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Publications - Bioorganic Chemistry

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Publications

Wolfram, K.; Schmidt, J.; Wray, V.; Milkowski, C.; Schliemann, W.; Strack, D.; Profiling of phenylpropanoids in transgenic low-sinapine oilseed rape (Brassica napus) Phytochemistry 71, 1076-1084, (2010) DOI: 10.1016/j.phytochem.2010.04.007

A dsRNAi approach silencing a key enzyme of sinapate ester biosynthesis (UDP-glucose:sinapate glucosyltransferase, encoded by the UGT84A9 gene) in oilseed rape (Brassica napus) seeds was performed to reduce the anti-nutritive properties of the seeds by lowering the content of the major seed component sinapine (sinapoylcholine) and various minor sinapate esters. The transgenic seeds have been produced so far to the T6 generation and revealed a steady suppression of sinapate ester accumulation. HPLC analysis of the wild-type and transgenic seeds revealed, as in the previous generations, marked alterations of the sinapate ester pattern of the transformed seeds. Besides strong reduction of the amount of the known sinapate esters, HPLC analysis revealed unexpectedly the appearance of several minor hitherto unknown rapeseed constituents. These compounds were isolated and identified by mass spectrometric and NMR spectroscopic analyses. Structures of 11 components were elucidated to be 4-O-glucosides of syringate, caffeyl alcohol and its 7,8-dihydro derivative as well as of sinapate and sinapine, along with sinapoylated kaempferol glycosides, a hexoside of a cyclic spermidine alkaloid and a sinapine derivative with an ether-bridge to a C6–C3-unit. These results indicate a strong impact of the transgenic approach on the metabolic network of phenylpropanoids in B. napus seeds. Silencing of UGT84A9 gene expression disrupt the metabolic flow through sinapoylglucose and alters the amounts and nature of the phenylpropanoid endproducts.
Publications

Westermann, B.; Ayaz, M.; van Berkel, S.; Enantiodivergente Organokaskadenreaktionen Angew. Chem. 122, 858-861, (2010) DOI: 10.1002/ange.200904638

In der Synthese strukturell und stereochemisch komplexer Moleküle mithilfe von Organokaskadenreaktionen können Katalysatoren auf enantiodivergente Weise wirken. Ein Beispiel ist der asymmetrische Aufbau quartärer Kohlenstoffzentren über komplementäre Enamin/Iminium‐Katalysen (siehe Schema; En=Enaminaktivierung, Im=Iminiumaktivierung).
Publications

Westermann, B.; Ayaz, M.; van Berkel, S.; Enantiodivergent Organocascade Reactions Angew. Chem. Int. Ed. 49, 846-849, (2010) DOI: 10.1002/anie.200904638

By targeting structural and stereochemical complexity with organocascade reactions, distinct catalysts can form molecular frameworks in an enantiodivergent way. This goal was elegantly achieved for the asymmetric synthesis of quaternary carbon centers by two complementary routes employing cascades of either enamine or iminium catalysis (see scheme; En=enamine activation, Im=iminium activation).
Publications

Doering, M.; Ba, L. A.; Lilienthal, N.; Nicco, C.; Scherer, C.; Abbas, M.; Zada, A. A. P.; Coriat, R.; Burkholz, T.; Wessjohann, L.; Diederich, M.; Batteux, F.; Herling, M.; Jacob, C.; Synthesis and Selective Anticancer Activity of Organochalcogen Based Redox Catalysts J. Med. Chem. 53, 6954-6963, (2010) DOI: 10.1021/jm100576z

