Publications

@article{cancers16203441,

title = {Targeting PARP-1 and DNA Damage Response Defects in Colorectal Cancer Chemotherapy with Established and Novel PARP Inhibitors},

author = {Demuth, Philipp and Thibol, Lea and Lemsch, Anna and Potlitz, Felix and Schulig, Lukas and Grathwol, Christoph and Manolikakes, Georg and Schade, Dennis and Roukos, Vassilis and Link, Andreas and Fahrer, Jörg},

url = {https://www.mdpi.com/2072-6694/16/20/3441},

doi = {10.3390/cancers16203441},

issn = {2072-6694},

year  = {2024},

date = {2024-10-10},

journal = {Cancers},

volume = {16},

number = {20},

issue = {3441},

abstract = {The DNA repair protein PARP-1 emerged as a valuable target in the treatment of tumor entities with deficiencies of BRCA1/2, such as breast cancer. More recently, the application of PARP inhibitors (PARPi) such as olaparib has been expanded to other cancer entities including colorectal cancer (CRC). We previously demonstrated that PARP-1 is overexpressed in human CRC and promotes CRC progression in a mouse model. However, acquired resistance to PARPi and cytotoxicity-mediated adverse effects limit their clinical applicability. Here, we detailed the role of PARP-1 as a therapeutic target in CRC and studied the efficacy of novel PARPi compounds in wildtype (WT) and DNA repair-deficient CRC cell lines together with the chemotherapeutics irinotecan (IT), 5-fluorouracil (5-FU), and oxaliplatin (OXA). Based on the ComPlat molecule archive, we identified novel PARPi candidates by molecular docking experiments in silico, which were then confirmed by in vitro PARP activity measurements. Two promising candidates (X17613 and X17618) also showed potent PARP-1 inhibition in a CRC cell-based assay. In contrast to olaparib, the PARPi candidates caused no PARP-1 trapping and, consistently, were not or only weakly cytotoxic in WT CRC cells and their BRCA2- or ATR-deficient counterparts. Importantly, both PARPi candidates did not affect the viability of nonmalignant human colonic epithelial cells. While both olaparib and veliparib increased the sensitivity of WT CRC cells towards IT, no synergism was observed for X17613 and X17618. Finally, we provided evidence that all PARPi (olaparib > veliparib > X17613 > X17618) synergize with chemotherapeutic drugs (IT > OXA) in a BRCA2-dependent manner in CRC cells, whereas ATR deficiency had only a minor impact. Collectively, our study identified novel lead structures with potent PARP-1 inhibitory activity in CRC cells but low cytotoxicity due to the lack of PARP-1 trapping, which synergized with IT in homologous recombination deficiency.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Sun2024b,

title = {Anti-Neuroinflammatory Effects of a Macrocyclic Peptide-Peptoid Hybrid in Lipopolysaccharide-Stimulated BV2 Microglial Cells},

author = {Lu Sun and Soraya Wilke Saliba and Matthias Apweiler and Kamil Akmermer and Claudine Herlan and Christoph Grathwol and Antônio Carlos Pinheiro Oliveira and Claus Normann and Nicole Jung and Stefan Bräse and Bernd L. Fiebich},

doi = {10.3390/ijms25084462},

issn = {14220067},

year  = {2024},

date = {2024-01-01},

journal = {International journal of molecular sciences},

volume = {25},

issue = {8},

abstract = {Inflammation processes of the central nervous system (CNS) play a vital role in the pathogenesis of several neurological and psychiatric disorders like depression. These processes are characterized by the activation of glia cells, such as microglia. Clinical studies showed a decrease in symptoms associated with the mentioned diseases after the treatment with anti-inflammatory drugs. Therefore, the investigation of novel anti-inflammatory drugs could hold substantial potential in the treatment of disorders with a neuroinflammatory background. In this in vitro study, we report the anti-inflammatory effects of a novel hexacyclic peptide-peptoid hybrid in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The macrocyclic compound X15856 significantly suppressed Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compound are partially explained by the modulation of the phosphorylation of p38 mitogen-activated protein kinases (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC), and the nuclear factor (NF)-κB, respectively. Due to its remarkable anti-inflammatory properties, this compound emerges as an encouraging option for additional research and potential utilization in disorders influenced by inflammation, such as depression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Synthesis of substituted triazole–pyrazole hybrids using triazenylpyrazole precursors},

author = {Simone Gräßle and Laura Holzhauer and Nicolai Wippert and Olaf Fuhr and Martin Nieger and Nicole Jung and Stefan Bräse},

doi = {10.3762/bjoc.20.121},

issn = {18605397},

year  = {2024},

date = {2024-01-01},

journal = {Beilstein Journal of Organic Chemistry},

volume = {20},

pages = {1396-1404},

publisher = {Beilstein-Institut Zur Forderung der Chemischen Wissenschaften},

abstract = {A synthesis route to access triazole–pyrazole hybrids via triazenylpyrazoles was developed. Contrary to existing methods, this route allows the facile N-functionalization of the pyrazole before the attachment of the triazole unit via a copper-catalyzed azide–alkyne cycloaddition. The developed methodology was used to synthesize a library of over fifty new multi-substituted pyrazole–triazole hybrids. We also demonstrate a one-pot strategy that renders the isolation of potentially hazardous azides obsolete. In addition, the compatibility of the method with solid-phase synthesis is shown exemplarily.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Neeb2024,

title = {Thio-2 Inhibits Key Signaling Pathways Required for the Development and Progression of Castration-resistant Prostate Cancer},

author = {Antje Neeb and Ines Figueiredo and Denisa Bogdan and Laura Cato and Jutta Stober and Juan M. Jiménez-Vacas and Victor Gourain and Irene I. Lee and Rebecca Seeger and Claudia Muhle-Goll and Bora Gurel and Jonathan Welti and Daniel Nava Rodrigues and Jan Rekowski and Xintao Qiu and Yija Jiang and Patrizio Di Micco and Borja Mateos and Stase Bielskute and Ruth Riisnaes and Ana Ferreira and Susana Miranda and Mateus Crespo and Lorenzo Buroni and Jian Ning and Suzanne Carreira and Stefan Bräse and Nicole Jung and Simone Gräßle and Amanda Swain and Xavier Salvatella and Stephen R. Plymate and Bissan Al-Lazikani and Henry W. Long and Wei Yuan and Myles Brown and Andrew C. B. Cato and Johann S. Bono and Adam Sharp},

