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Publikation

Méndez, Y.; Vasco, A. V.; Ebensen, T.; Schulze, K.; Yousefi, M.; Davari, M. D.; Wessjohann, L. A.; Guzmán, C. A.; Rivera, D. G.; Westermann, B.; Diversification of a novel α‐galactosyl ceramide hotspot boosts the adjuvant properties in parenteral and mucosal vaccines Angew. Chem. Int. Ed. 63, e202310983, (2024) DOI: 10.1002/anie.202310983

The development of potent adjuvants is an important step for improving the performance of subunit vaccines. CD1d agonists, such as the prototypical α‐galactosyl ceramide (α‐GalCer), are of special interest due to their ability to activate iNKT cells and trigger rapid dendritic cell maturation and B‐cell activation. Herein, we introduce a novel derivatization hotspot at the α‐GalCer skeleton, namely the N‐substituent at the amide bond. The multicomponent diversification of this previously unexplored glycolipid chemotype space permitted the introduction of a variety of extra functionalities that can either potentiate the adjuvant properties or serve as handles for further conjugation to antigens toward the development of self‐adjuvanting vaccines. This strategy led to the discovery of compounds eliciting enhanced antigen‐specific T cell stimulation and a higher antibody response when delivered by either the parenteral or the mucosal route, as compared to a known potent CD1d agonist. Notably, various functionalized α‐GalCer analogues showed a more potent adjuvant effect after intranasal immunization than a PEGylated α‐GalCer analogue previously optimized for this purpose. Ultimately, this work could open multiple avenues of opportunity for the use of mucosal vaccines against microbial infections.
Publikation

Hussain, H.; Xiao, J.; Ali, A.; Green, I. R.; Westermann, B.; Unusually cyclized triterpenoids: occurrence, biosynthesis and chemical synthesis Nat. Prod. Rep. 40, 412-451, (2023) DOI: 10.1039/d2np00033d

Covering: 2009 to 2021Biosynthetically, most of the syntheses of triterpenes follow the cascade cyclization and rearrangement of the acyclic precursors viz., squalene (S) and 2,3-oxidosqualene (OS), which lead to the very well known tetra- and pentacyclic triterpene skeletons. Aside from these, numerous other triterpenoid molecules are also reported from various natural sources and their structures are derived from \"S\" and \"OS\" via some unusual cyclization operations which are different from the usual tetra- and pentacyclic frameworks. Numerous compelling advances have been made and reported in the identification of these unusual cyclized mono-, di-, tri- and tetracyclic triterpenes between 2009 and 2021. Besides a dramatic increase in the newly isolated uncommon cyclized triterpenoids, substantial progress in the (bio)-synthesis of these triterpenes has been published along with significant progress in their biological effects. In this review, 180 new unusual cyclized triterpenoids together with their demonstrated biogenetic pathways, syntheses and biological effects will be categorized and discussed.
Publikation

Hernández, G.; Ramos, B.; Sultani, H. N.; Ortiz, Y.; Spengler, I.; Castañeda, R. F.; Rivera, D. G.; Arnold, N.; Westermann, B.; Mirabal, Y.; Cultural characterization and antagonistic activity of Cladobotryum virescens against some phytopathogenic fungi and oomycetes Agronomy 13, 389, (2023) DOI: 10.3390/agronomy13020389

In this study, the characteristic growth of Cladobotryum virescens on nine culture media was analyzed. The growing behavior of this fungus was dependent on the culture medium. In vitro analysis showed that oat agar was better than other media tested with the highest conidia production. The antifungal activity against Fusarium chlamydosporum and Alternaria brassicicola was evaluated by the Dual Culture method. C. virescens displayed high activity against both pathogens acting through antibiosis and mycoparasitism. This effect was increased by a higher competitiveness of the strain for the substrate. Furthermore, the crude ethyl acetate extract of the culture broth was tested in vitro against Botrytis cinerea and Septoria tritici, as well as the hemibiotrophic oomycete Phytophthora infestans using a microtiter plate assay at different concentrations. The extract showed excellent inhibition even below 5 ppm. According to these results, we concluded that C. virescens can be considered as a potential biological control agent in agriculture. To the best of our knowledge, this is the first study to investigate C. virescens as a biocontrol agent for different diseases caused by five relevant pathogens that affect cereals and vegetables.
Publikation

Milde, R.; Schnabel, A.; Ditfe, T.; Hoehenwarter, W.; Proksch, C.; Westermann, B.; Vogt, T.; Chemical synthesis of trans 8-methyl-6-nonenoyl-CoA and functional expression unravel capsaicin synthase activity encoded by the Pun1 Locus Molecules 27, 6878, (2022) DOI: 10.3390/molecules27206878

