Organic synthesis in flow mode by selective liquid-phase hydrogenation over heterogeneous non-noble metal catalysts.

Flow hydrogenation performed over heterogeneous catalysts makes organic synthesis more economical, safe and environmentally friendly. Over the past two decades, a significant amount of research with a major focus on noble metal catalysts has been carried out in this area. However, catalysts based on non-noble metals (Ni, Cu, Co, .

Cerastecins inhibit membrane lipooligosaccharide transport in drug-resistant Acinetobacter baumannii.

Carbapenem-resistant Acinetobacter baumannii infections have limited treatment options. Synthesis, transport and placement of lipopolysaccharide or lipooligosaccharide (LOS) in the outer membrane of Gram-negative bacteria are important for bacterial virulence and survival. Here we describe the cerastecins, inhibitors of the A.

Comparative Study of Batch and Continuous Flow Reactors in Selective Hydrogenation of Functional Groups in Organic Compounds: What Is More Effective?

Many research papers describe selective hydrogenation of functional groups, such as nitro groups, carbonyl groups, or unsaturated carbon bonds to obtain fine chemicals or precursors of pharmaceuticals. Quite often, the catalyst performance is investigated in batch or continuous flow reactors without finding advantages and disadvantages of this or that regime. At the same time, the transition from batch processes to continuous flow occurs on the industrial scale.

Potent targeted activator of cell kill molecules eliminate cells expressing HIV-1.

Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction is therefore an important HIV-1 cure strategy. Some HIV-1 nonnucleoside reverse transcriptase inhibitors induce HIV-1 selective cytotoxicity in vitro but require concentrations far exceeding approved dosages.

Effect of Phosphorus Precursor, Reduction Temperature, and Support on the Catalytic Properties of Nickel Phosphide Catalysts in Continuous-Flow Reductive Amination of Ethyl Levulinate.

Levulinic acid and its esters (e.g., ethyl levulinate, EL) are platform chemicals derived from biomass feedstocks that can be converted to a variety of valuable compounds.

Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen.

By employing a phenotypic screen, a set of compounds, exemplified by , were identified which potentiate the ability of histone deacetylase inhibitor vorinostat to reverse HIV latency. Proteome enrichment followed by quantitative mass spectrometric analysis employing a modified analogue of as affinity bait identified farnesyl transferase (FTase) as the primary interacting protein in cell lysates. This ligand-FTase binding interaction was confirmed via X-ray crystallography and temperature dependent fluorescence studies, despite lacking structural and binding similarity to known FTase inhibitors.

Two-Step One-Pot Reductive Amination of Furanic Aldehydes Using CuAlO Catalyst in a Flow Reactor.

Aminomethylhydroxymethylfuran derivatives are well known compounds which are used in the pharmaceutical industry. Reductive amination of 5-hydroxymethylfurfural (HMF) derived from available non-edible lignocellulosic biomass is an attractive method for the synthesis of this class of compounds. In the present study, the synthesis of N-substituted 5-(hydroxymethyl)-2-furfuryl amines and 5-(acetoxymethyl)-2-furfuryl amines was performed by two-step process, which includes the condensation of furanic aldehydes (HMF and 5-acetoxymethylfurfural) with primary amines in methanol on the first step and the reduction of obtained imines with hydrogen in a flow reactor over CuAlO catalyst derived from layered double hydroxide on the second step.

Identification of potent inhibitors of the sortilin-progranulin interaction.

High-throughput screening methods have been used to identify two novel series of inhibitors that disrupt progranulin binding to sortilin. Exploration of structure-activity relationships (SAR) resulted in compounds with sufficient potency and physicochemical properties to enable co-crystallization with sortilin. These co-crystal structures supported observed SAR trends and provided guidance for additional avenues for designing compounds with additional interactions within the binding site.

Structural characterization of nonactive site, TrkA-selective kinase inhibitors.

Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosin-related kinase A (TrkA) is linked to pain and elevated levels of NGF (the ligand for TrkA) are associated with chronic pain. Antibodies that block TrkA interaction with its ligand, NGF, are in clinical trials for pain relief.

Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD).

Discovery of a new class of DFG-out p38α kinase inhibitors with no hinge interaction is described. A computationally assisted, virtual fragment-based drug design (vFBDD) platform was utilized to identify novel non-aromatic fragments which make productive hydrogen bond interactions with Arg 70 on the αC-helix. Molecules incorporating these fragments were found to be potent inhibitors of p38 kinase.

Synthesis and pharmacological evaluation of N-(3-(1H-indol-4-yl)-5-(2-methoxyisonicotinoyl)phenyl)methanesulfonamide (LP-261), a potent antimitotic agent.

The synthesis and optimization of a series of orally bioavailable 1-(1H-indol-4-yl)-3,5-disubstituted benzene analogues as antimitotic agents are described. A functionalized dibromobenzene intermediate was used as a key scaffold, which when modified by sequential Suzuki coupling and Buchwald-Hartwig amination provided a flexible entry to 1,3,5-trisubstituted phenyl compounds. A 1H-indol-4-yl moiety at the 1-position was determined to be a critical feature for optimal potency.