doi = {10.1158/1535-7163.MCT-23-0354},

issn = {15388514},

year  = {2024},

date = {2024-01-01},

journal = {Molecular Cancer Therapeutics},

volume = {23},

issue = {6},

pages = {791-808},

publisher = {American Association for Cancer Research Inc.},

abstract = {Therapies that abrogate persistent androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain of the AR that drives transcriptional activity in CRPC remains a challenging therapeutic target. Herein we demonstrate that BCL-2–associated athanogene-1 (BAG-1) mRNA is highly expressed and associates with signaling pathways, including AR signaling, that are implicated in the development and progression of CRPC. In addition, interrogation of geometric and physiochemical properties of the BAG domain of BAG-1 isoforms identifies it to be a tractable but challenging drug target. Furthermore, through BAG-1 isoform mouse knockout studies, we confirm that BAG-1 isoforms regulate hormone physiology and that therapies targeting the BAG domain will be associated with limited “on-target” toxicity. Importantly, the postulated inhibitor of BAG-1 isoforms, Thio-2, suppressed AR signaling and other important pathways implicated in the development and progression of CRPC to reduce the growth of treatment-resistant prostate cancer cell lines and patient-derived models. However, the mechanism by which Thio-2 elicits the observed phenotype needs further elucidation as the genomic abrogation of BAG-1 isoforms was unable to recapitulate the Thio-2–mediated phenotype. Overall, these data support the interrogation of related compounds with improved drug-like properties as a novel therapeutic approach in CRPC, and further highlight the clinical potential of treatments that block persistent AR signaling which are currently undergoing clinical evaluation in CRPC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Sun2024,

title = {Anti-Inflammatory Effects of GPR55 Agonists and Antagonists in LPS-Treated BV2 Microglial Cells},

author = {Lu Sun and Matthias Apweiler and Claus Normann and Christoph W. Grathwol and Thomas Hurrle and Simone Gräßle and Nicole Jung and Stefan Bräse and Bernd L. Fiebich},

doi = {10.3390/ph17060674},

issn = {14248247},

year  = {2024},

date = {2024-01-01},

journal = {Pharmaceuticals},

volume = {17},

issue = {6},

publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},

abstract = {Chronic inflammation is driven by proinflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and chemokines, such as c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10. Inflammatory processes of the central nervous system (CNS) play an important role in the pathogenesis of various neurological and psychiatric disorders like Alzheimer’s disease, Parkinson’s disease, and depression. Therefore, identifying novel anti-inflammatory drugs may be beneficial for treating disorders with a neuroinflammatory background. The G-protein-coupled receptor 55 (GPR55) gained interest due to its role in inflammatory processes and possible involvement in different disorders. This study aims to identify the anti-inflammatory effects of the coumarin-based compound KIT C, acting as an antagonist with inverse agonistic activity at GPR55, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells in comparison to the commercial GPR55 agonist O-1602 and antagonist ML-193. All compounds significantly suppressed IL-6, TNF-α, CCL2, CCL3, CXCL2, and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compounds are partially explained by modulation of the phosphorylation of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC) pathways, and the transcription factor nuclear factor (NF)-κB, respectively. Due to its potent anti-inflammatory properties, KIT C is a promising compound for further research and potential use in inflammatory-related disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Pan2023,

title = {Identification of an Imidazopyridine-based Compound as an Oral Selective Estrogen Receptor Degrader for Breast Cancer Therapy},

author = {Mengwu Pan and Valeria Solozobova and Nane C. Kuznik and Nicole Jung and Simone Gräßle and Victor Gourain and Yvonne M. Heneka and Christina A. Cramer Clausbruch and Olaf Fuhr and Ravi S. N. Munuganti and Danilo Maddalo and Christine Blattner and Antje Neeb and Adam Sharp and Laura Cato and Carsten Weiss and Rinath M. Jeselsohn and Veronique Orian-Rousseau and Stefan Bräse and Andrew C. B. Cato},

doi = {10.1158/2767-9764.CRC-23-0111},

issn = {27679764},

year  = {2023},

date = {2023-01-01},

journal = {Cancer Research Communications},

volume = {3},

issue = {7},

pages = {1378-1396},

publisher = {American Association for Cancer Research Inc.},

abstract = {The pro-oncogenic activities of estrogen receptor alpha (ERα) drive breast cancer pathogenesis. Endocrine therapies that impair the production of estrogen or the action of the ERα are therefore used to prevent primary disease metastasis. Although recent successes with ERα degraders have been reported, there is still the need to develop further ERα antagonists with additional properties for breast cancer therapy. We have previously described a benzothiazole compound A4B17 that inhibits the proliferation of androgen receptor–positive prostate cancer cells by disrupting the interaction of the cochaperone BAG1 with the AR. A4B17 was also found to inhibit the proliferation of estrogen receptor—positive (ER+) breast cancer cells. Using a scaffold hopping approach, we report here a group of small molecules with imidazopyridine scaffolds that are more potent and efficacious than A4B17. The prototype molecule X15695 efficiently degraded ERα and attenuated estrogen-mediated target gene expression as well as transactivation by the AR. X15695 also disrupted key cellular protein–protein interactions such as BAG1–mortalin (GRP75) interaction as well as wild-type p53–mortalin or mutant p53–BAG2 interactions. These activities together reactivated p53 and resulted in cell-cycle block and the induction of apoptosis. When administered orally to in vivo tumor xenograft models, X15695 potently inhibited the growth of breast tumor cells but less efficiently the growth of prostate tumor cells. We therefore identify X15695 as an oral selective ER degrader and propose further development of this compound for therapy of ER+ breast cancers. Significance: An imidazopyridine that selectively degrades ERα and is orally bioavailable has been identified for the development of ER+ breast cancer therapeutics. This compound also activates wild-type p53 and disrupts the gain-of-function tumorigenic activity of mutant p53, resulting in cell-cycle arrest and the induction of apoptosis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Raudszus2023,

title = {Pharmacological inhibition of TRPV2 attenuates phagocytosis and lipopolysaccharide-induced migration of primary macrophages},

author = {Rick Raudszus and Andrea Paulig and Nicole Urban and Anke Deckers and Simone Gräßle and Sylvia Vanderheiden and Nicole Jung and Stefan Bräse and Michael Schaefer and Kerstin Hill},