Capsaicin, produced by diverse Capsicum species, is among the world’s most popular spices and of considerable pharmaceutical relevance. Although the capsaicinoid biosynthetic pathway has been investigated for decades, several biosynthetic steps have remained partly hypothetical. Genetic evidence suggested that the decisive capsaicin synthase is encoded by the Pun1 locus. Yet, the genetic evidence of the Pun1 locus was never corroborated by functionally active capsaicin synthase that presumably catalyzes an amide bond formation between trans 8-methyl-6-nonenoyl-CoA derived from branched-chain amino acid biosynthesis and vanilloylamine derived from the phenylpropanoid pathway. In this report, we demonstrate the enzymatic activity of a recombinant capsaicin synthase encoded by Pun1, functionally expressed in Escherichia coli, and provide information on its substrate specificity and catalytic properties. Recombinant capsaicin synthase is specific for selected aliphatic CoA-esters and highly specific for vanilloylamine. Partly purified from E. coli, the recombinant active enzyme is a monomeric protein of 51 kDa that is independent of additional co-factors or associated proteins, as previously proposed. These data can now be used to design capsaicin synthase variants with different properties and alternative substrate preferences.
Publikation

Humpierre, A. R.; Zanuy, A.; Saenz, M.; Vasco, A. V.; Méndez, Y.; Westermann, B.; Cardoso, F.; Quintero, L.; Santana, D.; Verez, V.; Valdés, Y.; Rivera, D. G.; Garrido, R.; Quantitative NMR for the structural analysis of novel bivalent glycoconjugates as vaccine candidates J. Pharm. Biomed. Anal. 214, 114721, (2022) DOI: 10.1016/j.jpba.2022.114721

Novel unimolecular bivalent glycoconjugates were assembled combining several functionalized capsular polysaccharides of Streptococcus pneumoniae and Neisseria meningitidis to a carrier protein by using an effective strategy based on the Ugi 4-component reaction. The development of multivalent glycoconjugates opens new opportunities in the field of vaccine design, but their high structural complexity involves new analytical challenges. Nuclear Magnetic Resonance has found wide applications in the characterization and impurity profiling of carbohydrate-based vaccines. Eight bivalent conjugates were studied by quantitative NMR analyzing the structural identity, the content of each capsular polysaccharide, the ratios between polysaccharides, the polysaccharide to protein ratios and undesirable contaminants. The qNMR technique involves experiments with several modified parameters for obtaining spectra with quantifiable signals. In addition, the achieved NMR results were combined with the results of colorimetric assay and Size Exclusion HPLC for assessing the protein content and free protein percentage, respectively. The application of quantitative NMR showed to be efficient to clear up the new structural complexities while allowing the quantitative assessment of the components.
Bücher und Buchkapitel

Ceballos, L. G.; Pacheco, D. F.; Westermann, B.; Garcia-Rivera, D.; Solid-phase heterocycle synthesis using multicomponent reactions (Erik Van der Eycken, Upendra K. Sharma). Multicomponent Reactions towards Heterocycles: Concepts and Applications 4, 139-162, (2022) ISBN: 9783527349081 DOI: 10.1002/9783527832439.ch4

Heterocycle chemistry has traditionally relied on solution-phase synthesis as technological platform to discover and produce bioactive scaffolds. With the advent of solid-phase synthesis (SPS) at the end of last century, combinatorial approaches using on-resin procedures were applied to create skeletal and appendage diversity in heterocyclic compounds. Multicomponent reactions (MCRs) were part of that endeavor for developing solid-phase protocols capable to accelerate drug discovery. This chapter highlights methodological aspects of the implementation of on-resin MCRs to produce heterocycle compounds. Different name reactions, synthetic strategies, and solid supports are analyzed with a critical view hoping to encourage the new generation of chemists to adapt the more recent multicomponent – especially catalytic – processes to the SPS technology.
Publikation

Sultani, H. N.; Morgan, I.; Hussain, H.; Roos, A. H.; Haeri, H. H.; Kaluđerović, G. N.; Hinderberger, D.; Westermann, B.; Access to new cytotoxic triterpene and steroidal Acid-TEMPO Conjugates by ugi multicomponent-reactions Int. J. Mol. Sci. 22, 7125, (2021) DOI: 10.3390/ijms22137125

Multicomponent reactions, especially the Ugi-four component reaction (U-4CR), provide powerful protocols to efficiently access compounds having potent biological and pharmacological effects. Thus, a diverse library of betulinic acid (BA), fusidic acid (FA), cholic acid (CA) conjugates with TEMPO (nitroxide) have been prepared using this approach, which also makes them applicable in electron paramagnetic resonance (EPR) spectroscopy. Moreover, convertible amide modified spin-labelled fusidic acid derivatives were selected for post-Ugi modification utilizing a wide range of reaction conditions which kept the paramagnetic center intact. The nitroxide labelled betulinic acid analogue 6 possesses cytotoxic effects towards two investigated cell lines: prostate cancer PC3 (IC50 7.4 ± 0.7 μM) and colon cancer HT29 (IC50 9.0 ± 0.4 μM). Notably, spin-labelled fusidic acid derivative 8 acts strongly against these two cancer cell lines (PC3: IC50 6.0 ± 1.1 μM; HT29: IC50 7.4 ± 0.6 μM). Additionally, another fusidic acid analogue 9 was also found to be active towards HT29 with IC50 7.0 ± 0.3 μM (CV). Studies on the mode of action revealed that compound 8 increased the level of caspase-3 significantly which clearly indicates induction of apoptosis by activation of the caspase pathway. Furthermore, the exclusive mitochondria targeting of compound 18 was successfully achieved, since mitochondria are the major source of ROS generation.
Publikation

