Synthesis and Photophysical Characterization of Azoheteroarenes

A set of azoheteroarenes have been synthesized with Buchwald–Hartwig coupling and microwave-assisted O₂ oxidation as the key steps. Several compounds exhibit good to excellent photoswitching properties (high switching efficiency, good fatigue resistance, and thermal stability of <i>Z</i>-isomer) relevant for photocontrolled applications, which pave the way for use in photopharmacology

Effect of Chirality on Common in Vitro Experiments: An Enantiomeric Pair Analysis

This analysis elucidates the impact of small molecule architecture on common in vitro ADME assays. In vitro parameters considered in this analysis included Caco-2 permeability/efflux, CYP3A4 inhibition, hERG inhibition, and rat microsomal extraction ratio (ER). The statistical significance and practical meaningfulness of chirality were determined by comparison of the distribution of enantiomers with the experimental variation distribution observed from duplicate measurements. Statistical tools were applied to characterize the role of molecular architecture on the outcome of a given in vitro assay. We found that CYP3A4 inhibition, hERG inhibition, Caco-2 permeability, and efflux are unlikely to be modulated by chirality. However, rat microsomal ER provides a statistically significant, <i>and quantitatively meaningful</i>, chance of being influenced by chirality

Sakurai Reaction of 3,3-Bis(silyl) Silyl Enol Ethers with Acetals Involving Selective Desilylation of the Geminal Bis(silane). Concise Synthesis of Nematocidal Oxylipid

3,3-Bis(silyl) silyl enol ethers have been shown to exhibit predominantly Sakurai reactivity, rather than Mukaiyama aldol reactivity, in their Lewis acid promoted reactions with acetals. Starting from a geminal bis(silyl) moiety consisting of two different silyl groups, such as SiMe₃ and SiMe₂Ph, the SiMe₃ is selectively eliminated to give monoprotected <i>E</i>- vinylsilyl diols with good to excellent <i>syn</i>-diastereoselectivity. This reaction also underpinned a synthesis of the nematocidal oxylipid from <i>Notheia anomala</i>, demonstrating the attractive bifunctionality of geminal bis(silanes)

1,4-Hydroiodination of Dienyl Alcohols with TMSI To Form Homoallylic Alcohols Containing a Multisubstituted <i>Z</i>‑Alkene and Application to Prins Cyclization

A regioselective 1,4-hydroiodination of dienyl alcohols has been developed using trimethylsilyl iodide as Lewis acid and iodide source. A range of homoallylic alcohols containing a multisubstituted <i>Z</i>-alkene was synthesized with good to excellent configurational control. The approach was applied in sequential hydroiodination/Prins cyclization to afford multisubstituted tetrahydropyrans diastereoselectively

Discovery of a Selective and Potent Inhibitor of Mitogen-Activated Protein Kinase-Interacting Kinases 1 and 2 (MNK1/2) Utilizing Structure-Based Drug Design

The discovery of a highly potent and selective small molecule inhibitor <b>9</b> for in vitro target validation of MNK1/2 kinases is described. The aminopyrazine benzimidazole series was derived from an HTS hit and optimized by utilization of a docking model, conformation analysis, and binding pocket comparison against antitargets

Discovery of a Selective and Potent Inhibitor of Mitogen-Activated Protein Kinase-Interacting Kinases 1 and 2 (MNK1/2) Utilizing Structure-Based Drug Design

The discovery of a highly potent and selective small molecule inhibitor <b>9</b> for in vitro target validation of MNK1/2 kinases is described. The aminopyrazine benzimidazole series was derived from an HTS hit and optimized by utilization of a docking model, conformation analysis, and binding pocket comparison against antitargets

Novel Small Molecule Inhibitors of Choline Kinase Identified by Fragment-Based Drug Discovery

