Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway

• Paul M. Hershberger,
• Satyamaheshwar Peddibhotla,
• E. Hampton Sessions,
• Daniela B. Divlianska,
• Ricardo G. Correa,
• Anthony B. Pinkerton,
• John C. Reed and
• Gregory P. Roth

Beilstein J. Org. Chem. 2013, 9, 900–907, doi:10.3762/bjoc.9.103

• pathways for NF-κB activation converge on the IκB kinases (IKKs), and more than nine signaling routes have been identified [6]. While IKKs therefore represent attractive targets for drug discovery programs, the selectivity envisioned for an acceptable therapeutic index has remained elusive as inhibitors of

• IKKs indiscriminately suppress all known NF-κB activation pathways. Within this project, new probes were sought that were not active via the currently known receptor-driven pathways and IκB kinases, but attenuated NF-κB transcriptional activity as measured by a luciferase-based reporter gene assay with

• IKK inhibitors and the broad-spectrum kinase inhibitor staurosporine afforded potent inhibition [9][10][11]. Further selectivity profiling revealed that 4 inhibited (>50% at 10 uM) only 3 out of the 353 kinases surveyed by using a KINOMEscan™ (DiscoveRx) platform. None of these 3 (TLK1 (70% inhibition

Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

• Allison S. Limpert,
• Margrith E. Mattmann and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2013, 9, 717–732, doi:10.3762/bjoc.9.82

• induce cellular stress through mitochondrial inhibition led to the formation of TDP-43 aggregates in the cytoplasm. The formation of TDP-43-containing cellular inclusions was dependent on the activation of stress-induced kinases such as c-Jun N-terminal kinase (JNK). Treatment of cells with bis

Synthesis and evaluation of cell-permeable biotinylated PU-H71 derivatives as tumor Hsp90 probes

• Tony Taldone,
• Anna Rodina,
• Erica M. DaGama Gomes,
• Matthew Riolo,
• Hardik J. Patel,
• Raul Alonso-Sabadell,
• Danuta Zatorska,
• Maulik R. Patel,
• Sarah Kishinevsky and
• Gabriela Chiosis

Beilstein J. Org. Chem. 2013, 9, 544–556, doi:10.3762/bjoc.9.60

• clinical trials, has been the ATP-competitive inhibitors that bind to the N-terminal nucleotide binding pocket [4][5]. Hsp90 belongs to the family of GHKL (G = DNA gyrase subunit B; H = Hsp90; K = histidine kinases; L = MutL) ATPases, which is distinguished by a unique bent shape of its nucleotide binding

From bead to flask: Synthesis of a complex β-amido-amide for probe-development studies

• Kevin S. Martin,
• Cristian Soldi,
• Kellan N. Candee,
• Hiromi I. Wettersten,
• Robert H. Weiss and
• Jared T. Shaw

Beilstein J. Org. Chem. 2013, 9, 260–264, doi:10.3762/bjoc.9.31

• that modulates the activity of cyclin kinases [13][14][15]. One function of p21 is that it acts downstream of p53 to repair DNA-damaged cells and may function to convey anti-apoptotic activity to cancer cells (Figure 1) [13]. As such, an inhibitor of p21 could sensitize malignant cells to DNA-damaging

Synthesis of 5-(ethylsulfonyl)-2-methoxyaniline: An important pharmacological fragment of VEGFR2 and other inhibitors

• Miroslav Murár,
• Gabriela Addová and
• Andrej Boháč

Beilstein J. Org. Chem. 2013, 9, 173–179, doi:10.3762/bjoc.9.20

• . Compound 5 is used for the development of small organic compounds, i.e., modulators targeting a broad spectrum of important human protein receptors or enzymes, e.g., VEGFR2, EGFR, PDGFR, TEK kinase, ckit, EphB4, ErbB-2 receptor tyrosine kinase, cyclin-dependent kinases 2 and 4, neu receptor, polo-like

Dipyrazolo[1,5-a:4',3'-c]pyridines – a new heterocyclic system accessed via multicomponent reaction