doi = {10.1111/bph.16154},

issn = {14765381},

year  = {2023},

date = {2023-01-01},

journal = {British Journal of Pharmacology},

volume = {180},

issue = {21},

pages = {2736-2749},

publisher = {John Wiley and Sons Inc},

abstract = {Background and Purpose: In macrophages, transient receptor potential vanilloid 2 (TRPV2) channel contributes to various cellular processes such as cytokine production, differentiation, phagocytosis and migration. Due to a lack of selective pharmacological tools, its function in immunological processes is not well understood and the identification of novel and selective TRPV2 modulators is highly desirable. Experimental Approach: Novel and selective TRPV2 modulators were identified by screening a compound library using Ca2+ influx assays with human embryonic kidney 293 (HEK293) cells heterologously expressing rat TRPV2. Hits were further characterized and validated with Ca2+ influx and electrophysiological assays. Phagocytosis and migration of macrophages were analysed and the contribution of TRPV2 to the generation of Ca2+ microdomains was studied by total internal reflection fluorescence microscopy (TIRFM). Key Results: The compound IV2-1, a dithiolane derivative (1,3-dithiolan-2-ylidene)-4-methyl-5-phenylpentan-2-one), is a potent inhibitor of heterologously expressed TRPV2 channels (IC50 = 6.3 ± 0.7 μM) but does not modify TRPV1, TRPV3 or TRPV4 channels. IV2-1 also inhibits TRPV2-mediated Ca2+ influx in macrophages. IV2-1 inhibits macrophage phagocytosis along with valdecoxib and after siRNA-mediated knockdown. Moreover, TRPV2 inhibition inhibits lipopolysaccharide-induced migration of macrophages whereas TRPV2 activation promotes migration. After activation, TRPV2 shapes Ca2+ microdomains predominantly at the margin of macrophages, which are important cellular regions to promote phagocytosis and migration. Conclusions and Implications: IV2-1 is a novel TRPV2-selective blocker and underline the role of TRPV2 in macrophage-mediated phagocytosis and migration. Furthermore, we provide evidence that TRPV2 activation generates Ca2+ microdomains, which may be involved in phagocytosis and migration of macrophages.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Tosino2023,

title = {F-Tag Induced Acyl Shift in the Photochemical Cyclization of o-Alkynylated N-Alkyl-N-acylamides to Indoles**},

author = {Helena Simek Tosino and André Jung and Olaf Fuhr and Claudia Muhle-Goll and Nicole Jung and Stefan Bräse},

url = {https://doi.org/10.26434/chemrxiv-2022-9shrz},

doi = {10.26434/chemrxiv-2022-9shrz},

year  = {2023},

date = {2023-01-01},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Macara2023,

title = {Practical synthesis and biological screening of sulfonyl hydrazides},

author = {João Macara and Catarina Caldeira and José Cunha and Jaime A. S. Coelho and Maria J. S. A. Silva and Konrad Krämer and Christoph W. Grathwol and Stefan Bräse and M. Manuel B. Marques},

doi = {10.1039/d2ob02160a},

issn = {14770520},

year  = {2023},

date = {2023-01-01},

journal = {Organic and Biomolecular Chemistry},

volume = {21},

issue = {10},

pages = {2118-2126},

publisher = {Royal Society of Chemistry},

abstract = {A methodology for the synthesis of sulfonyl hydrazides mediated by hypervalent iodine is described. Taking advantage of the umpolung properties of hypervalent iodine reagents, the polarity of sodium sulfinate salts is reversed, and a key intermediate is generated and reacted with mono- and disubstituted hydrazines. To highlight the practical utility of this protocol, a diverse range of sulfonyl hydrazides were synthesized in yields up to 62%. Furthermore, a gram-scale reaction was performed, showing the robustness of the procedure. Mechanistic studies, including DFT calculations, were performed and the bioactivity of the generated compounds was evaluated.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Klein2023,

title = {Controlled, Stepwise Syntheses of Oligomers with Modified Quinoxaline Backbones},

author = {Jerome Klein and Nicole Jung and Stefan Bräse},

doi = {10.1002/ejoc.202200764},

issn = {10990690},

year  = {2023},

date = {2023-01-01},

journal = {European Journal of Organic Chemistry},

volume = {26},

issue = {6},

publisher = {John Wiley and Sons Inc},

abstract = {New oligomers based on quinoxaline units were successfully synthesized through multistep reactions using Wittig coupling, affording (E)-(quinoxalin-2-yl)ethene oligomers. Diverse quinoxaline-based phosphonium salts were designed and synthesized, enabling versatility and compatibility regarding the oligomer-building process. The characterization of the oligomers showed excellent stereoisomer specificity, i.e., a fully E-configurated conjugated π-system. The oligomers’ light absorption/emission profiles indicate potential properties for an application in materials science.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Frei2022,

title = {Metal Complexes as Antifungals? from a Crowd-Sourced Compound Library to the First in Vivo Experiments},

author = {Angelo Frei and Alysha G. Elliott and Alex Kan and Hue Dinh and Stefan Bräse and Alice E. Bruce and Mitchell R. Bruce and Feng Chen and Dhirgam Humaidy and Nicole Jung and A. Paden King and Peter G. Lye and Hanna K. Maliszewska and Ahmed M. Mansour and Dimitris Matiadis and María Paz Muñoz and Tsung Yu Pai and Shyam Pokhrel and Peter J. Sadler and Marina Sagnou and Michelle Taylor and Justin J. Wilson and Dean Woods and Johannes Zuegg and Wieland Meyer and Amy K. Cain and Matthew A. Cooper and Mark A. T. Blaskovich},

doi = {10.1021/jacsau.2c00308},

issn = {26913704},

year  = {2022},

date = {2022-01-01},

journal = {JACS Au},

volume = {2},

issue = {10},

pages = {2277-2294},

abstract = {There are currently fewer than 10 antifungal drugs in clinical development, but new fungal strains that are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work, we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or hemolytic properties at similar concentrations. The structures of 21 metal complexes that display high antifungal activity (MIC ≤1.25 μM) are discussed and evaluated further against a broad panel of yeasts. Most of these have not been previously tested for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larva model, revealing that only one compound showed signs of toxicity at the highest injected concentration. Lastly, we demonstrated that the organo-Pt(II) cyclooctadiene complex Pt1 significantly reduces fungal load in an in vivo G. mellonella infection model. These findings showcase that the structural and chemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Apweiler2022,

title = {Functional Selectivity of Coumarin Derivates Acting via GPR55 in Neuroinflammation},