Choline kinase α (ChoKα) is an enzyme involved in the synthesis of phospholipids and thereby plays key roles in regulation of cell proliferation, oncogenic transformation, and human carcinogenesis. Since several inhibitors of ChoKα display antiproliferative activity in both cellular and animal models, this novel oncogene has recently gained interest as a promising small molecule target for cancer therapy. Here we summarize our efforts to further validate ChoKα as an oncogenic target and explore the activity of novel small molecule inhibitors of ChoKα. Starting from weakly binding fragments, we describe a structure based lead discovery approach, which resulted in novel highly potent inhibitors of ChoKα. In cancer cell lines, our lead compounds exhibit a dose-dependent decrease of phosphocholine, inhibition of cell growth, and induction of apoptosis at low micromolar concentrations. The druglike lead series presented here is optimizable for improvements in cellular potency, drug target residence time, and pharmacokinetic parameters. These inhibitors may be utilized not only to further validate ChoKα as antioncogenic target but also as novel chemical matter that may lead to antitumor agents that specifically interfere with cancer cell metabolism

Novel Small Molecule Inhibitors of Choline Kinase Identified by Fragment-Based Drug Discovery

Choline kinase α (ChoKα) is an enzyme involved in the synthesis of phospholipids and thereby plays key roles in regulation of cell proliferation, oncogenic transformation, and human carcinogenesis. Since several inhibitors of ChoKα display antiproliferative activity in both cellular and animal models, this novel oncogene has recently gained interest as a promising small molecule target for cancer therapy. Here we summarize our efforts to further validate ChoKα as an oncogenic target and explore the activity of novel small molecule inhibitors of ChoKα. Starting from weakly binding fragments, we describe a structure based lead discovery approach, which resulted in novel highly potent inhibitors of ChoKα. In cancer cell lines, our lead compounds exhibit a dose-dependent decrease of phosphocholine, inhibition of cell growth, and induction of apoptosis at low micromolar concentrations. The druglike lead series presented here is optimizable for improvements in cellular potency, drug target residence time, and pharmacokinetic parameters. These inhibitors may be utilized not only to further validate ChoKα as antioncogenic target but also as novel chemical matter that may lead to antitumor agents that specifically interfere with cancer cell metabolism

FOCUS  Development of a Global Communication and Modeling Platform for Applied and Computational Medicinal Chemists

Communication of data and ideas within a medicinal chemistry project on a global as well as local level is a crucial aspect in the drug design cycle. Over a time frame of eight years, we built and optimized FOCUS, a platform to produce, visualize, and share information on various aspects of a drug discovery project such as cheminformatics, data analysis, structural information, and design. FOCUS is tightly integrated with internal services that involveamong othersdata retrieval systems and <i>in-silico</i> models and provides easy access to automated modeling procedures such as pharmacophore searches, R-group analysis, and similarity searches. In addition, an interactive 3D editor was developed to assist users in the generation and docking of close analogues of a known lead. In this paper, we will specifically concentrate on issues we faced during development, deployment, and maintenance of the software and how we continually adapted the software in order to improve usability. We will provide usage examples to highlight the functionality as well as limitations of FOCUS at the various stages of the development process. We aim to make the discussion as independent of the software platform as possible, so that our experiences can be of more general value to the drug discovery community

Fragment Growing and Linking Lead to Novel Nanomolar Lactate Dehydrogenase Inhibitors

Lactate dehydrogenase A (LDH-A) catalyzes the interconversion of lactate and pyruvate in the glycolysis pathway. Cancer cells rely heavily on glycolysis instead of oxidative phosphorylation to generate ATP, a phenomenon known as the Warburg effect. The inhibition of LDH-A by small molecules is therefore of interest for potential cancer treatments. We describe the identification and optimization of LDH-A inhibitors by fragment-based drug discovery. We applied ligand based NMR screening to identify low affinity fragments binding to LDH-A. The dissociation constants (<i>K</i>_d) and enzyme inhibition (IC₅₀) of fragment hits were measured by surface plasmon resonance (SPR) and enzyme assays, respectively. The binding modes of selected fragments were investigated by X-ray crystallography. Fragment growing and linking, followed by chemical optimization, resulted in nanomolar LDH-A inhibitors that demonstrated stoichiometric binding to LDH-A. Selected molecules inhibited lactate production in cells, suggesting target-specific inhibition in cancer cell lines