• Wolfgang Holzer,
• Gytė Vilkauskaitė,
• Eglė Arbačiauskienė and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2012, 8, 2223–2229, doi:10.3762/bjoc.8.251

• of adenosine and, thus, has been incorporated in various compounds impairing protein kinases and ATPases [7][8][9]. Moreover, a large variety of additional fused pyrazoles exhibit interesting biological activities, such as, pyrazolo[1,5-a]quinolones [10], pyrazolo[4,3-c]quinolones [11], pyrazolo[5,1

Thermodynamic and kinetic stabilization of divanadate in the monovanadate/divanadate equilibrium using a Zn-cyclene derivative: Towards a simple ATP synthase model

• Hanno Sell,
• Anika Gehl,
• Frank D. Sönnichsen and
• Rainer Herges

Beilstein J. Org. Chem. 2012, 8, 81–89, doi:10.3762/bjoc.8.8

• condensation, e.g., the formation of ATP [8]. A large number of thoroughly investigated enzymes hydrolyze phosphates and provide insight into conceivable mechanisms of phosphate or vanadate condensations. In phosphatases, kinases and ATP synthase, the catalyzed transfer of phosphate usually requires the

• hold for natural systems – particularly ATP synthase, phosphatases and kinases catalyzing the condensation, hydrolysis and phosphate transfer in phosphate esters and phosphate oligomers – which are unsymmetric with respect to metal complexation of the substrates. In the P–O bond forming/cleaving step

Marilones A–C, phthalides from the sponge-derived fungus Stachylidium sp.

• Celso Almeida,
• Stefan Kehraus,
• Miguel Prudêncio and
• Gabriele M. König

Beilstein J. Org. Chem. 2011, 7, 1636–1642, doi:10.3762/bjoc.7.192

• serotonin receptors, and marilone B showed a specific antagonistic effect on the serotonin receptor 5-HT2B with a Ki value of 7.7 µM. Compounds 1–4 were further evaluated for antiviral activity, for inhibition of protein kinases and proteases, for growth inhibition of antibiotic-resistant Mycobacterium

• Phosphorylation & Disease, CNRS, Roscoff, France) for performing the protein kinases assays and Dr. C. Pannecouque (Rega Institute for Medical Research, Leuven, Belgium) for performing the HIV-1 and HIV-2 antiviral assays; we also kindly thank Indra Bergval (KIT Biomedical Research, Royal Tropical Institute

C–C (alkynylation) vs C–O (ether) bond formation under Pd/C–Cu catalysis: synthesis and pharmacological evaluation of 4-alkynylthieno[2,3-d]pyrimidines

• Dhilli Rao Gorja,
• K. Shiva Kumar,
• K. Mukkanti and
• Manojit Pal

Beilstein J. Org. Chem. 2011, 7, 338–345, doi:10.3762/bjoc.7.44

• ., alkynyl substituted thienopyrimidines of potential pharmacological interest. Notably, 6-ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-aniline derivatives were found to be potent inhibitors of ErbB family receptor tyrosine kinases (EGFR, ErbB-2) and the proliferation of tumor cells that

• highly express these kinases [6]. In continuation of our research program into new drug discovery, we became interested in the generation of a small-molecule library A (Figure 1) based on thieno[2,3-d]pyrimidine for in-house pharmacological evaluation. Accordingly, we recently reported the synthesis of 4

Approaches towards the synthesis of 5-aminopyrazoles

• Ranjana Aggarwal,
• Vinod Kumar,
• Rajiv Kumar and
• Shiv P. Singh

Beilstein J. Org. Chem. 2011, 7, 179–197, doi:10.3762/bjoc.7.25

• spectrum [12]. Recently, components of the mitotic machinery have been targeted in an attempt to develop novel anticancer agents. These include critical signaling kinases such as the Aurora, PLK, and the cyclin-dependent kinases (CDK). Compound VII (AZD1152) is the first Aurora-B selective inhibitor to