author = {Matthias Apweiler and Jana Streyczek and Soraya Wilke Saliba and Juan Antonio Collado and Thomas Hurrle and Simone Gräßle and Eduardo Muñoz and Claus Normann and Sabine Hellwig and Stefan Bräse and Bernd L. Fiebich},

doi = {10.3390/ijms23020959},

issn = {14220067},

year  = {2022},

date = {2022-01-01},

journal = {International Journal of Molecular Sciences},

volume = {23},

issue = {2},

publisher = {MDPI},

abstract = {Anti-neuroinflammatory treatment has gained importance in the search for pharmacological treatments of different neurological and psychiatric diseases, such as depression, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Clinical studies demonstrate a reduction of the mentioned diseases’ symptoms after the administration of anti-inflammatory drugs. Novel coumarin derivates have been shown to elicit anti-neuroinflammatory effects via G-protein coupled receptor GPR55, with possibly reduced side-effects compared to the known anti-inflammatory drugs. In this study, we, therefore, evaluated the anti-inflammatory capacities of the two novel coumarin-based compounds, KIT C and KIT H, in human neuroblastoma cells and primary murine microglia. Both compounds reduced PGE2-concentrations likely via the inhibition of COX-2 synthesis in SK-N-SH cells but only KIT C decreased PGE2-levels in primary microglia. The examination of other pro-and anti-inflammatory parameters showed varying effects of both compounds. Therefore, the differences in the effects of KIT C and KIT H might be explained by functional selectivity as well as tissue-or cell-dependent expression and signal pathways coupled to GPR55. Understanding the role of chemical residues in functional selectivity and specific cell-and tissue-targeting might open new therapeutic options in pharmacological drug development and might improve the treatment of the mentioned diseases by intervening in an early step of their pathogenesis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Holzhauer2022,

title = {Scope of tetrazolo[1,5-a]quinoxalines in CuAAC reactions for the synthesis of triazoloquinoxalines, imidazoloquinoxalines, and rhenium complexes thereof},

author = {Laura Holzhauer and Chloé Liagre and Olaf Fuhr and Nicole Jung and Stefan Bräse},

doi = {10.3762/bjoc.18.111},

issn = {18605397},

year  = {2022},

date = {2022-01-01},

journal = {Beilstein Journal of Organic Chemistry},

volume = {18},

pages = {1088-1099},

publisher = {Beilstein-Institut Zur Forderung der Chemischen Wissenschaften},

abstract = {The conversion of tetrazolo[1,5-a]quinoxalines to 1,2,3-triazoloquinoxalines and triazoloimidazoquinoxalines under typical conditions of a CuAAC reaction has been investigated. Derivatives of the novel compound class of triazoloimidazoquinoxalines (TIQ) and rhenium(I) triazoloquinoxaline complexes as well as a new TIQ rhenium complex were synthesized. As a result, a small 1,2,3-triazoloquinoxaline library was obtained and the method could be expanded towards 4-substituted tetrazoloquinoxalines. The compatibility of various aliphatic and aromatic alkynes towards the reaction was investigated and the denitrogenative annulation towards imidazoloquinoxalines could be observed as a competing reaction depending on the alkyne concentration and the substitutions at the quinoxaline.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Lei2022,

title = {Droplet Microarray as a Powerful Platform for Seeking New Antibiotics Against Multidrug-Resistant Bacteria},

author = {Wenxi Lei and Anke Deckers and Charlotte Luchena and Anna Popova and Markus Reischl and Nicole Jung and Stefan Bräse and Thomas Schwartz and Ilga K. Krimmelbein and Lutz F. Tietze and Pavel A. Levkin},

doi = {10.1002/adbi.202200166},

issn = {27010198},

year  = {2022},

date = {2022-01-01},

journal = {Advanced Biology},

volume = {6},

issue = {12},

publisher = {John Wiley and Sons Inc},

abstract = {Multidrug-resistant (MDR) bacteria is a severe threat to public health. Therefore, it is urgent to establish effective screening systems for identifying novel antibacterial compounds. In this study, a highly miniaturized droplet microarray (DMA) based high-throughput screening system is established to screen over 2000 compounds for their antimicrobial properties against carbapenem-resistant Klebsiella pneumoniae and methicillin resistant Staphylococcus aureus (MRSA). The DMA consists of an array of hydrophilic spots divided by superhydrophobic borders. Due to the differences in the surface wettability between the spots and the borders, arrays of hundreds of nanoliter-sized droplets containing bacteria and different drugs can be generated for screening applications. A simple colorimetric viability readout utilizing a conventional photo scanner is developed for fast single-step detection of the inhibitory effect of the compounds on bacterial growth on the whole array. Six hit compounds, including coumarins and structurally simplified estrogen analogs are identified in the primary screening and validated with minimum inhibition concentration assay for their antibacterial effect. This study demonstrates that the DMA-based high-throughput screening system enables the identification of potential antibiotics from novel synthetic compound libraries, offering opportunities for development of new treatments against multidrug-resistant bacteria.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Kuznik2022,

title = {A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway},

author = {Nane C. Kuznik and Valeria Solozobova and Irene I. Lee and Nicole Jung and Linxiao Yang and Karin Nienhaus and Emmanuel A. Ntim and Jaice T. Rottenberg and Claudia Muhle-Goll and Amrish Rajendra Kumar and Ravindra Peravali and Simone Gräßle and Victor Gourain and Célia Deville and Laura Cato and Antje Neeb and Marco Dilger and Christina A. Cramer Clausbruch and Carsten Weiss and Bruno Kieffer and G. Ulrich Nienhaus and Myles Brown and Stefan Bräse and Andrew C. B. Cato},

doi = {10.1016/j.isci.2022.104175},

issn = {25890042},

year  = {2022},

date = {2022-01-01},

journal = {iScience},

volume = {25},

issue = {5},

publisher = {Elsevier Inc.},

abstract = {BAG1 is a family of polypeptides with a conserved C-terminal BAG domain that functions as a nucleotide exchange factor for the molecular chaperone HSP70. BAG1 proteins also control several signaling processes including proteostasis, apoptosis, and transcription. The largest isoform, BAG1L, controls the activity of the androgen receptor (AR) and is upregulated in prostate cancer. Here, we show that BAG1L regulates AR dynamics in the nucleus and its ablation attenuates AR target gene expression especially those involved in oxidative stress and metabolism. We show that a small molecule, A4B17, that targets the BAG domain downregulates AR target genes similar to a complete BAG1L knockout and upregulates the expression of oxidative stress-induced genes involved in cell death. Furthermore, A4B17 outperformed the clinically approved antagonist enzalutamide in inhibiting cell proliferation and prostate tumor development in a mouse xenograft model. BAG1 inhibitors therefore offer unique opportunities for antagonizing AR action and prostate cancer growth.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Warmuth2021,

