Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

• Eszter Lajkó,
• Sarah Spring,
• Rózsa Hegedüs,
• Beáta Biri-Kovács,
• Sven Ingebrandt,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 2495–2509, doi:10.3762/bjoc.14.226

• of phosphatidylinositol 3-kinase in the antitumor effects of conjugates Binding of GnRH or its conjugates to the GnRH-R receptor on tumor cells could stimulate different signaling elements (e.g., phosphatidylinositol 3-kinase – PI3K, mitogen-activated protein kinases) and effector proteins, which

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• ., pentetreotide (DTPA-d-Phe-c[Cys-Phe-d-Trp-Lys-Thr-Cys]-Thr-ol) [71]. Epidermal growth factor (EGF): Epidermal growth factor receptor (EGFR) is a transmembrane protein belonging to the ErbB family of receptor tyrosine kinases which consists of 4 structurally-related members: EGFR/HER1 (ErbB-1), HER2/neu (ErbB-2

• kinases. Gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP) are the active metabolites which inhibit processes required for DNA synthesis [91]. The incorporation of dFdCTP into DNA during polymerization, which causes DNA polymerases unable to proceed, is the major mechanism by which

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• Pyrazolo[3,4-b]pyrazines have received great attention because of their interesting biological activities such as inhibition of protein kinases [137], blood platelet aggregation [138], bone metabolism improvers [139] as well as antifungal [140], antibacterial [141], antiparasitic [142] and antiviral [143

A novel synthetic approach to hydroimidazo[1,5-b]pyridazines by the recyclization of itaconimides and HPLC–HRMS monitoring of the reaction pathway

• Dmitry Yu. Vandyshev,
• Khidmet S. Shikhaliev,
• Andrey Yu. Potapov,
• Michael Yu. Krysin,
• Fedor I. Zubkov and
• Lyudmila V. Sapronova

Beilstein J. Org. Chem. 2017, 13, 2561–2568, doi:10.3762/bjoc.13.252

• imidazo[1,5-a]pyrazine structure show inhibitory activity against kinases BTK [1], MEK [2], ACK1 [3], mTORC1(2) [4], c-Src [5], growth factor IGF-1R [6] and act as the antagonists of Hedgehog pathway dependent malignancies [7]. Imidazo[1,5-a]pyrimidines are inhibitors of the bone morphogenic protein [8

An improved preparation of phorbol from croton oil

• Alberto Pagani,
• Simone Gaeta,
• Andrei I. Savchenko,
• Craig M. Williams and
• Giovanni Appendino

Beilstein J. Org. Chem. 2017, 13, 1361–1367, doi:10.3762/bjoc.13.133

• molecular target of PMA was identified in a series of isoforms of PKC, a family of serine/threonine kinases involved in a host of cellular activities [9]. Because of its kinase-activating properties, PMA has become an indispensable tool in the study of cell function, with a single vendor claiming to have

G-Protein coupled receptors: answers from simulations

• Timothy Clark

Beilstein J. Org. Chem. 2017, 13, 1071–1078, doi:10.3762/bjoc.13.106

• activation. The structures shown are based on homology models. (a) After activation of the GPCR and dissociation of the β/γ subunits, IL3 and the C-terminus of the GPCR is phosphorylated by G-protein regulating kinases (GRKs). (b) Arrestin is recruited by the phosphorylated tail. (c) The fully bound arrestin

Inhibition of peptide aggregation by means of enzymatic phosphorylation

• Kristin Folmert,
• Malgorzata Broncel,
• Hans v. Berlepsch,
• Christopher H. Ullrich,
• Mary-Ann Siegert and
• Beate Koksch

Beilstein J. Org. Chem. 2016, 12, 2462–2470, doi:10.3762/bjoc.12.240

• ][29]. Phosphorylation caused by abnormal activities of phosphatases and/or kinases is associated with known diseases such as cancer [30], multiple sclerosis [31], diabetes [32] and Alzheimer’s disease [33]. The accumulation of hyperphosphorylated tau protein as trigger for several dementias was