Hussain, H.; Ali, I.; Wang, D.; Hakkim, F. L.; Westermann, B.; Ahmed, I.; Ashour, A. M.; Khan, A.; Hussain, A.; Green, I. R.; Shah, S. T. A.; Glycyrrhetinic acid: a promising scaffold for the discovery of anticancer agents Expert Opinion on Drug Discovery 16, 1497-1516, (2021) DOI: 10.1080/17460441.2021.1956901

Introduction: Oleanane-type pentacyclic triterpenes named glycyrrhetinic acids (GAs) featuring a C-30 carboxylic acid group, are extracted from the licorice (Glycyrrhiza uralensis). Numerous biological properties of GA have been reported and have attracted researchers from all over the world in recent years due to the peculiar GA scaffold-based semisynthetic cytotoxic effects.Areas covered: This review represents the applications of semisynthetic derivatives of GA for the development of future cancer treatments. Included in the review are important structural features of the semisynthetic GAs crucial for cytotoxic effects.Expert opinion: Numerous semisynthetic GA derivatives illustrated excellent cytotoxic effects toward various cancer cells. Notably the C-3(OH) at ring A along with C30-CO2H at ring E as vital structural features, make GA very appealing as a lead scaffold for medicinal chemistry, since these two groups permit the creation of further chemical diversity geared toward improved cytotoxic effects. Furthermore, numerous GA derivatives have been synthesized and indicate that compounds featuring cyanoenone moieties in ring A, or compounds having the amino group or nitrogen comprising heterocycles and hybrids thereof, illustrate more potent cytotoxicity. Furthermore, GA has a great capability to be conjugated with other anticancer molecules to synergistically enhance their combined cytotoxicity.
Publikation

Hussain, H.; Ali, I.; Wang, D.; Hakkim, F. L.; Westermann, B.; Rashan, L.; Ahmed, I.; Green, I. R.; Boswellic acids: privileged structures to develop lead compounds for anticancer drug discovery Expert Opinion on Drug Discovery 16, 851-867, (2021) DOI: 10.1080/17460441.2021.1892640

Introduction: Cancer has been identified to be the second major cause of death internationally as exemplified by ca. 9.6 million deaths in 2018 along with ca. 18 million new patients in 2018 that have been recorded. Natural boswellic acids (BAs) and their source, frankincense, have been reported to possess in vitro and in vivo anticancer effects toward various cancer cells.Areas covered: This comprehensive review focuses on the importance of boswellic acids (BAs) for the establishment of future treatments of cancer. Moreover, potent semisynthetic derivatives of BAs have been described along with their mode of action. In addition, important structural features of the semisynthetic BAs required for cytotoxic effects are also discussed.Expert opinion: Numerous semisynthetic BAs illustrate excellent cytotoxic effects. Of note, compounds bearing cyanoenone moieties in ring A, endoperoxides and hybrids display increased and more potent cytotoxic effects compared with other semisynthetic BAs. Moreover, BAs have the potential to conjugate or couple with other anticancer compounds to synergistically increase their combined anticancer effects. In addition, to get derived BAs to become lead anticancer compounds, future research should focus on the preparation of ring A cyanoenones, endoperoxides, and C-24 amide analogs.
Publikation

Ditfe, T.; Bette, E.; N. Sultani, H.; Otto, A.; Wessjohann, L. A.; Arnold, N.; Westermann, B.; Synthesis and biological evaluation of highly potent fungicidal deoxy‐hygrophorones Eur. J. Org. Chem. 2021, 3827-3836, (2021) DOI: 10.1002/ejoc.202100729

Although stripped from hydroxyl-groups, deoxygenated hygrophorones remain highly active against severe phytopathogens. The synthesis to these natural product congeners is achieved in rearrangement sequences, with an optimized deprotection strategy avoiding retro-aldol reactions. The activities are comparable to fungicides used in agriculture. Based on naturally occurring hygrophorones, racemic di- and mono-hydroxylated cyclopentenones bearing an aliphatic side chain have been produced in short synthetic sequences starting from furfuryl aldehyde. For the series of dihydroxylated trans-configured derivatives, an Achmatowicz-rearrangement and a Caddick-ring contraction were employed, and for the series of trans-configured mono-hydroxylated derivatives a Piancatelli-rearrangement. All final products showed good to excellent fungicidal activities against the plant pathogens B. cinerea, S. tritici and P. infestans.
  • Die Leibniz-Gemeinschaft
  • Digitalisierung in der Landwirtschaft
  • Martin-Luther Universität Halle
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