Many tumor cells exhibit a disturbed intracellular redox state resulting in higher levels of reactive oxygen species (ROS). As these contribute to tumor initiation and sustenance, catalytic redox agents combining significant activity with substrate specificity promise high activity and selectivity against oxidatively stressed malignant cells. We describe here the design and synthesis of novel organochalcogen based redox sensor/effector catalysts. Their selective anticancer activity at submicromolar and low micromolar concentrations was established here in a range of tumor entities in various biological systems including cell lines, primary tumor cell cultures, and animal models. In the B-cell derived chronic lymphocytic leukemia (CLL), for instance, such compounds preferentially induce apoptosis in the cancer cells while peripheral blood mononuclear cells (PBMC) from healthy donors and the subset of normal B-cells remain largely unaffected. In support of the concept of sensor/effector based ROS amplification, we are able to demonstrate that underlying this selective activity against CLL cells are pre-existing elevated ROS levels in the leukemic cells compared to their nonmalignant counterparts. Furthermore, the catalysts act in concert with certain chemotherapeutic drugs in several carcinoma cell lines to decrease cell proliferation while showing no such interactions in normal cells. Overall, the high efficacy and selectivity of (redox) catalytic sensor/effector compounds warrant further, extensive testing toward transfer into the clinical arena.
Publications

Busch, C.; Jacob, C.; Anwar, A.; Burkholz, T.; Ba, L. A.; Cerella, C.; Diederich, M.; Brandt, W.; Wessjohann, L.; Montenarh, M.; Diallylpolysulfides induce growth arrest and apoptosis Int. J. Oncol. 36, 743-749, (2010) DOI: 10.3892/ijo_00000550

Garlic-derived organo sulphur compounds such as diallylsulfides provide a significant protection against carcinogenesis. Chemically synthesized, and highly pure diallylsulfides with a chain of 1-4 sulphur atoms, as well as a range of control compounds, were employed to investigate the influence of these agents on cell viability, cell cycle arrest and induction of apoptosis in HCT116 human colon cancer cells. Diallyltrisulfide, and even more efficiently diallyltetrasulfide treatment of HCT116 cells led to a reduced cell viability, cell cycle arrest and apoptosis. A similar activity was found for the propyl-analogues, while mono- and disulfides were considerably less active. Initial calculations point toward the ability of tri- and tetrasulfides to form reactive oxygen species (ROS). Here, we found that the induction of apoptosis was indeed dependent on the redox-state of the cell, with anti-oxidants being able to prevent sulfide-induced apoptosis. Furthermore, using HCT116 cells which were either positive or negative for p53 revealed that p53 is clearly dispensable for induction of apoptosis. Growth arrest and induction of apoptosis is associated with a considerable reduction of the level of cdc25C. These results support the therapeutic potential of polysulfides and allow insight into the mechanisms based on the polysulfide biochemistry.
Publications

Brauch, S.; Gabriel, L.; Westermann, B.; Seven-component reactions by sequential chemoselective Ugi–Mumm/Ugi–Smiles reactions Chem. Commun. 46, 3387-3389, (2010) DOI: 10.1039/B927388C

A seven-component reaction was accomplished by utilizing the different chemoselectivities of the Ugi–Mumm and the Ugi–Smiles reaction. The sequential multicomponent reactions led to highly diverse peptide and glycopeptide like structures.
Publications

Brandt, W.; Kufka, J.; Schulze, D.; Schulze, E.; Rausch, F.; Wessjohann, L.; The membrane bound aromatic p-hydroxybenzoic acid oligoprenyltransferase (UbiA) - how iterative improvements lead to a realistic structure that offers new insights into functional aspects of prenyl transferases and terpene synthases J. Cheminform. 2, O20, (2010) DOI: 10.1186/1758-2946-2-S1-O20

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Publications

Brandt, W.; Haupt, V. J.; Wessjohann, L. A.; Chemoinformatic Analysis of Biologically Active Macrocycles Curr. Top. Med. Chem. 10, 1361-1379, (2010) DOI: 10.2174/156802610792232060

In this review, macrocycles are defined as organic molecules containing at least one non-bridged cycle of 12 or more covalently connected atoms. Common statistical aspects as well as structure activity relationships (SAR) of macrocycles based on chemoinformatics methods are discussed. Can macrocyclic structural features be linked to activities against cancer cells, viruses like HIV, or bacteria? General challenges and problems in using chemoinformatics for more detailed analyses of macrocycles based on large compound databases are outlined.
Publications

Braga, A. L.; Wessjohann, L. A.; Taube, P. S.; Galetto, F. Z.; de Andrade, F. M.; Straightforward Method for the Synthesis of Selenocysteine and Selenocystine Derivatives from L-Serine Methyl Ester Synthesis 2010, 3131-3137, (2010) DOI: 10.1055/s-0030-1258188