Antibiotics from predatory bacteria

• Juliane Korp,
• María S. Vela Gurovic and
• Markus Nett

Beilstein J. Org. Chem. 2016, 12, 594–607, doi:10.3762/bjoc.12.58

• , requires a tight regulatory network in predatory myxobacteria [80]. This is also reflected in the genome of M. xanthus DK1622, which features an unusual high duplication frequency of genes encoding regulatory proteins like serine-threonine kinases and enhancer binding proteins (EBPs) [43]. EBPs are

Biosynthesis of α-pyrones

• Till F. Schäberle

Beilstein J. Org. Chem. 2016, 12, 571–588, doi:10.3762/bjoc.12.56

• inhibited 10 out of the 24 kinases tested. The results of the MTT and the kinase assay showed a similar pattern, and hence it was concluded that protein kinase inhibition should be one mechanism leading to the cytotoxicity of 17. In a study using human colon carcinoma cells to elucidate the cell death mode

Art, auto-mechanics, and supramolecular chemistry. A merging of hobbies and career

• Eric V. Anslyn

Beilstein J. Org. Chem. 2016, 12, 362–376, doi:10.3762/bjoc.12.40

• wine fraud may be a real-life application for the method. As has Rotello, we are taking our differential sensing work to the biological arena. Kinases are enzymes that are involved in cellular signaling and regulation. Monitoring their activity has commonly involved the creation of highly selective

• much of the same concept is just a simple 96-well plate. a) LDA plot of the response from different wine varietals with array Z [103]. b) Three-dimensional LDA plot of the response from the SOX-peptides showing in vitro differentiation of nine MAP kinases [106]. c) LDA plot of data collected from 96

Design, synthesis and photochemical properties of the first examples of iminosugar clusters based on fluorescent cores

• Mathieu L. Lepage,
• Antoine Mirloup,
• Manon Ripoll,
• Fabien Stauffert,
• Anne Bodlenner,
• Raymond Ziessel and
• Philippe Compain

Beilstein J. Org. Chem. 2015, 11, 659–667, doi:10.3762/bjoc.11.74

• kinases [4] and cholinesterases [5], which are enzymes that act on non-sugar substrates. The versatility of iminosugars as inhibitors of enzymes of therapeutic interest has been harnessed to cure a diversity of diseases including diabetes, viral infection, lysosomal storage disorders, tumour metastasis

Natural phenolic metabolites with anti-angiogenic properties – a review from the chemical point of view

• Qiu Sun,
• Jörg Heilmann and
• Burkhard König

Beilstein J. Org. Chem. 2015, 11, 249–264, doi:10.3762/bjoc.11.28

• the processing of soya products, a significant amount of the aglycone genistein is released. Genistein was originally described as an exclusive inhibitor of tyrosine-specific protein kinases [79]. These kinases are responsible for the tyrosine-specific protein phosphorylation, which is required for

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

• Yiyang Liu,
• Marc Liniger,
• Ryan M. McFadden,
• Jenny L. Roizen,
• Jacquie Malette,
• Corey M. Reeves,
• Douglas C. Behenna,
• Masaki Seto,
• Jimin Kim,
• Justin T. Mohr,
• Scott C. Virgil and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2014, 10, 2501–2512, doi:10.3762/bjoc.10.261

• and found to have inhibitory activity toward protein phosphatase cdc25, with an IC50 value of 9.4 µM [45]. This enzyme is a member of the protein family responsible for dephosphorylation of cyclin-dependent kinases [46]. Thus, inhibitors of cdc25 might allow for targeted cell-cycle disruption [45

Facile synthesis of 1-alkoxy-1H-benzo- and 7-azabenzotriazoles from peptide coupling agents, mechanistic studies, and synthetic applications

• Mahesh K. Lakshman,
• Manish K. Singh,
• Mukesh Kumar,
• Raghu Ram Chamala,
• Vijayender R. Yedulla,
• Domenick Wagner,
• Evan Leung,
• Lijia Yang,
• Asha Matin and
• Sadia Ahmad

Beilstein J. Org. Chem. 2014, 10, 1919–1932, doi:10.3762/bjoc.10.200

• inhibit proliferation of hepatocarcinoma [6]. Several N-alkylbenzotriazoles show potent antimicrobial action [7] and others have been evaluated as aromatase inhibitors [8]. Benzotriazole derivatives have also been reported to be inhibitors of MAP kinases [9]. Although esters of BtOH are generally