title = {Total synthesis of decarboxyaltenusin},

author = {Lucas Warmuth and Aaron Weiß and Marco Reinhardt and Anna Meschkov and Ute Schepers and Joachim Podlech},

doi = {10.3762/BJOC.17.22},

issn = {18605397},

year  = {2021},

date = {2021-01-01},

journal = {Beilstein Journal of Organic Chemistry},

volume = {17},

pages = {224-228},

publisher = {Beilstein-Institut Zur Forderung der Chemischen Wissenschaften},

abstract = {The total synthesis of decarboxyaltenusin (5'-methoxy-6-methyl-[1,1'-biphenyl]-3,3',4-triol), a toxin produced by various mold fungi, has been achieved in seven steps in a yield of 31% starting from 4-methylcatechol and 1-bromo-3,5-dimethoxybenzene, where the longest linear sequence consists of five steps. The key reaction was a palladium-catalyzed Suzuki coupling of an aromatic boronate with a brominated resorcin derivative.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Sedlmeier2021,

title = {Id1 and Id3 Are Regulated Through Matrix-Assisted Autocrine BMP Signaling and Represent Therapeutic Targets in Melanoma},

author = {Georg Sedlmeier and Vanessa Al-Rawi and Justyna Buchert and Klaus Yserentant and Melanie Rothley and Anastasia Steshina and Simone Gräßle and Ruo Lin Wu and Thomas Hurrle and Wilfrid Richer and Charles Decraene and Wilko Thiele and Jochen Utikal and Wasim Abuillan and Motomu Tanaka and Dirk Peter Herten and Caroline S. Hill and Boyan K. Garvalov and Nicole Jung and Stefan Bräse and Jonathan P. Sleeman},

doi = {10.1002/adtp.202000065},

issn = {23663987},

year  = {2021},

date = {2021-01-01},

journal = {Advanced Therapeutics},

volume = {4},

issue = {2},

publisher = {Blackwell Publishing Ltd},

abstract = {The tumorigenicity of cancer cells is highly influenced by the extracellular matrix (ECM) through mechanisms that are poorly understood. Here it is reported that a variety of 3D ECM microenvironments strongly induce expression of Id1 and Id3 in melanoma cells. Genetic ablation of Id1/Id3 impairs melanoma cell outgrowth in 3D Matrigel culture and inhibits melanoma initiation in vivo. Mechanistically, 3D ECM microenvironments hinder diffusion of endogenously produced bone morphogenetic proteins, thereby fostering autocrine signaling and Id1/Id3 expression. A compound screen identifies new coumarin derivatives that potently inhibit both Id1/Id3 expression and melanoma initiation in vivo. Together, the findings reveal a novel mechanism through which the ECM increases tumorigenicity, identify Id1/Id3 as melanoma-relevant therapeutic targets, and characterize inhibitors of Id1/Id3 expression with therapeutic potential.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Wippert2021,

title = {Synthesis of new pyrazolo[1,2,3]triazines by cyclative cleavage of pyrazolyltriazenes},

author = {Nicolai Wippert and Martin Nieger and Claudine Herlan and Nicole Jung and Stefan Bräse},

doi = {10.3762/bjoc.17.187},

issn = {18605397},

year  = {2021},

date = {2021-01-01},

journal = {Beilstein Journal of Organic Chemistry},

volume = {17},

pages = {2773-2780},

publisher = {Beilstein-Institut Zur Forderung der Chemischen Wissenschaften},

abstract = {We describe the synthesis of so far synthetically not accessible 3,6-substituted-4,6-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines as nitrogen-rich heterocycles. The target compounds were obtained in five steps, including an amidation and a cyclative cleavage reaction as key reaction steps. The introduction of two side chains allowed a variation of the pyrazolo[3,4-d][1,2,3]triazine core with commercially available building blocks, enabling the extension of the protocol to gain other derivatives straightforwardly. Attempts to synthesize 3,7-substituted-4,7-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines, the regioisomers of the successfully gained 3,6-substituted 4,6-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines, were not successful under similar conditions due to the higher stability of the triazene functionality in the regioisomeric precursors and thus, the failure of the removal of the protective group.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Saliba2021,

title = {Effects of a novel gpr55 antagonist on the arachidonic acid cascade in lps‐activated primary microglial cells},

author = {Soraya Wilke Saliba and Franziska Gläser and Anke Deckers and Albrecht Keil and Thomas Hurrle and Matthias Apweiler and Florian Ferver and Nicole Volz and Dominique Endres and Stefan Bräse and Bernd L. Fiebich},

doi = {10.3390/ijms22052503},

issn = {14220067},

year  = {2021},

date = {2021-01-01},

journal = {International Journal of Molecular Sciences},

volume = {22},

issue = {5},

pages = {1-16},

publisher = {MDPI AG},

abstract = {Neuroinflammation is a crucial process to maintain homeostasis in the central nervous system (CNS). However, chronic neuroinflammation is detrimental, and it is described in the pathogenesis of CNS disorders, including Alzheimerʹs disease (AD) and depression. This process is characterized by the activation of immune cells, mainly microglia. The role of the orphan G‐protein‐coupled receptor 55 (GPR55) in inflammation has been reported in different models. However, its role in neuroinflammation in respect to the arachidonic acid (AA) cascade in activated microglia is still lacking of comprehension. Therefore, we synthesized a novel GPR55 antagonist (KIT 10, 0.1–25 μM) and tested its effects on the AA cascade in lipopolysaccharide (LPS, 10 ng / mL)‐treated primary rat microglia using Western blot and EIAs. We show here that KIT 10 potently prevented the release of prostaglandin E2 (PGE2), reduced microsomal PGE2 synthase (mPGES‐1) and cyclooxygenase‐2 (COX‐2) synthesis, and inhibited the phosphorylation of Ikappa B‐alpha (IκB‐α), a crucial upstream step of the inflammation‐related nuclear factor‐kappaB (NF‐κB) signaling pathway. However, no effects were observed on COX‐1 and ‐2 activities and mitogen‐activated kinases (MAPK). In summary, the novel GPR55 receptor antagonist KIT 10 reduces neuroinflammatory parameters in microglia by inhibiting the COX‐2/PGE2 pathway. Further experiments are necessary to better elucidate its effects and mechanisms. Nevertheless, the modulation of inflammation by GPR55 might be a new therapeutic option to treat CNS disorders with a neuroinflammatory background such as AD or depression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Mohr2021,

