- Synthesis and biological evaluation of cystobactamid 507: A bacterial topoisomerase inhibitor from Cystobacter sp.
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Abstract The first total synthesis of cystobactamid 507, a member of a class of new natural products with strong inhibitory activity towards bacterial topoisomerases, is reported. Synthetic key challenges are the central tetrasubstitued arene and the low chemical reactivity of anilines and ortho-phenolic and isopropoxy-substituted benzoic acids. Biological evaluations demonstrate that cystobactamid 507 inhibits several Gram-positive pathogens but at significantly lower concentrations than described for the larger members of this natural product family.
- Moreno, María,Elgaher, Walid A.M.,Herrmann, Jennifer,Schl?ger, Nadin,Hamed, Mostafa M.,Baumann, Sascha,Müller, Rolf,Hartmann, Rolf W.,Kirschning, Andreas
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- Discovery of new ATP-competitive inhibitors of human DNA topoisomerase IIα through screening of bacterial topoisomerase inhibitors
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Human DNA topoisomerase II is one of the major targets in anticancer therapy, however ATP-competitive inhibitors of this target have not yet reached their full potential. ATPase domain of human DNA topoisomerase II belongs to the GHKL ATPase superfamily and shares a very high 3D structural similarity with other superfamily members, including bacterial topoisomerases. In this work we report the discovery of a new chemotype of ATP-competitive inhibitors of human DNA topoisomerase IIα that were discovered through screening of in-house library of ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV. Systematic screening of this library provided us with 20 hit compounds. 1,2,4-Substituted N-phenylpyrrolamides were selected for a further exploration which resulted in 13 new analogues, including 52 with potent activity in relaxation assay (IC50 = 3.2 μM) and ATPase assay (IC50 = 0.43 μM). Cytotoxic activity of all hits was determined in MCF-7 cancer cell line and the most potent compounds, 16 and 20, showed an IC50 value of 8.7 and 8.2 μM, respectively.
- Baran?oková, Michaela,Durcik, Martina,Gramec Skledar, Darja,Ila?, Janez,Kikelj, Danijel,Peterlin Ma?i?, Lucija,Skok, ?iga,Toma?i?, Tihomir,Zega, Anamarija,Zidar, Nace
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- A structure—activity relationship study of bis-benzamides as inhibitors of androgen receptor—coactivator interaction
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The interaction between androgen receptor (AR) and coactivator proteins plays a critical role in AR-mediated prostate cancer (PCa) cell growth, thus its inhibition is emerging as a promising strategy for PCa treatment. To develop potent inhibitors of the
- Lee, Tae-Kyung,Ravindranathan, Preethi,Sonavane, Rajni,Raj, Ganesh V.,Ahn, Jung-Mo
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supporting information
(2019/08/07)
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- An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors
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ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC50 values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1–50 μM range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 μM, 1.56 μM, 0.78 μM and 0.72 μM, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 μM on both strains, and MIC value of 32 μM against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action.
- Tiz, Davide Benedetto,Skok, ?iga,Durcik, Martina,Toma?i?, Tihomir,Ma?i?, Lucija Peterlin,Ila?, Janez,Zega, Anamarija,Draskovits, Gábor,Révész, Tamás,Nyerges, ákos,Pál, Csaba,Cruz, Cristina D.,Tammela, P?ivi,?igon, Du?an,Kikelj, Danijel,Zidar, Nace
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p. 269 - 290
(2019/02/20)
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- NOVEL CYSTOBACTAMIDE DERIVATIVES
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The present invention relates to novel derivatives of cystobactamides of formula (lb) and the use thereof for the treatment or prophylaxis of bacterial infections.
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- Synthesis and Evaluation of N-Phenylpyrrolamides as DNA Gyrase B Inhibitors
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ATP-competitive inhibitors of DNA gyrase and topoisomerase IV are among the most interesting classes of antibacterial drugs that are unrepresented in the antibacterial pipeline. We developed 32 new N-phenylpyrrolamides and evaluated them against DNA gyrase and topoisomerase IV from E. coli and Staphylococcus aureus. Antibacterial activities were studied against Gram-positive and Gram-negative bacterial strains. The most potent compound displayed an IC50 of 47 nm against E. coli DNA gyrase, and a minimum inhibitory concentration (MIC) of 12.5 μm against the Gram-positive Enterococcus faecalis. Some compounds displayed good antibacterial activities against an efflux-pump-deficient E. coli strain (MIC=6.25 μm) and against wild-type E. coli in the presence of efflux pump inhibitor PAβN (MIC=3.13 μm). Here we describe new findings regarding the structure–activity relationships of N-phenylpyrrolamide DNA gyrase B inhibitors and investigate the factors that are important for the antibacterial activity of this class of compounds.