The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity.

We have designed and synthesized analogues of compound C, a non-specific inhibitor of 5'-AMP-activated protein kinase (AMPK), using a computational fragment-based drug design (FBDD) approach. Synthesizing only twenty-seven analogues yielded a compound that was equipotent to compound C in the inhibition of the human AMPK (hAMPK) α2 subunit in the heterotrimeric complex in vitro, exhibited significantly improved selectivity against a subset of relevant kinases, and demonstrated enhanced cellular inhibition of AMPK.

Discovery and SAR of a series of 4,6-diamino-1,3,5-triazin-2-ol as novel non-nucleoside reverse transcriptase inhibitors of HIV-1.

The discovery and SAR study of a series of 4,6-diamino-1,3,5-triazin-2-ol compounds as novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are reported. The lead compounds in this series showed excellent activity against wild-type and drug-resistant RT enzymes and viral strains. In addition, compounds from this series demonstrated favorable pharmacokinetic profile in rat.

Analysis of imatinib and sorafenib binding to p38alpha compared with c-Abl and b-Raf provides structural insights for understanding the selectivity of inhibitors targeting the DFG-out form of protein kinases.

Protein kinases c-Abl, b-Raf, and p38alpha are recognized as important targets for therapeutic intervention. c-Abl and b-Raf are major targets of marketed oncology drugs Imatinib (Gleevec) and Sorafenib (Nexavar), respectively, and BIRB-796 is a p38alpha inhibitor that reached Phase II clinical trials. A shared feature of these drugs is the fact that they bind to the DFG-out forms of their kinase targets.

Structure-based design of substituted biphenyl ethylene ethers as ligands binding in the hydrophobic pocket of gp41 and blocking the helical bundle formation.

A series of substituted biphenyl ethylene ether compounds has been designed to target the gp41N-trimer in order to inhibit formation of the six-helical bundle that represents the end state of gp41-mediated viral fusion. A size exclusion HPLC based helical bundle formation (HBF) assay was developed to evaluate in vitro inhibitory affinity of the inhibitors. The most potent compound 1 had an IC(50) of 31microM.

Mutagenesis of p38alpha MAP kinase establishes key roles of Phe169 in function and structural dynamics and reveals a novel DFG-OUT state.

In order to study the role of Phe169 in p38alpha MAP kinase structure and function, wild-type p38alpha and five p38alpha DFG motif mutants were examined in vitro for phosphorylation by MKK6, kinase activity toward ATF2 substrate, thermal stability, and X-ray crystal structure. All six p38alpha variants were efficiently phosphorylated by MKK6. However, only one activated p38alpha mutant (F169Y) possessed measurable kinase activity (1% compared to wild-type).

Two classes of p38alpha MAP kinase inhibitors having a common diphenylether core but exhibiting divergent binding modes.

Two new classes of diphenylether inhibitors of p38alpha MAP kinase are described. Both chemical classes are based on a common diphenylether core that is identified by simulated fragment annealing as one of the most favored chemotypes within a prominent hydrophobic pocket of the p38alpha ATP-binding site. In the fully elaborated molecules, the diphenylether moiety acts as an anchor occupying the deep pocket, while polar extensions make specific interactions with either the adenine binding site or the phosphate binding site of ATP.

Improved expression, purification, and crystallization of p38alpha MAP kinase.

p38alpha mitogen-activated protein (MAP) kinase is widely expressed in many mammalian tissues and is activated as a part of signal transduction cascades that respond to inflammatory stimuli. The activation of p38 is known to trigger various biological effects, including cell death, differentiation, and proliferation. The central role played by p38alpha in cellular signaling events, including those that control a wide range of inflammatory and autoimmune diseases, makes it an attractive drug target.

A Biacore biosensor method for detailed kinetic binding analysis of small molecule inhibitors of p38alpha mitogen-activated protein kinase.

Protein kinases are emerging as one of the most intensely studied classes of enzymes as their central roles in physiologically and clinically important cellular signaling events become more clearly understood. We report here the development of a real-time, label-free method to study protein kinase inhibitor binding kinetics using surface plasmon resonance-based biomolecular interaction analysis (Biacore). Utilizing p38alpha mitogen-activated protein kinase as a model system, we studied the binding properties of two known small molecule p38alpha inhibitors (SB-203580 and SKF-86002).

Hepatitis C virus NS3 protease requires its NS4A cofactor peptide for optimal binding of a boronic acid inhibitor as shown by NMR.

NMR spectroscopy was used to characterize the hepatitis C virus (HCV) NS3 protease in a complex with the 24 residue peptide cofactor from NS4A and a boronic acid inhibitor, Ac-Asp-Glu-Val-Val-Pro-boroAlg-OH. Secondary-structure information, NOE constraints between protease and cofactor, and hydrogen-deuterium exchange rates revealed that the cofactor was an integral strand in the N-terminal beta-sheet of the complex as observed in X-ray crystal structures. Based upon chemical-shift perturbations, inhibitor-protein NOEs, and the protonation state of the catalytic histidine, the boronic acid inhibitor was bound in the substrate binding site as a transition state mimic.