title = {Synthesis and SAR evaluation of coumarin derivatives as potent cannabinoid receptor agonists},

author = {Florian Mohr and Thomas Hurrle and Lindsey Burggraaff and Lukas Langer and Martijn P. Bemelmans and Maximilian Knab and Martin Nieger and Gerard J. P. Westen and Laura H. Heitman and Stefan Bräse},

doi = {10.1016/j.ejmech.2021.113354},

issn = {17683254},

year  = {2021},

date = {2021-01-01},

journal = {European Journal of Medicinal Chemistry},

volume = {220},

publisher = {Elsevier Masson s.r.l.},

abstract = {We report the development and extensive structure-activity relationship evaluation of a series of modified coumarins as cannabinoid receptor ligands. In radioligand, and [35S]GTPγS binding assays the CB receptor binding affinities and efficacies of the new ligands were determined. Furthermore, we used a ligand-based docking approach to validate the empirical observed results. In conclusion, several crucial structural requirements were identified. The most potent coumarins like 3-butyl-7-(1-butylcyclopentyl)-5-hydroxy-2H-chromen-2-one (36b, Ki CB2 13.7 nM, EC50 18 nM), 7-(1-butylcyclohexyl)-5-hydroxy-3-propyl-2H-chromen-2-one (39b, Ki CB2 6.5 nM, EC50 4.51 nM) showed a CB2 selective agonistic profile with low nanomolar affinities.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Kuznik2021,

title = {Development of a Benzothiazole Scaffold-Based Androgen Receptor N-Terminal Inhibitor for Treating Androgen-Responsive Prostate Cancer},

author = {Nane C. Kuznik and Valeria Solozobova and Nicole Jung and Simone Gräßle and Qing Lei and Eric M. Lewandowski and Ravi Munuganti and Amina Zoubeidi and Yu Chen and Stefan Bräse and Andrew C. B. Cato},

doi = {10.1021/acschembio.1c00390},

issn = {15548937},

year  = {2021},

date = {2021-01-01},

journal = {ACS Chemical Biology},

volume = {16},

issue = {11},

pages = {2103-2108},

publisher = {American Chemical Society},

abstract = {All current clinically approved androgen deprivation therapies for prostate cancer target the C-terminal ligand-binding domain of the androgen receptor (AR). However, the main transactivation function of the receptor is localized at the AR N-terminal domain (NTD). Targeting the AR NTD directly is a challenge because of its intrinsically disordered structure and the lack of pockets for drugs to bind. Here, we have taken an alternative approach using the cochaperone BAG1L, which interacts with the NTD, to develop a novel AR inhibitor. We describe the identification of 2-(4-fluorophenyl)-5-(trifluoromethyl)-1,3-benzothiazole (A4B17), a small molecule that inhibits BAG1L-AR NTD interaction, attenuates BAG1L-mediated AR NTD activity, downregulates AR target gene expression, and inhibits proliferation of AR-positive prostate cancer cells. This compound represents a prototype of AR antagonists that could be key in the development of future prostate cancer therapeutics.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Apweiler2021,

title = {Targeting Oxidative Stress: Novel Coumarin-Based Inverse Agonists of GPR55},

author = {Matthias Apweiler and Soraya Wilke Saliba and Jana Streyczek and Thomas Hurrle and Simone Gräßle and Stefan Bräse and Bernd L Fiebich},

url = {https://www.mdpi.com/1422-0067/22/21/11665},

doi = {10.3390/ijms222111665},

issn = {1422-0067},

year  = {2021},

date = {2021-01-01},

journal = {International Journal of Molecular Sciences},

volume = {22},

issue = {21},

abstract = {Oxidative stress is associated with different neurological and psychiatric diseases. Therefore, development of new pharmaceuticals targeting oxidative dysregulation might be a promising approach to treat these diseases. The G-protein coupled receptor 55 (GPR55) is broadly expressed in central nervous tissues and cells and is involved in the regulation of inflammatory and oxidative cell homeostasis. We have recently shown that coumarin-based compounds enfold inverse agonistic activities at GPR55 resulting in the inhibition of prostaglandin E2. However, the antioxidative effects mediated by GPR55 were not evaluated yet. Therefore, we investigated the antioxidative effects of two novel synthesized coumarin-based compounds, KIT C and KIT H, in primary mouse microglial and human neuronal SK-N-SK cells. KIT C and KIT H show antioxidative properties in SK-N-SH cells as well as in primary microglia. In GPR55-knockout SK-N-SH cells, the antioxidative effects are abolished, suggesting a GPR55-dependent antioxidative mechanism. Since inverse agonistic GPR55 activation in the brain seems to be associated with decreased oxidative stress, KIT C and KIT H possibly act as inverse agonists of GPR55 eliciting promising therapeutic options for oxidative stress related diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Frei2021,

title = {Platinum Cyclooctadiene Complexes with Activity against Gram-positive Bacteria},

author = {Angelo Frei and Soumya Ramu and Gabrielle J. Lowe and Hue Dinh and Lucie Semenec and Alysha G. Elliott and Johannes Zuegg and Anke Deckers and Nicole Jung and Stefan Bräse and Amy K. Cain and Mark A. T. Blaskovich},

doi = {10.1002/cmdc.202100157},

issn = {18607187},

year  = {2021},

date = {2021-01-01},

journal = {ChemMedChem},

volume = {16},

issue = {20},

pages = {3165-3171},

publisher = {John Wiley and Sons Ltd},

abstract = {Antimicrobial resistance is a looming health crisis, and it is becoming increasingly clear that organic chemistry alone is not sufficient to continue to provide the world with novel and effective antibiotics. Recently there has been an increased number of reports describing promising antimicrobial properties of metal-containing compounds. Platinum complexes are well known in the field of inorganic medicinal chemistry for their tremendous success as anticancer agents. Here we report on the promising antibacterial properties of platinum cyclooctadiene (COD) complexes. Amongst the 15 compounds studied, the simplest compounds Pt(COD)X2 (X=Cl, I, Pt1 and Pt2) showed excellent activity against a panel of Gram-positive bacteria including vancomycin and methicillin resistant Staphylococcus aureus. Additionally, the lead compounds show no toxicity against mammalian cells or haemolytic properties at the highest tested concentrations, indicating that the observed activity is specific against bacteria. Finally, these compounds showed no toxicity against Galleria mellonella at the highest measured concentrations. However, preliminary efficacy studies in the same animal model found no decrease in bacterial load upon treatment with Pt1 and Pt2. Serum exchange studies suggest that these compounds exhibit high serum binding which reduces their bioavailability in vivo, mandating alternative administration routes such as e. g. topical application.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Rational prioritization strategy allows the design of macrolide derivatives that overcome antibiotic resistance},