- Durcik, Martina,Tammela, P?ivi,Baran?oková, Michaela,Toma?i?, Tihomir,Ila?, Janez,Kikelj, Danijel,Zidar, Nace
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p. 186 - 198
(2018/02/06)
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- New N-phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity
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The ATP binding site located on the subunit B of DNA gyrase is an attractive target for the development of new antibacterial agents. In recent decades, several small-molecule inhibitor classes have been discovered but none has so far reached the market. We present here the discovery of a promising new series of N-phenylpyrrolamides with low nanomolar IC50 values against DNA gyrase, and submicromolar IC50 values against topoisomerase IV from Escherichia coli and Staphylococcus aureus. The most potent compound in the series has an IC50 value of 13 nM against E. coli gyrase. Minimum inhibitory concentrations (MICs) against Gram-positive bacteria are in the low micromolar range. The oxadiazolone derivative 11a, with an IC50 value of 85 nM against E. coli DNA gyrase displays the most potent antibacterial activity, with MIC values of 1.56 μM against Enterococcus faecalis, and 3.13 μM against wild type S. aureus, methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). The activity against wild type E. coli in the presence of efflux pump inhibitor phenylalanine-arginine β-naphthylamide (PAβN) is 4.6 μM.
- Durcik, Martina,Lovison, Denise,Skok, ?iga,Durante Cruz, Cristina,Tammela, P?ivi,Toma?i?, Tihomir,Benedetto Tiz, Davide,Draskovits, Gábor,Nyerges, ákos,Pál, Csaba,Ila?, Janez,Peterlin Ma?i?, Lucija,Kikelj, Danijel,Zidar, Nace
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p. 117 - 132
(2018/05/24)
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- Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers
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The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly wiTheR and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers.
- Raj, Ganesh V.,Sareddy, Gangadhara Reddy,Ma, Shihong,Lee, Tae-Kyung,Viswanadhapalli, Suryavathi,Li, Rui,Liu, Xihui,Murakami, Shino,Chen, Chien-Cheng,Lee, Wan-Ru,Mann, Monica,Krishnan, Samaya Rajeshwari,Manandhar, Bikash,Gonugunta, Vijay K.,Strand, Douglas,Tekmal, Rajeshwar Rao,Ahn, Jung-Mo,Vadlamudi, Ratna K.
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supporting information
(2017/09/18)
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- CYSTOBACTAMIDES
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The present invention provides cystobactamides of formula (I) and the use thereof for the treatment or prophylaxis of bacterial infections:
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- Assessment of Bromodomain Target Engagement by a Series of BI2536 Analogues with Miniaturized BET-BRET
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Evaluating the engagement of a small molecule ligand with a protein target in cells provides useful information for chemical probe optimization and pharmaceutical development. While several techniques exist that can be performed in a low-throughput manner, systematic evaluation of large compound libraries remains a challenge. In-cell engagement measurements are especially useful when evaluating compound classes suspected to target multiple cellular factors. In this study we used a bioluminescent resonant energy transfer assay to assess bromodomain engagement by a compound series containing bromodomain- and kinase-biasing polypharmacophores based on the known dual BRD4 bromodomain/PLK1 kinase inhibitor BI2536. With this assay, we discovered several novel agents with bromodomain-selective specificity profiles and cellular activity. Thus, this platform aids in distinguishing molecules whose cellular activity is difficult to assess due to polypharmacologic effects.
- Koblan, Luke W.,Buckley, Dennis L.,Ott, Christopher J.,Fitzgerald, Mark E.,Ember, Stuart W. J.,Zhu, Jin-Yi,Liu, Shuai,Roberts, Justin M.,Remillard, David,Vittori, Sarah,Zhang, Wei,Schonbrunn, Ernst,Bradner, James E.
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supporting information
p. 2575 - 2581
(2016/12/09)
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- The Albicidin Resistance Factor AlbD Is a Serine Endopeptidase That Hydrolyzes Unusual Oligoaromatic-Type Peptides
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The para-aminobenzoic acid-containing peptide albicidin is a pathogenicity factor synthesized by Xanthomonas albilineans in infections of sugar cane. Albicidin is a nanomolar inhibitor of the bacterial DNA gyrase with a strong activity against various Gram-negative bacteria. The bacterium Pantoea dispersa expresses the hydrolase AlbD, conferring natural resistance against albicidin. We show that AlbD is a novel type of endopeptidase that catalyzes the cleavage of albicidin at a peptide backbone amide bond, thus abolishing its antimicrobial activity. Additionally, we determined the minimal cleavage motif of AlbD with substrates derived by chemical synthesis. Our results clearly identify AlbD as a unique endopeptidase that is the first member of a new subfamily of peptidases. Our findings provide the molecular basis for a natural detoxification mechanism, potentially rendering a new tool in biological chemistry approaches.
