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Publikationen - Natur- und Wirkstoffchemie

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Publikation

Ruela, H. S.; Leal, I. C. R.; de Almeida, M. R. A.; dos Santos, K. R. N.; Wessjohann, L. A.; Kuster, R. M.; Antibacterial and antioxidant activities and acute toxicity of Bumelia sartorum Mart., Sapotaceae, a Brazilian medicinal plant Rev. Bras. Farmacogn. 21, 86-91, (2011) DOI: 10.1590/S0102-695X2011005000035

In order to validate the Bumelia sartorum Mart., Sapotaceae, traditional use for infection diseases, this study evaluates the antibacterial activity of the stem bark fractions against methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus strains by using the agar dilution method and reported as MIC (minimal inhibitory concentration). In addition, the DPPH scavenging activity of these fractions was measured and the chemical composition and acute toxicity of the active fraction were also determined. The ethyl acetate (EtOAc) extract was chemically analyzed by LC/MS, direct ionization APCI/MS, 1H NMR and 13C-NMR. All fractions, except butanol extract, presented high antioxidant activity, especially the methanol and the EtOAc extracts, which showed EC50 values (5.67 and 5.30 µg/mL, respectively) considerably lower than the Gingko-standard EGb 761® (38.58 µg/mL). The antibacterial activity against S. aureus strains was observed in EtOAc (MIC 256-512 µg/mL), which showed a very low toxicity. The chemical study of this fraction revealed the abundant presence of polyphenolic compounds. The antibacterial and antioxidant activities reported in this paper for EtOAc extract from B. sartorum and the low toxicity of this fraction opens the possibility that it could be helpful for the developing of new antibacterial agents for treating S. aureus infections.
Publikation

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.
Publikation

Rashan, L. J.; Franke, K.; Khine, M. M.; Kelter, G.; Fiebig, H. H.; Neumann, J.; Wessjohann, L. A.; Characterization of the anticancer properties of monoglycosidic cardenolides isolated from Nerium oleander and Streptocaulon tomentosum J. Ethnopharmacol. 134, 781-788, (2011) DOI: 10.1016/j.jep.2011.01.038

Aim of the studyFor identification of the active constituents we investigated the anticancer activity of cardenolides from Streptocaulon tomentosum Wight & Arn. (Asclepiadaceae) and from Nerium oleander L. (Apocynaceae) which are both used against cancer in the traditional medicine in their region of origin.Material, methods and resultsThe antiproliferative activity of cardenolides isolated from roots of Streptocaulon tomentosum (IC50 < 1–15.3 μM after 2 days in MCF7) and of cardenolide containing fractions from the cold aqueous extract of Nerium oleander leaves (“Breastin”, mean IC50 0.85 μg/ml in a panel of 36 human tumor cell lines), their influence on the cellular viability and on the cell cycle (block at the G2/M-phase or at the S-phase in tumor cells, respectively) were determined using different cell lines. The murine cell line L929 and normal non-tumor cells were not affected. Bioactivity guided fractionation of Breastin resulted in the isolation of the monoglycosidic cardenolides oleandrine, oleandrigeninsarmentoside, neritaloside, odoroside H, and odoroside A (IC50-values between 0.010 and 0.071 μg/ml).ConclusionsThe observed anticancer activities of extracts and isolated cardenolides are in agreement with the ethnomedicinal use of Streptocaulon tomentosum and Nerium oleander. The most active anticancer compounds from both species are monoglycosidic cardenolides possessing the 3β,14β-dihydroxy-5β-card-20(22)-enolide structure with or without an acetoxy group at C-16. The results indicate that the cytotoxic effects are induced by the inhibition of the plasma membrane bound Na+/K+-ATPase.
Publikation

Pando, O.; Stark, S.; Denkert, A.; Porzel, A.; Preusentanz, R.; Wessjohann, L. A.; The Multiple Multicomponent Approach to Natural Product Mimics: Tubugis, N-Substituted Anticancer Peptides with Picomolar Activity J. Am. Chem. Soc. 133, 7692-7695, (2011) DOI: 10.1021/ja2022027

The synthesis of a new generation of highly cytotoxic tubulysin analogues (i.e., tubugis) is described. In the key step, the rare, unstable, and synthetically difficult to introduce tertiary amide–N,O-acetal moiety required for high potency in natural tubulysins is replaced by a dipeptoid element formed in an Ugi four-component reaction. Two of the four components required are themselves produced by other multicomponent reactions (MCRs). Thus, the tubugis represent the first examples of the synthesis of natural-product-inspired compounds using three intertwined isonitrile MCRs.
Publikation