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• inhibitors (2000) Protein tyrosine phosphatases (PTPs) are part of a superfamily of enzymes that catalyze protein tyrosine dephosphorylation. They are key regulators in various, crucial kinase-dependent signal transduction pathways and act to counterbalance the kinases. In particular, PTP1B has attracted

Synthesis of trifluoromethyl-substituted pyrazolo[4,3-c]pyridines – sequential versus multicomponent reaction approach

• Barbara Palka,
• Angela Di Capua,
• Maurizio Anzini,
• Gyté Vilkauskaité,
• Algirdas Šačkus and
• Wolfgang Holzer

Beilstein J. Org. Chem. 2014, 10, 1759–1764, doi:10.3762/bjoc.10.183

• -substituted pyrazolo[4,3-c]pyridines. The latter heterocyclic system represents the core of several biologically active compounds, acting, for instance, as SSAO inhibitors [10], or inhibitors of different kinases (LRRK2 [11][12], TYK2 [13], JAK [14][15]). Results and Discussion Chemistry The construction of

C–H-Functionalization logic guides the synthesis of a carbacyclopamine analog

• Sebastian Rabe,
• Johann Moschner,
• Marina Bantzi,
• Philipp Heretsch and
• Athanassios Giannis

Beilstein J. Org. Chem. 2014, 10, 1564–1569, doi:10.3762/bjoc.10.161

• -carbon E-ring and a pyridine F-ring. Cyclopamine inhibits the 7-transmembrane protein smoothened from converting into its active form [18][19]. Without active smoothened, protein kinases like PKA, GSK3β, and CK1ε phosphorylate the transcription factors Gli2 and Gli3, thereby creating binding sites for

A unified approach to the important protein kinase inhibitor balanol and a proposed analogue

• Tapan Saha,
• Ratnava Maitra and
• Shital K. Chattopadhyay

Beilstein J. Org. Chem. 2013, 9, 2910–2915, doi:10.3762/bjoc.9.327

• developed using an efficient fragment coupling protocol which proceeded in good overall yield. Keywords: azepane; balanol; Garner’s aldehyde; PKC inhibitor; ring-closing metathesis; Introduction Protein kinase C (PKC) is a family of phospholipid-dependent kinases that phosphorylate serine and threonine

Multigramme synthesis and asymmetric dihydroxylation of a 4-fluorobut-2E-enoate

• James A. B. Laurenson,
• John A. Parkinson,
• Jonathan M. Percy,
• Giuseppe Rinaudo and
• Ricard Roig

Beilstein J. Org. Chem. 2013, 9, 2660–2668, doi:10.3762/bjoc.9.301

• . Modifications of this type are sometimes accepted by sugar-processing enzymes such as the kinases and transferases involved in oligosaccharide assembly, or in antibiotic biosynthesis. Mechanistic insights, and new routes to hybrid natural products represent the rewards of this endeavour [1][2][3][4][5][6][7][8

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• kinase inhibitory effects of 26 [18]. Solving the crystal structure of the catalytic subunit Cα of cAMP-dependent protein kinase bound to 26 gave pivotal insights in the binding mode [19]. Staurosporine (26) targets the active site of the adenosine-binding pocket of most protein kinases. This is achieved

• mimicking several aspects of the adenosine moiety, by induced-fit structural changes and the conformational flexibility of the enzyme residues (Figure 3). Together with several related analogues, 26 displays significant cytotoxic and antiproliferative effects [19]. Due to the key role of protein kinases in

• -(deoxyadenosin-N6-yl)aristolactam I (dA–AAI, 128). Interestingly, aristolactams are not mutagenic themselves but show immunosuppressant [104], antiplatelet [105], antimycobacterial [106], neuroprotective [107] activities and are excellent inhibitors of cyclin-dependent kinases (CDKs) with IC50 values in the

Methylidynetrisphosphonates: Promising C₁ building block for the design of phosphate mimetics

• Vadim D. Romanenko and
• Valery P. Kukhar

Beilstein J. Org. Chem. 2013, 9, 991–1001, doi:10.3762/bjoc.9.114

• blocks in the synthesis of the nucleotide analogues with enhanced affinity for receptors and better charge correlation with transition states for selected kinases. Two synthetically useful approaches to the parent trisphosphonic acid HC(PO3H2)3 have been developed. One of the procedures is based on the

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