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Publications - Bioorganic Chemistry

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Publications

Schneider, A.; Wessjohann, L. A.; Severi, J. A.; Wagner, V.; Comparison of Impurity Profiles of Lipiblock® vs. Orlistat using HPLC and LC-MS/MS Lat. Am. J. Pharm. 31, 91-96, (2012)

Comparative HPLC-UV and LC-MS/MS studies of impurity profiles of a reference sample (Xenical®, F. Hoffmann–La Roche Ltd., Switzerland) vs. generic (Lipiblock®, EMS–Sigma Pharma, a generic drug) were carried out with ethanol extracts of commercial samples. The generic formulation contained higher levels of common impurities as well as a considerable number of impurities not found in the reference product. The detected impurity profile of Lipiblock® revealed that it most likely is based on fermentation. Since the effect of the impurities is unknown, at this point fully synthetic Xenical® appears to offer a better safety margin than Lipiblock® which, however, compares quite well to other generic formulations.
Publications

Schierling, A.; Dettner, K.; Schmidt, J.; Seifert, K.; Biosynthesis of the defensive alkaloid cicindeloine in Stenus solutus beetles Naturwissenschaften 99, 665-669, (2012) DOI: 10.1007/s00114-012-0945-x

To protect themselves from predation and microorganismic infestation, rove beetles of the genus Stenus produce and store bioactive alkaloids like stenusine, 3-(2-methyl-1-butenyl)pyridine, and cicindeloine in their pygidial glands. The biosynthesis of stenusine and 3-(2-methyl-1-butenyl)pyridine was previously investigated in Stenus bimaculatus and Stenus similis, respectively. Both molecules follow the same biosynthetic pathway, where the N-heterocyclic ring is derived from l-lysine and the side chain from l-isoleucine. The different alkaloids are finally obtained by slight modifications of shared precursor molecules. The piperideine alkaloid cicindeloine occurs as a main compound additionally to (E)-3-(2-methyl-1-butenyl)pyridine and traces of stenusine in the pygidial gland secretion of Stenus cicindeloides and Stenus solutus. Feeding of S. solutus beetles with [D,15N]-labeled amino acids followed by GC/MS analysis techniques showed that cicindeloine is synthesized via the identical pathway and precursor molecules as the other two defensive alkaloids.
Publications

Rivera, D. G.; Pérez-Labrada, K.; Lambert, L.; Dörner, S.; Westermann, B.; Wessjohann, L. A.; Carbohydrate–steroid conjugation by Ugi reaction: one-pot synthesis of triple sugar/pseudo-peptide/spirostane hybrids Carbohyd. Res. 359, 102-110, (2012) DOI: 10.1016/j.carres.2012.05.003

The one-pot synthesis of novel molecular chimeras incorporating sugar, pseudo-peptide, and steroidal moieties is described. For this, a new carbohydrate–steroid conjugation approach based on the Ugi four-component reaction was implemented for the ligation of glucose and chacotriose to spirostanic steroids. The approach proved wide substrate scope, as both mono and oligosaccharides functionalized with amino, carboxy, and isocyano groups were conjugated to steroidal substrates in an efficient, multicomponent manner. Two alternative strategies based on the hydrazoic acid variant of the Ugi reaction were employed for the synthesis of tetrazole-based chacotriose–diosgenin conjugates resembling naturally occurring spirostan saponins. This is the first time that triple sugar/pseudo-peptide/steroid hybrids are produced, thus opening up an avenue of opportunities for applications in drug discovery and biological chemistry.
Publications

Rausch, F.; Schicht, M.; Paulsen, F.; Ngueya, I.; Bräuer, L.; Brandt, W.; “SP-G”, a Putative New Surfactant Protein – Tissue Localization and 3D Structure PLOS ONE 7, e47789, (2012) DOI: 10.1371/journal.pone.0047789

Surfactant proteins (SP) are well known from human lung. These proteins assist the formation of a monolayer of surface-active phospholipids at the liquid-air interface of the alveolar lining, play a major role in lowering the surface tension of interfaces, and have functions in innate and adaptive immune defense. During recent years it became obvious that SPs are also part of other tissues and fluids such as tear fluid, gingiva, saliva, the nasolacrimal system, and kidney. Recently, a putative new surfactant protein (SFTA2 or SP-G) was identified, which has no sequence or structural identity to the already know surfactant proteins. In this work, computational chemistry and molecular-biological methods were combined to localize and characterize SP-G. With the help of a protein structure model, specific antibodies were obtained which allowed the detection of SP-G not only on mRNA but also on protein level. The localization of this protein in different human tissues, sequence based prediction tools for posttranslational modifications and molecular dynamic simulations reveal that SP-G has physicochemical properties similar to the already known surfactant proteins B and C. This includes also the possibility of interactions with lipid systems and with that, a potential surface-regulatory feature of SP-G. In conclusion, the results indicate SP-G as a new surfactant protein which represents an until now unknown surfactant protein class.
Publications

Rausch, F.; Molekülsimulation von Surfactant-Proteinen Ophthalmologische Nachrichten 12.2012, 13, (2012)

