New Class Of Ligands Research Articles

Computationally Guided Ligand Discovery from Compound Libraries and Discovery of a New Class of Ligands for Ni-Catalyzed Cross-Electrophile Coupling of Challenging Quinoline Halides.

Although screening technology has heavily impacted the fields of metal catalysis and drug discovery, its application to the discovery of new catalyst classes has been limited. The diversity of on- and off-cycle pathways, combined with incomplete mechanistic understanding, means that screens of potential new ligands have thus far been guided by intuitive analysis of the metal binding potential. This has resulted in the discovery of new classes of ligands, but the low hit rates have limited the use of this strategy because large screens require considerable cost and effort. Here, we demonstrate a method to identify promising screening directions via simple and scalable computational and linear regression tools that leads to a substantial improvement in hit rate, enabling the use of smaller screens to find new ligands. The application of this approach to a particular example of Ni-catalyzed cross-electrophile coupling of aryl halides with alkyl halides revealed a previously overlooked trend: reactions with more electron-poor amidine ligands result in a higher yield. Focused screens utilizing this trend were more successful than serendipity-based screening and led to the discovery of two new types of ligands, pyridyl oxadiazoles and pyridyl oximes. These ligands are especially effective for couplings of bromo- and chloroquinolines and isoquinolines, where they are now the state of the art. The simplicity of these models with parameters derived from metal-free ligand structures should make this approach scalable and widely accessible.

Palladium‐Catalyzed Chemoselective Amination of Chloro(hetero)aryl Triflates Enabled by Alkyl‐Pyrazole‐Based Phosphine Ligands

AbstractThis study describes the palladium‐catalyzed chemoselective amination of chloro(hetero)aryl triflates in the C−Cl bond for the first time. A newly designed and synthesized alkyl‐pyrazole‐based phosphine ligand, L26 (BirdPhos), which is featured with the pyrazole ligand core and the cyclohexyl group at the C3 and C5 positions, was key to the success of this reaction. A variety of chloro(hetero)aryl triflates coupled with aromatic, aliphatic, and heterocyclic amines smoothly afforded the corresponding products up to 97% yields with general chemoselectivity (>99%) in the C−Cl bond. Drug analogs were also synthesized via the chemoselective intermolecular amination. This study attempts to investigate the structure‐activity relationship of this new class of ligand through experimental and density functional theory (DFT) calculations.

P-096 - Novel pyrazolethiazole derivatives as a promising new class of ligands for alpha-synuclein fibrils and potential PET tracers for the detection of α-synucleinopathies

P-096 - Novel pyrazolethiazole derivatives as a promising new class of ligands for alpha-synuclein fibrils and potential PET tracers for the detection of α-synucleinopathies

Chiral Ligands Based on Binaphthyl Scaffolds for Pd-Catalyzed Enantioselective C-H Activation/Cycloaddition Reactions.

We report the first examples of the use of a new class of ligands (NOBINAc) for performing asymmetric C-H activations using palladium catalysts. These ligands combine the axial chirality of binaphthyl scaffolds with the bifunctional and bidentate coordination properties of mono-N-protected amino acids (MPAAs), which are well-known to favor Pd-promoted C-H activations via concerted metalation-deprotonation mechanisms. We demonstrate that our new ligands enable substantially higher enantioselectivities than MPAAs in the assembly of 2-benzazepines through formal (5 + 2) cycloadditions between homobenzyltriflamides or o-methylbenzyltriflamides and allenes.

Discovery and Optimization of 5-Hydroxy-Diclofenac toward a New Class of Ligands with Nanomolar Affinity for the CaMKIIα Hub Domain.

The Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) is a brain-relevant kinase involved in long-term potentiation and synaptic plasticity. We have recently pinpointed the CaMKIIα hub domain as the long-sought-after high-affinity target of γ-hydroxybutyrate ligands substantiated with a high-resolution cocrystal of 5-hydroxydiclofenac (3). Herein, we employed in silico approaches to rationalize and guide the synthesis and pharmacological characterization of a new series of analogues circumventing chemical stability problems associated with 3. The oxygen-bridged analogue 4d showed mid-nanomolar affinity and notable ligand-induced stabilization effects toward the CaMKIIα hub oligomer. Importantly, 4d displayed superior chemical and metabolic stability over 3 by showing excellent chemical stability in phosphate-buffered saline and high resistance to form reactive intermediates and subsequent sulfur conjugates. Altogether, our study highlights 4d as a new CaMKIIα hub high-affinity ligand with enhanced pharmacokinetic properties, representing a powerful tool compound for allosteric regulation of kinase activity with subtype specificity.

Targeting the liver X receptor with dendrogenin A differentiates tumour cells to secrete immunogenic exosome-enriched vesicles.