author = {Gerhard König and Pandian Sokkar and Niclas Pryk and Sascha Heinrich and David Möller and Giuseppe Cimicata and Donna Matzov and Pascal Dietze and Walter Thiel and Anat Bashan and Julia Elisabeth Bandow and Johannes Zuegg and Ada Yonath and Frank Schulz and Elsa Sanchez-Garcia},

url = {https://www.pnas.org/doi/abs/10.1073/pnas.2113632118},

doi = {10.1073/pnas.2113632118},

year  = {2021},

date = {2021-01-01},

journal = {Proceedings of the National Academy of Sciences},

volume = {118},

issue = {46},

pages = {e2113632118},

abstract = {Due to the development of resistance against commonly used antibiotics, new derivatives that avoid resistance mechanisms need to be developed. To address this problem, a rational prioritization strategy is outlined for macrolide antibiotics. Candidates are screened based on their solubility, membrane permeability, and binding affinity using a tiered optimization approach of free energy simulations and quantum mechanics/molecular mechanics calculations. After prioritization by computational methods, the best candidates are evaluated experimentally. The strategy creates a targeted substance library that is highly enriched in compounds with antibacterial activity. This allows for faster iterations in the development of new antibiotic derivatives. Antibiotic resistance is a major threat to global health; this problem can be addressed by the development of new antibacterial agents to keep pace with the evolutionary adaptation of pathogens. Computational approaches are essential tools to this end since their application enables fast and early strategical decisions in the drug development process. We present a rational design approach, in which acylide antibiotics were screened based on computational predictions of solubility, membrane permeability, and binding affinity toward the ribosome. To assess our design strategy, we tested all candidates for in vitro inhibitory activity and then evaluated them in vivo with several antibiotic-resistant strains to determine minimal inhibitory concentrations. The predicted best candidate is synthetically more accessible, exhibits higher solubility and binding affinity to the ribosome, and is up to 56 times more active against resistant pathogens than telithromycin. Notably, the best compounds designed by us show activity, especially when combined with the membrane-weakening drug colistin, against Acinetobacter baumanii, Pseudomonas aeruginosa, and Escherichia coli, which are the three most critical targets from the priority list of pathogens of the World Health Organization.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Hofmann2021,

title = {A small molecule screen identifies novel inhibitors of mechanosensory nematocyst discharge in Hydra},

author = {Diana Hofmann and Niharika Garg and Simone Grässle and Sylvia Vanderheiden and Bruno Gideon Bergheim and Stefan Bräse and Nicole Jung and Suat Özbek},

doi = {10.1038/s41598-021-99974-7},

issn = {20452322},

year  = {2021},

date = {2021-01-01},

journal = {Scientific Reports},

volume = {11},

issue = {1},

publisher = {Nature Research},

abstract = {Cnidarians are characterized by the possession of stinging organelles, called nematocysts, which they use for prey capture and defense. Nematocyst discharge is controlled by a mechanosensory apparatus with analogies to vertebrate hair cells. Members of the transient receptor potential (TRPN) ion channel family are supposed to be involved in the transduction of the mechanical stimulus. A small molecule screen was performed to identify compounds that affect nematocyst discharge in Hydra. We identified several [2.2]paracyclophanes that cause inhibition of nematocyst discharge in the low micro-molar range. Further structure–activity analyses within the compound class of [2.2]paracyclophanes showed common features that are required for the inhibitory activity of the [2.2]paracyclophane core motif. This study demonstrates that Hydra can serve as a model for small molecule screens targeting the mechanosensory apparatus in native tissues.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Keiser2020,

title = {Naturally Occurring Cardenolides Affecting Schistosoma mansoni},

author = {Jennifer Keiser and Vanessa Koch and Anke Deckers and H. T. Andrew Cheung and Nicole Jung and Stefan Bräse},

doi = {10.1021/acsinfecdis.0c00175},

issn = {23738227},

year  = {2020},

date = {2020-01-01},

journal = {ACS Infectious Diseases},

volume = {6},

issue = {7},

pages = {1922-1927},

publisher = {American Chemical Society},

abstract = {Schistosomiasis is a neglected tropical disease of considerable public health burden. We recently discovered a micromolar activity of several cardenolides against newly transformed schistosomula (NTS) of the parasitic flatworm Schistosoma mansoni in a small compound screen including different substance classes of both natural products as well as synthetic molecules. In further experiments, a focused library of naturally occurring and synthetic steroids was explored against NTS and adult S. mansoni, revealing seven cardenolides with comparable activities as known anthelminthics such as praziquantel. Of these, gomphoside monoacetate and uscharin showed suitable therapeutic indices. In a first in vivo study, at a dose of 10 mg/kg, only minor activity in mice harboring a chronic S. mansoni infection could be shown, which will be further investigated by structure-activity relationship studies as well as pharmacodynamic and pharmacokinetic approaches.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Frei2020,

title = {Metal complexes as a promising source for new antibiotics},

author = {Angelo Frei and Johannes Zuegg and Alysha G. Elliott and Murray Baker and Stefan Braese and Christopher Brown and Feng Chen and Christopher G. Dowson and Gilles Dujardin and Nicole Jung and A. Paden King and Ahmed M. Mansour and Massimiliano Massi and John Moat and Heba A. Mohamed and Anna K. Renfrew and Peter J. Rutledge and Peter J. Sadler and Matthew H. Todd and Charlotte E. Willans and Justin J. Wilson and Matthew A. Cooper and Mark A. T. Blaskovich},

doi = {10.1039/c9sc06460e},

issn = {20416539},

year  = {2020},

date = {2020-01-01},

journal = {Chemical Science},

volume = {11},

issue = {10},

pages = {2627-2639},

publisher = {Royal Society of Chemistry},

abstract = {There is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant S. aureus (MRSA). 23 of these complexes have not been reported for their antimicrobial properties before. This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Koch2019,

title = {Synthesis, Characterization, and Biological Properties of Steroidal Ruthenium(II) and Iridium(III) Complexes Based on the Androst-16-en-3-ol Framework},