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Publications

Pereira, C.; Barreto Júnior, C. B.; Kuster, R. M.; Simas, N. K.; Sakuragui, C. M.; Porzel, A.; Wessjohann, L.; Flavonoids and a neolignan glucoside from Guarea macrophylla (Meliaceae) Quím. Nova 35, 1123-1126, (2012) DOI: 10.1590/S0100-40422012000600010

This work describes the phytochemical study of the methanol extract obtained from leaves of Guarea macrophylla, leading to the isolation and identification of three flavonoid glycosides (quercetin 3-O-β-D-glucopyranoside, quercetin 3-O-b-D-galactopyranoside, kaempferol 7-O-β-D-glucopyranoside) and a neolignan glucoside, dehydrodiconiferyl alcohol-4-β-D-glucoside. All compounds were identified by a combination of spectroscopic methods (1H, 1D, 2D NMR, 13C and UV), ESI-MS and comparison with the literature data. This is the first report of flavonoids in the genus Guarea and of a neolignan glucoside in the Meliaceae family.
Publications

Neves Filho, R. A. W.; Stark, S.; Westermann, B.; Wessjohann, L. A.; The multicomponent approach to N-methyl peptides: total synthesis of antibacterial (–)-viridic acid and analogues Beilstein J. Org. Chem. 8, 2085-2090, (2012) DOI: 10.3762/bjoc.8.234

Two syntheses of natural viridic acid, an unusual triply N-methylated peptide with two anthranilate units, are presented. The first one is based on peptide-coupling strategies and affords the optically active natural product in 20% overall yield over six steps. A more economical approach with only four steps leads to the similarly active racemate by utilizing a Ugi four-component reaction (Ugi-4CR) as the key transformation. A small library of viridic acid analogues is readily available to provide first SAR insight. The biological activities of the natural product and its derivatives against the Gram-negative bacterium Aliivibrio fischeri were evaluated.
Publications

Neves Filho, R. A. W.; Brauer, M. C. N.; Palm-Forster, M. A. T.; de Oliveira, R. N.; Wessjohann, L. A.; Patented Catalysts for the Synthesis and Biological Applications of Dihydropyrimidinones: Recent Advances of the Biginelli Reaction Recent Pat. Catal. 1, 51-73, (2012) DOI: 10.2174/2211548X11201010051

The acid-catalyzed and thermal multicomponent cyclocondensation between an aldehyde, a beta-keto ester and urea to generate dihydropyrimidinones (DHPMs) is one of the best studied multicomponent reactions in organic synthesis. It is frequently employed in the synthesis of natural products and biologically active compounds. After several years under academic development, this reaction drew the attention of researchers in the chemical and pharmaceutical industry. This critical review is focused on the development and applications of the Biginelli three component reaction (B-3CR) patented in the last three decades.
Publications

Neves Filho, R. A. W.; Stark, S.; Morejon, M. C.; Westermann, B.; Wessjohann, L. A.; 4-Isocyanopermethylbutane-1,1,3-triol (IPB): a convertible isonitrile for multicomponent reactions Tetrahedron Lett. 53, 5360-5363, (2012) DOI: 10.1016/j.tetlet.2012.07.064

The synthesis and applications of 4-isocyanopermethylbutane-1,1,3-triol (IPB) as a new convertible isonitrile (isocyanide) for isocyanide-based multicomponent reactions (IMCRs) like Ugi, Ugi-Smiles, and Passerini reactions are described. The primary products obtained from these IMCRs can be converted into highly activated N-acylpyrroles, which upon treatment with nucleophiles can be transformed into carboxylic acids, esters, amides, alcohols, and olefins. In this sense the reagent can be seen as a neutral carbanion equivalent to formate (HO2C−), and carboxylates or carboxamides etc. (RNu-CO−).
Publications

Müller, A. O.; Mrestani-Klaus, C.; Schmidt, J.; Ulbrich-Hofmann, R.; Dippe, M.; New cardiolipin analogs synthesized by phospholipase D-catalyzed transphosphatidylation Chem. Phys. Lipids 165, 787-793, (2012) DOI: 10.1016/j.chemphyslip.2012.09.005

Cardiolipin (CL) and related diphosphatidyl lipids are hardly accessible because of the complexity of their chemical synthesis. In the present paper, the transphosphatidylation reaction catalyzed by phospholipase D (PLD) from Streptomyces sp. has been proven as an alternative enzyme-assisted strategy for the synthesis of new CL analogs. The formation of this type of compounds from phosphatidylcholine was compared for a series of N- and C2-substituted ethanolamine derivatives as well as non-charged alcohols such as glycerol and ethylene glycol. The rapid exchange of the choline head group by ethanolamine derivatives having a low molecular volume (diethanolamine and serinol) gave rise to an efficient production of the corresponding CL analogs. In contrast, the yields were comparably low in the reaction with bulky nitrogenous acceptor alcohols (triethanolamine, tris(hydroxymethyl)aminomethane, tetrakis(hydroxyethyl)ammonium) or the non-charged alcohols. Therefore, a strong dependence of the conversion of the monophosphatidyl to the diphosphatidyl compound on steric parameters and the head group charge was concluded. The enzyme-assisted strategy was used for the preparation of purified diphosphatidyldiethanolamine and diphosphatidylserinol.
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