resolution ESI mass-spectrometric investigations. In vitro cytotoxicity studies against human tumor cell lines (8505C, A2780, HeLa, SW480, and MCF-7) showed the highest activities for the neutral complex 7. Furthermore, complexes 7 and 9 against the A2780 cell line induced an apoptotic mode of cell death, which was further supported by morphological investigation and DNA laddering. Cell cycle perturbation studies showed that both complexes induced faster cell death than cisplatin.
Publications

Brauch, S.; van Berkel, S. S.; Westermann, B.; Higher-order multicomponent reactions: beyond four reactants Chem. Soc. Rev. 42, 4948-4962, (2013) DOI: 10.1039/C3CS35505E

Multicomponent reactions (MCRs) are by far the most successful class of reactions leading to high structural diversity and molecular complexity through a single transformation. As part of the ongoing search for pharmacologically active lead structures, the obtained structural diversity allows for the fast exploration of a large chemical space. Not surprisingly, the development of MCRs, leading to new structural frameworks or serving as key transformations in the total synthesis of natural products, has expanded rapidly over the last few decades. To date a multitude of new three- and four-component reactions have already been described; however, examples of “higher-order” MCRs where five or even more components are combined in a single reaction vessel are remarkably scarce. This tutorial review aims to critically describe the developments achieved in recent years, charting the ideas, challenges, and milestone reactions that were essential for the progress of this field.
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