- Vieweg, Laura,Kretz, Julian,Pesic, Alexander,Kerwat, Dennis,Gr?tz, Stefan,Royer, Monique,Cociancich, Stéphane,Mainz, Andi,Süssmuth, Roderich D.
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p. 7608 - 7611
(2015/07/02)
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- Relaxation of the rigid backbone of an oligoamide-foldamer-based α-helix mimetic: Identification of potent Bcl-xL inhibitors
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By conducting a structure-activity relationship study of the backbone of a series of oligoamide-foldamer-based α-helix mimetics of the Bak BH3 helix, we have identified especially potent inhibitors of Bcl-xL. The most potent compound has a Ki value of 94 nM in vitro, and single-digit micromolar IC50 values against the proliferation of several Bcl-xL-overexpressing cancer cell lines. The Royal Society of Chemistry 2012.
- Yap, Jeremy L.,Cao, Xiaobo,Vanommeslaeghe, Kenno,Jung, Kwan-Young,Peddaboina, Chander,Wilder, Paul T.,Nan, Anjan,MacKerell, Alexander D.,Smythe, W. Roy,Fletcher, Steven
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p. 2928 - 2933
(2012/05/07)
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- 2-O-Alkylated para-benzamide α-helix mimetics: The role of scaffold curvature
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The design and synthesis of a new 2-O-alklyated benzamide α-helix mimetic is described. Comparison with regioisomeric 3-O-alkylated benzamides permits a preliminary evaluation of the role that mimetic curvature has in determining molecular recognition properties.
- Azzarito, Valeria,Prabhakaran, Panchami,Bartlett, Alice I.,Murphy, Natasha S.,Hardie, Michaele J.,Kilner, Colin A.,Edwards, Thomas A.,Warriner, Stuart L.,Wilson, Andrew J.
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p. 6469 - 6472
(2012/09/08)
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- Hydrophobic side-chain interactions in a family of dimeric amide foldamers-potential alpha-helix mimetics
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A series of new alpha-helix mimetics based on a benzamide scaffold and potentially able to disrupt protein-protein interactions have been synthesized and characterized by X-ray analysis. Inspection of the solid state structures of aromatic amide dimers co
- Kulikov, Oleg V.,Incarvito, Christopher,Hamilton, Andrew D.
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scheme or table
p. 3705 - 3709
(2011/08/06)
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- HALO-SUBSTITUTED PYRIMIDODIAZEPINES
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The present invention provides PLK1 inhibitor compounds of formula I: useful in the treatment or control of cell proliferative disorders, particularly oncological disorders. These compounds and formulations containing such compounds may be useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors and other oncological diseases such as non-Hodgkin's lymphomas. Also provided are intermediate compounds useful in the synthesis of compounds of formula I.
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(2009/12/28)
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- Synthesis of functionalised aromatic oligamide rods
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A current goal in synthetic chemistry is the design and synthesis of molecules that adopt well defined conformations - so called foldamers. In this manuscript we describe a modular approach for construction of rod shaped para-oligobenzamide molecules. Our approach permits regiospecific incorporation of side chains through a phenolic ether linkage on the scaffold; a feature that partly restricts the conformation of the rod through intramolecular hydrogen-bonding. The Royal Society of Chemistry 2008.
- Plante, Jeffrey,Campbell, Fred,Malkova, Barbora,Kilner, Colin,Warriner, Stuart L.,Wilson, Andrew J.
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p. 138 - 146
(2008/09/20)
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- COMPOUNDS CONTAINING PHENYL LINKED TO ARYL OR HETEROARYL BY AN ALIPHATIC- OR HETEROATOM-CONTAINING LINKING GROUP
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This invention is directed to the pharmaceutical use of phenyl compounds, which are linked to an aryl moiety by various linkages, for inhibiting tumor necrosis factor. The invention is also directed to the compounds, their preparation and pharmaceutical compositions containing these compounds. Furthermore, this invention is directed to the pharmaceutical use of the compounds for inhibiting cyclic AMP phosphodiesterase
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- Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic-or heteroatom-containing linking group
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This invention is directed to the pharmaceutical use of phenyl compounds, which are linked to an aryl moiety by various linkages, for inhibiting tumor necrosis factor. The invention is also directed to the compounds, their preparation and pharmaceutical compositions containing these compounds. Furthermore, this invention is directed to the pharmaceutical use of the compounds for inhibiting cyclic AMP phosphodiesterase.
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