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Publikationen - Natur- und Wirkstoffchemie

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Publikation

Ricardo, M. G.; Llanes, D.; Wessjohann, L. A.; Rivera, D. G. Introducing the Petasis Reaction for Late-Stage Multicomponent Diversification, Labeling, and Stapling of Peptides Angew Chem 131, 2726-2730, (2019) DOI: 10.1002/ange.201812620

For the first time, the Petasis (borono‐Mannich) reaction is employed for the multicomponent labeling and stapling of peptides. The report includes the solid‐phase derivatization of peptides at the N‐terminus, Lys, and Nϵ‐MeLys side‐chains by an on‐resin Petasis reaction with variation of the carbonyl and boronic acid components. Peptides were simultaneously functionalized with aryl/vinyl substituents bearing fluorescent/affinity tags and oxo components such as dihydroxyacetone, glyceraldehyde, glyoxylic acid, and aldoses, thus encompassing a powerful complexity‐generating approach without changing the charge of the peptides. The multicomponent stapling was conducted in solution by linking Nϵ‐MeLys or Orn side‐chains, positioned at i, i+7 and i, i+4, with aryl tethers, while hydroxy carbonyl moieties were introduced as exocyclic fragments. The good efficiency and diversity oriented character of these methods show prospects for peptide drug discovery and chemical biology.
Publikation

Nganou, B. K.; Mbaveng, A. T.; Fobofou, S. A.; Fankam, A. G.; Bitchagno, G. T. M.; Simo Mpetga, J. D.; Wessjohann, L. A.; Kuete, V.; Efferth, T.; Tane, P. Furoquinolines and dihydrooxazole alkaloids with cytotoxic activity from the stem bark of Araliopsis soyauxii Fitoterapia 133, 193-199, (2019) DOI: 10.1016/j.fitote.2019.01.003

Two new furoquinoline alkaloids, maculine B (1) and kokusaginine B (2) and one new dihydrooxazole alkaloid, veprisazole (3), along with four known compounds namely, N13-methyl-3-methoxyrutaecarpine (4), flindersiamine (5), skimmianine (6) and tilianin (7) were isolated from the methanol extract of the stem bark of Araliopsis soyauxii Engl. by various chromatographic methods. Their structures were determined using spectrometry and spectroscopic techniques including NMR and MS. The cytotoxicity of the new compounds compared to that of doxorubicin, the reference anticancer compound, was determined on a panel of nine cancer cell lines including sensitive and drug resistant phenotypes. The three previously undescribed alkaloids displayed selective activities. Maculine B (1), the most active one among the newly described compounds, exhibited IC50 below 30 μM against CCRF-CEM leukemia and U87MG glioblastoma cells.
Publikation

Farag, M. A.; El-Kersh, D. M.; Ehrlich, A.; Choucry, M. A.; El-Seedi, H.; Frolov, A.; Wessjohann, L. A. Variation in Ceratonia siliqua pod metabolome in context of its different geographical origin, ripening stage and roasting process Food Chem 283, 675-687, (2019) DOI: 10.1016/j.foodchem.2018.12.118

Carob is a legume tree of a considerable commercial importance for the flavor and sweet industry. In this context, it is cultivated mostly for its pods, which are known for their nutritive value and multiple health benefits. However, metabolite patterns, underlying these properties are still mostly uncharacterized. In this study, the role of geographical origin, ontogenetic changes and thermal processing on the Ceratonia siliqua pod metabolome was assessed by mass spectrometry (MS)-based metabolomics. Thereby, a total of 70 fruits primary metabolites, represented mainly by carbohydrates, organic and amino acids were detected. Analysis of secondary bioactive metabolites assessed by ultra-high-performance liquid chromatography-electrospray ionization high resolution mass spectrometry (UHPLC-ESI-HR-MS) revealed in total 83 signals. The major signals, most significantly contributing in discrimination of C. siliqua specimens were assigned to tannins and flavonoids. PCA models derived from either UHPLC-MS or GC-MS proved to be powerful tools for discrimination of C. siliqua specimens.
Publikation

Podolskaya, E. P.; Gladchuk, A. S.; Keltsieva, O. A.; Dubakova, P. S.; Silyavka, E. S.; Lukasheva, E.; Zhukov, V.; Lapina, N.; Makhmadalieva, M. R.; Gzgzyan, A. M.; Sukhodolov, N. G.; Krasnov, K. A.; Selyutin, A. A.; Frolov, A. Thin Film Chemical Deposition Techniques as a Tool for Fingerprinting of Free Fatty Acids by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry Anal Chem 91, 1636-1643, (2019) DOI: 10.1021/acs.analchem.8b05296