author = {Vanessa Koch and Anna Meschkov and Wolfram Feuerstein and Juliana Pfeifer and Olaf Fuhr and Martin Nieger and Ute Schepers and Stefan Bräse},

doi = {10.1021/acs.inorgchem.9b02402},

issn = {1520510X},

year  = {2019},

date = {2019-01-01},

journal = {Inorganic Chemistry},

volume = {58},

issue = {23},

pages = {15917-15926},

publisher = {American Chemical Society},

abstract = {A range of novel cyclometalated ruthenium(II) and iridium(III) complexes with a steroidal backbone based on androsterone were synthesized and characterized by NMR spectroscopy and X-ray crystallography. Their cytotoxic properties in RT112 and RT112 cP (cisplatin-resistant) cell lines as well as in MCF7 and somatic fibroblasts were compared with those of the corresponding nonsteroidal complexes and the noncyclometalated pyridyl complexes as well as with cisplatin as reference. All steroidal complexes were more active in RT112 cP cells than cisplatin, whereby the cyclometalated pyridinylphenyl complexes based on 5c showed high cytotoxicity while maintaining low resistant factors of 0.33 and 0.50.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Saliba2018,

title = {Anti-neuroinflammatory effects of GPR55 antagonists in LPS-activated primary microglial cells},

author = {Soraya Wilke Saliba and Hannah Jauch and Brahim Gargouri and Albrecht Keil and Thomas Hurrle and Nicole Volz and Florian Mohr and Mario Van Der Stelt and Stefan Bräse and Bernd L. Fiebich},

doi = {10.1186/s12974-018-1362-7},

issn = {17422094},

year  = {2018},

date = {2018-01-01},

journal = {Journal of Neuroinflammation},

volume = {15},

issue = {1},

publisher = {BioMed Central Ltd.},

abstract = {Background: Neuroinflammation plays a vital role in Alzheimer's disease and other neurodegenerative conditions. Microglia are the resident mononuclear immune cells of the central nervous system, and they play essential roles in the maintenance of homeostasis and responses to neuroinflammation. The orphan G-protein-coupled receptor 55 (GPR55) has been reported to modulate inflammation and is expressed in immune cells such as monocytes and microglia. However, its effects on neuroinflammation, mainly on the production of members of the arachidonic acid pathway in activated microglia, have not been elucidated in detail. Methods: In this present study, a series of coumarin derivatives, that exhibit GPR55 antagonism properties, were designed. The effects of these compounds on members of the arachidonic acid cascade were studied in lipopolysaccharide (LPS)-treated primary rat microglia using Western blot, qPCR, and ELISA. Results: We demonstrate here that the various compounds with GPR55 antagonistic activities significantly inhibited the release of PGE2 in primary microglia. The inhibition of LPS-induced PGE2 release by the most potent candidate KIT 17 was partially dependent on reduced protein synthesis of mPGES-1 and COX-2. KIT 17 did not affect any key enzyme involved on the endocannabinoid system. We furthermore show that microglia expressed GPR55 and that a synthetic antagonist of the GPR receptor (ML193) demonstrated the same effect of the KIT 17 on the inhibition of PGE2. Conclusions: Our results suggest that KIT 17 is acting as an inverse agonist on GPR55 independent of the endocannabinoid system. Targeting GPR55 might be a new therapeutic option to treat neurodegenerative diseases with a neuroinflammatory background such as Alzheimer's disease, Parkinson, and multiple sclerosis (MS).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Cato2017,

title = {Development of bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer},

author = {Laura Cato and Antje Neeb and Adam Sharp and Victor Buzón and Scott B. Ficarro and Linxiao Yang and Claudia Muhle-Goll and Nane C. Kuznik and Ruth Riisnaes and Daniel Nava Rodrigues and Olivier Armant and Victor Gourain and Guillaume Adelmant and Emmanuel A. Ntim and Thomas Westerling and David Dolling and Pasquale Rescigno and Ines Figueiredo and Friedrich Fauser and Jennifer Wu and Jaice T. Rottenberg and Liubov Shatkina and Claudia Ester and Burkhard Luy and Holger Puchta and Jakob Troppmair and Nicole Jung and Stefan Bräse and Uwe Strähle and Jarrod A. Marto and Gerd Ulrich Nienhaus and Bissan Al-Lazikani and Xavier Salvatella and Johann S. De Bono and Andrew C. B. Cato and Myles Brown},

doi = {10.7554/eLife.27159},

issn = {2050084X},

year  = {2017},

date = {2017-01-01},

journal = {eLife},

volume = {6},

publisher = {eLife Sciences Publications Ltd},

abstract = {Targeting the activation function-1 (AF-1) domain located in the N-terminus of the androgen receptor (AR) is an attractive therapeutic alternative to the current approaches to inhibit AR action in prostate cancer (PCa). Here we show that the AR AF-1 is bound by the cochaperone Bag-1L. Mutations in the AR interaction domain or loss of Bag-1L abrogate AR signaling and reduce PCa growth. Clinically, Bag-1L protein levels increase with progression to castration-resistant PCa (CRPC) and high levels of Bag-1L in primary PCa associate with a reduced clinical benefit from abiraterone when these tumors progress. Intriguingly, residues in Bag-1L important for its interaction with the AR AF-1 are within a potentially druggable pocket, implicating Bag-1L as a potential therapeutic target in PCa.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Synthesis and Investigation of S-Substituted 2-Mercaptobenzoimidazoles as Inhibitors of Hedgehog Signaling},

author = {Simone Gräßle and Steven Susanto and Sonja Sievers and Emel Tavsan and Martin Nieger and Nicole Jung and Stefan Bräse},

doi = {10.1021/acsmedchemlett.7b00100},

issn = {19485875},

year  = {2017},

date = {2017-01-01},

journal = {ACS Medicinal Chemistry Letters},

volume = {8},

issue = {9},

pages = {931-935},

publisher = {American Chemical Society},

abstract = {Due to the arising resistance of common drugs targeting the Hedgehog signaling pathway, the identification of new compound classes with inhibitory effect is urgently needed. We were able to identify S-alkylated 2-mercaptobenzoimidazoles as a new compound class that exhibits Hedgehog signaling activity in a low micromolar range. The scope of the 2-mercaptobenzoimidazole motif has been investigated by the syntheses of diverse derivatives, revealing that the elongation of the linker unit and the exchange of particular substitution patterns are tolerable with respect to the activity of the compound class.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}