Neves Filho, R. A. W.; Westermann, B.; Wessjohann, L. A.; Synthesis of (−)-julocrotine and a diversity oriented Ugi-approach to analogues and probes Beilstein J. Org. Chem. 7, 1504-1507, (2011) DOI: 10.3762/bjoc.7.175

An improved total synthesis of (−)-julocrotine in three steps from Cbz-glutamine, in 51% overall yield, is presented. To demonstrate the potential of the heterocyclic moiety for diversity oriented synthesis, a series of (−)-julocrotine analogues was synthesized by employing the heterocyclic precursor as an amino input in Ugi four-component reactions (Ugi-4CR) [1].
Publikation

Nawaz, S. A.; Ayaz, M.; Brandt, W.; Wessjohann, L. A.; Westermann, B.; Cation–π and π–π stacking interactions allow selective inhibition of butyrylcholinesterase by modified quinine and cinchonidine alkaloids Biochem. Biophys. Res. Commun. 404, 935-940, (2011) DOI: 10.1016/j.bbrc.2010.12.084

Scaffold varied quaternized quinine and cinchonidine alkaloid derivatives were evaluated for their selective butyrylcholinesterase (BChE) inhibitory potential. Ki values were between 0.4–260.5 μM (non-competitive inhibition) while corresponding Kivalues to acetylcholinesterase (AChE) ranged from 7.0–400 μM exhibiting a 250-fold selectivity for BChE.Docking arrangements (GOLD, PLANT) revealed that the extended aromatic moieties and the quaternized nitrogen of the inhibitors were responsible for specific π–π stacking and π–cation interactions with the choline binding site and the peripheral anionic site of BChE’s active site.
Publikation

Mansfeld, J.; Brandt, W.; Haftendorn, R.; Schöps, R.; Ulbrich-Hofmann, R.; Discrimination between the regioisomeric 1,2- and 1,3-diacylglycerophosphocholines by phospholipases Chem. Phys. Lipids 164, 196-204, (2011) DOI: 10.1016/j.chemphyslip.2010.12.009

The artificial 1,3-diacyl-glycero-2-phosphocholines (1,3-PCs), which form similar aggregate structures as the naturally occurring 1,2-diacyl-sn-glycero-3-phosphocholines (1,2-PCs), were tested as substrates for different classes of phospholipases such as phospholipase A2 (PLA2) from porcine pancreas, bee and snake venom, and Arabidopsis thaliana, phospholipase C (PLC) from Bacillus cereus, and phospholipase D (PLD) from cabbage and Streptomyces species. The regioisomers of the natural phospholipids were shown to bind to all investigated phospholipases with an affinity similar to the corresponding naturally occurring phospholipids, however their hydrolysis was reduced to different degrees (PLA2s and PLC) or even abolished (PLDs belonging to the PLD superfamily). The results are in accordance with binding models obtained by docking the substrates to the crystal structures or homology models of the phospholipases.
Publikation

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.
Publikation

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.
Publikation

Heinke, R.; Franke, K.; Porzel, A.; Wessjohann, L. A.; Awadh Ali, N. A.; Schmidt, J.; Furanocoumarins from Dorstenia foetida Phytochemistry 72, 929-934, (2011) DOI: 10.1016/j.phytochem.2011.03.008

The linear furanocoumarins 5-(2,3-epoxy-3-methyl-butoxy)-chalepensin, 5-methoxy-3-(3-methyl-2,3-dihydroxybutyl)-psoralen-diacetate (7), 5-methoxy-3-[3-(β-d-glucopyranosyloxy)-2-acetyloxy-3-methyl-butyl]-psoralen and 5-(3-methyl-2,3-dihydroxybutyloxy)-3-[3-(β-d-glucopyranosyloxy)-2-hydroxy-3-methyl-butyl]-psoralen, and the coumarin derivative 7-hydroxy-5-methoxy-6-carboxymethyl-3-[3-(β-d-glucopyranosyloxy)-2-hydroxy-3-methyl-butyl]-coumarin were isolated from the leaves of Dorstenia foetida (Moraceae) along with the known compounds psoralen, bergapten, isopimpinellin, phellopterin, 5-methoxychalepensin and turbinatocoumarin. Further furanocoumarins were characterized by ESI-MS/MS investigations. The nonpolar extracts of D. foetida exhibit antifungal, antibacterial and cytotoxic activity, however, no anthelminthic activity.
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