Metabolic fingerprinting is a powerful analytical technique, giving access to high-throughput identification and relative quantification of multiple metabolites. Because of short analysis times, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) is the preferred instrumental platform for fingerprinting, although its power in analysis of free fatty acids (FFAs) is limited. However, these metabolites are the biomarkers of human pathologies and indicators of food quality. Hence, a high-throughput method for their fingerprinting is required. Therefore, here we propose a MALDI-TOF-MS method for identification and relative quantification of FFAs in biological samples of different origins. Our approach relies on formation of monomolecular Langmuir films (LFs) at the interphase of aqueous barium acetate solution, supplemented with low amounts of 2,5-dihydroxybenzoic acid, and hexane extracts of biological samples. This resulted in detection limits of 10–13–10–14 mol and overall method linear dynamic range of at least 4 orders of magnitude with accuracy and precision within 2 and 17%, respectively. The method precision was verified with eight sample series of different taxonomies, which indicates a universal applicability of our approach. Thereby, 31 and 22 FFA signals were annotated by exact mass and identified by tandem MS, respectively. Among 20 FFAs identified in Fucus algae, 14 could be confirmed by gas chromatography-mass spectrometry.
Publikation

Ricardo, M. G.; Marrrero, J. F.; Valdés, O.; Rivera, D. G.; Wessjohann, L. A. A Peptide Backbone Stapling Strategy Enabled by the Multicomponent Incorporation of Amide N‐Substituents Chem-Eur J 25, 769-774, (2019) DOI: 10.1002/chem.201805318

The multicomponent backbone N‐modification of peptides on solid‐phase is presented as a powerful and general method to enable peptide stapling at the backbone instead of the side chains. This work shows that a variety of functionalized N‐substituents suitable for backbone stapling can be readily introduced by means of on‐resin Ugi multicomponent reactions conducted during solid‐phase peptide synthesis. Diverse macrocyclization chemistries were implemented with such backbone N‐substituents, including the ring‐closing metathesis, lactamization, and thiol alkylation. The backbone N‐modification method was also applied to the synthesis of α‐helical peptides by linking N‐substituents to the peptide N‐terminus, thus featuring hydrogen‐bond surrogate structures. Overall, the strategy proves useful for peptide backbone macrocyclization approaches that show promise in peptide drug discovery.
Publikation

Kufka, R.; Rennert, R.; Kaluđerović, G. N.; Weber, L.; Richter, W.; Wessjohann, L. A. Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells Beilstein J Org Chem 15, 96-105, (2019) DOI: 10.3762/bjoc.15.11

Tubugi-1 is a small cytotoxic peptide with picomolar cytotoxicity. To improve its cancer cell targeting, it was conjugated using a universal, modular disulfide derivative. This allowed conjugation to a neuropeptide-Y (NPY)-inspired peptide [K4(C-βA-),F7,L17,P34]-hNPY, acting as NPY Y1 receptor (hY1R)-targeting peptide, to form a tubugi-1–SS–NPY disulfide-linked conjugate. The cytotoxic impacts of the novel tubugi-1–NPY peptide–toxin conjugate, as well as of free tubugi-1, and tubugi-1 bearing the thiol spacer (liberated from tubugi-1–NPY conjugate), and native tubulysin A as reference were investigated by in vitro cell viability and proliferation screenings. The tumor cell lines HT-29, Colo320 (both colon cancer), PC-3 (prostate cancer), and in conjunction with RT-qPCR analyses of the hY1R expression, the cell lines SK-N-MC (Ewing`s sarcoma), MDA-MB-468, MDA-MB-231 (both breast cancer) and 184B5 (normal breast; chemically transformed) were investigated. As hoped, the toxicity of tubugi-1 was masked, with IC50 values decreased by ca. 1,000-fold compared to the free toxin. Due to intracellular linker cleavage, the cytotoxic potency of the liberated tubugi-1 that, however, still bears the thiol spacer (tubugi-1-SH) was restored and up to 10-fold higher compared to the entire peptide–toxin conjugate. The conjugate shows toxic selectivity to tumor cell lines overexpressing the hY1R receptor subtype like, e.g., the hard to treat triple-negative breast cancer MDA-MB-468 cells.
Publikation

Vasco, A. V.; Mendez, Y.; Porzel, A.; Balbach, J.; Wessjohann, L. A.; Rivera, D. G. A Multicomponent Stapling Approach to Exocyclic Functionalized Helical Peptides: Adding Lipids, Sugar, PEGs, Labels and Handles to the Lactam Bridge Bioconjugate Chem 30, 253-259, (2019) DOI: 10.1021/acs.bioconjchem.8b00906