A set of selenoamino acids has been efficiently synthesized under smooth conditions by a simple, flexible and modular strategy. In this method, O-mesylated l-serine methyl ester is generated in situ and directly substituted with various selenolate anions to afford selenocysteine, selenolanthionine, and selenocystine derivatives in good yields. Also, a tellurocysteine derivative can be obtained by this method.
Publications

Block, M.; Kluge, T.; Bette, M.; Schmidt, J.; Steinborn, D.; On the Reactivity of Rhodium(I) Complexes with κP-Coordinated γ-Phosphino-Functionalized Propyl Phenyl Sulfide Ligands: Routes to Cyclic Rhodium Complexes with κC,κP- and κP,κS-Coordinated Ligands as Well as Bis(diphenylphosphino)methanide Ligands Organometallics 29, 6749-6762, (2010) DOI: 10.1021/om100878n

Reactions of dinuclear μ-chlorido rhodium(I) complexes [(RhL2)2(μ-Cl)2] (L2 = cycloocta-1,5-diene, cod, 3; L2 = P∧P: Ph2PCH2PPh2, dppm, 4a; Ph2P(CH2)2PPh2, dppe, 4b; Ph2P(CH2)3PPh2, dppp, 4c; Me2P(CH2)2PMe2, dmpe, 4d) with γ-phosphino-functionalized propyl phenyl sulfides PhSCH2CH2CH2PR2 (R = Ph, 1; Cy, 2) afforded mononuclear rhodium(I) complexes of the type [RhCl(R2PCH2CH2CH2SPh-κP)L2] ] (R = Ph/L2 = P∧P, 5a−c; R = Ph/L2 = cod, 6; R = Cy/L2 = P∧P, 7a−d; R = Cy/L2 = cod, 8). Single-crystal X-ray diffraction analysis of 7b·C6H6 exhibited the expected square-planar coordination of the rhodium atom having coordinated dppe-κ2P,P′, Cy2PCH2CH2CH2SPh-κP, and a chlorido ligand. Deprotonation of complexes 5b/c, 6, 7b/c, and 8 with lithium diisopropyl amide (LDA) yielded, with a selective deprotonation of the CH2 group next to the sulfur atom (α-CH2 group), complexes of the type [Rh{CH(SPh)CH2CH2PR2-κC,κP}L2] (13b/c, 14, 15b/c, 16), thus being organorhodium intramolecular coordination compounds. Unexpectedly, reactions of the dppm complexes 5a and 7a with LDA led to deprotonation of the CH2 group of the dppm ligand, resulting in formation of mononuclear rhodium complexes with a bis(diphenylphosphino)methanide-κ2P,P′ ligand and a R2P∧SPh-κP,κS ligand, as well (17, 18). Single-crystal X-ray diffraction analysis of [Rh(dppm−H-κ2P,P′)(Cy2PCH2CH2CH2SPh-κP,κS)]·THF (18·THF) shows the rhodium atom located in the center of a distorted square-planar environment having bound the P∧S-κP,κS ligand and the anionic dppm−H-κ2P,P′ ligand with a very small P2−Rh−P3 angle (68.8(2)°) reflecting the small bite of that ligand. Addition of Tl[PF6] to complexes 5−8 afforded cationic rhodium(I) complexes of the type [Rh(R2PCH2CH2CH2SPh-κP,κS)L2][PF6] (9−12) bearing bidentately coordinated neutral co-ligands (P∧P: 9, 11; cod, 10, 12) and κP,κS-coordinated γ-phosphino-functionalized propyl phenyl sulfide ligands, as well. Single-crystal X-ray diffraction analysis of 10 reveals that the rhodium atom adopts a slightly distorted square-planar conformation. Complexes 9a−c and 11a−d were found to react with carbon monoxide, yielding cationic rhodium carbonyl complexes [Rh(CO)(R2PCH2CH2CH2SPh-κP,κS)(P∧P-κ2P,P′)]+ (19, 20), being in a dynamic equilibrium between two diastereomers each at room temperature, which was additionally verified by DFT calculations.
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