Peptide stapling is traditionally used to lock peptide conformations into α-helical structures using a variety of macrocyclization chemistries. In an endeavor to add a diversity-generating tool to this repertoire, we introduce a multicomponent stapling approach enabling the simultaneous stabilization of helical secondary structures and the exocyclic N-functionalization of the side chain-tethering lactam bridge. This is accomplished by means of a novel solid-phase methodology comprising, for the first time, the on-resin Ugi reaction-based macrocyclization of peptide side chains bearing amino and carboxylic acid groups. The exocyclic diversity elements arise from the isocyanide component used in the Ugi multicomponent stapling protocol, which allows for the incorporation of relevant fragments such as lipids, sugars, polyethylene glycol, fluorescent labels, and reactive handles. We prove the utility of such exocyclic reactive groups in the bioconjugation of a maleimide-armed lactam-bridged peptide to a carrier protein. The on-resin multicomponent stapling proved efficient for the installation of not only one, but also two consecutive lactam bridges having either identical or dissimilar N-functionalities. The easy access to helical peptides with a diverse set of exocyclic functionalities shows prospect for applications in peptide drug discovery and chemical biology.
Publikation

Ceafalan, L. C.; Fertig, T. E.; Gheorghe, T. C.; Hinescu, M. E.; Popescu, B. O.; Pahnke, J.; Gherghiceanu, M. Age-related ultrastructural changes of the basement membrane in the mouse blood-brain barrier J Cell Mol Med 23, 819-827, (2019) DOI: 10.1111/jcmm.13980

The blood‐brain barrier (BBB) is essential for a functional neurovascular unit. Most studies focused on the cells forming the BBB, but very few studied the basement membrane (BM) of brain capillaries in ageing. We used transmission electron microscopy and electron tomography to investigate the BM of the BBB in ageing C57BL/6J mice. The thickness of the BM of the BBB from 24‐month‐old mice was double as compared with that of 6‐month‐old mice (107 nm vs 56 nm). The aged BBB showed lipid droplets gathering within the BM which further increased its thickness (up to 572 nm) and altered its structure. The lipids appeared to accumulate toward the glial side of the BM. Electron tomography showed that the lipid‐rich BM regions are located in small pockets formed by the end‐feet of astrocytes. These findings suggest an imbalance of the lipid metabolism and that may precede the structural alteration of the BM. These alterations may favour the accretion of abnormal proteins that lead to neurodegeneration in ageing. These findings warrant further investigation of the BM of brain capillaries and of adjoining cells as potential targets for future therapies.
Publikation

D’Eustacchio, D.; Centorame, M.; Fanfani, A.; Senczuk, G.; Jiménez-Alemán, G. H.; Vasco-Vidal, A.; Méndez, Y.; Ehrlich, A.; Wessjohann, L.; Francioso, A. Iridoids and volatile pheromones of Tapinoma darioi ants: chemical differences to the closely related species Tapinoma magnum Chemoecology 29, 51-60, (2019) DOI: 10.1007/s00049-018-00275-9

Tapinoma species, and more general dolichoderine ants, are able to produce a variety of volatile compounds they use as chemical defense, alarm, and communication pheromones. Among these, iridoids and volatile ketones are the predominant molecule classes produced by the anal glands of these ants. A recent taxonomic revision of the genus Tapinoma in Europe revealed that the supercolonial species Tapinoma nigerrimum consists of a complex of four cryptic species. Two of them, Tapinoma magnum and the newly described Tapinoma darioi, are closely related species that evolutionary diverged recently. In this work, we determine and characterize the chemical profile of pheromones and volatile compounds of two Tapinoma species. From a chemical point of view, T. darioi and T. magnum show both qualitative and quantitative differences in the pheromones produced, supporting the taxonomic revision of the T. nigerrimum complex. Our data confirm T. darioi and T. magnum as separate species also from a biochemical point of view demonstrating the value of chemotaxonomy as a suitable tool for integrative studies of species differentiation even for closely related taxa.
Publikation

Ricardo, M. G.; Llanes, D.; Wessjohann, L. A.; Rivera, D. G. Introducing the Petasis Reaction for Late-Stage Multicomponent Diversification, Labeling, and Stapling of Peptides Angew Chem Int Ed 58, 2700-2704, (2019) DOI: 10.1002/anie.201812620

For the first time, the Petasis (borono‐Mannich) reaction is employed for the multicomponent labeling and stapling of peptides. The report includes the solid‐phase derivatization of peptides at the N‐terminus, Lys, and Nϵ‐MeLys side‐chains by an on‐resin Petasis reaction with variation of the carbonyl and boronic acid components. Peptides were simultaneously functionalized with aryl/vinyl substituents bearing fluorescent/affinity tags and oxo components such as dihydroxyacetone, glyceraldehyde, glyoxylic acid, and aldoses, thus encompassing a powerful complexity‐generating approach without changing the charge of the peptides. The multicomponent stapling was conducted in solution by linking Nϵ‐MeLys or Orn side‐chains, positioned at i, i+7 and i, i+4, with aryl tethers, while hydroxy carbonyl moieties were introduced as exocyclic fragments. The good efficiency and diversity oriented character of these methods show prospects for peptide drug discovery and chemical biology.
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