Tumour cells are characterized by having lost their differentiation state. They constitutively secrete small extracellular vesicles (sEV) called exosomes when they come from late endosomes. Dendrogenin A (DDA) is an endogenous tumour suppressor cholesterol‐derived metabolite. It is a new class of ligand of the nuclear Liver X receptors (LXR) which regulate cholesterol homeostasis and immunity. We hypothesized that DDA, which induces tumour cell differentiation, inhibition of tumour growth and immune cell infiltration into tumours, could functionally modify sEV secreted by tumour cells. Here, we have shown that DDA differentiates tumour cells by acting on the LXRβ. This results in an increased production of sEV (DDA‐sEV) which includes exosomes. The DDA‐sEV secreted from DDA‐treated cells were characterized for their content and activity in comparison to sEV secreted from control cells (C‐sEV). DDA‐sEV were enriched, relatively to C‐sEV, in several proteins and lipids such as differentiation antigens, “eat‐me” signals, lipidated LC3 and the endosomal phospholipid bis(monoacylglycero)phosphate, which stimulates dendritic cell maturation and a Th1 T lymphocyte polarization. Moreover, DDA‐sEV inhibited the growth of tumours implanted into immunocompetent mice compared to control conditions. This study reveals a pharmacological control through a nuclear receptor of exosome‐enriched tumour sEV secretion, composition and immune function. Targeting the LXR may be a novel way to reprogram tumour cells and sEV to stimulate immunity against cancer.

4-Phosphoryl Pyrazolones for Highly Selective Lithium Separation from Alkali Metal Ions.

Effective receptors for the separation of Li+ from a mixture with other alkali metal ions under mild conditions remains an important challenge that could benefit from new approaches. In this study, it is demonstrated that the 4‐phosphoryl pyrazolones, HL 2‐HL 4, in the presence of the typical industrial organophosphorus co‐ligands tributylphosphine oxide (TBPO), tributylphosphate (TBP) and trioctylphosphine oxide (TOPO), are able to selectively recognise and extract lithium ions from aqueous solution. Structural investigations in solution as well as in the solid state reveal the existence of a series of multinuclear Li+ complexes that include dimers (TBPO, TBP) as well as rarely observed trimers (TOPO) and represent the first clear evidence for the synergistic role of the co‐ligands in the extraction process. Our findings are supported by detailed NMR, MS and extraction studies. Liquid‐liquid extraction in the presence of TOPO revealed an unprecedented high Li+ extraction efficiency (78 %) for HL 4 compared to the use of the industrially employed acylpyrazolone HL 1 (15 %) and benzoyl‐1,1,1‐trifluoroacetone (52 %) extractants. In addition, a high selectivity for Li+ over Na+, K+ and Cs+ under mild conditions (pH ∼8.2) confirms that HL 2‐HL 4 represent a new class of ligands that are very effective extractants for use in lithium separation.

Identification and characterization of novel candidate compounds targeting 6- and 7-transmembrane μ-opioid receptor isoforms.

The μ-opioid receptor (μ receptor) is the primary target for opioid analgesics. The 7-transmembrane (TM) and 6TM μ receptor isoforms mediate inhibitory and excitatory cellular effects. Here, we developed compounds selective for 6TM- or 7TM-μ receptors to further our understanding of the pharmacodynamic properties of μ receptors. We performed virtual screening of the ZINC Drug Now library of compounds using in silico 7TM- and 6TM-μ receptor structural models and identified potential compounds that are selective for 6TM- and/or 7TM-μ receptors. Subsequently, we characterized the most promising candidate compounds in functional in vitro studies using Be2C neuroblastoma transfected cells, behavioural in vivo pain assays using various knockout mice and in ex vivo electrophysiology studies. Our virtual screen identified 30 potential candidate compounds. Subsequent functional in vitro cellular assays shortlisted four compounds (#5, 10, 11 and 25) that demonstrated 6TM- or 7TM-μ receptor-dependent NO release. In in vivo pain assays these compounds also produced dose-dependent hyperalgesic responses. Studies using mice that lack specific opioid receptors further established the μ receptor-dependent nature of identified novel ligands. Ex vivo electrophysiological studies on spontaneous excitatory postsynaptic currents in isolated spinal cord slices also validated the hyperalgesic properties of the most potent 6TM- (#10) and 7TM-μ receptor (#5) ligands. Our novel compounds represent a new class of ligands for μ receptors and will serve as valuable research tools to facilitate the development of opioids with significant analgesic efficacy and fewer side-effects.

Synthesis, Molecular Pharmacology, and Structure-Activity Relationships of 3-(Indanoyl)indoles as Selective Cannabinoid Type 2 Receptor Antagonists.

Synthetic indole cannabinoids characterized by a 2',2'-dimethylindan-5'-oyl group at the indole C3 position constitute a new class of ligands possessing high affinity for human CB2 receptors at a nanomolar concentration and a good selectivity index. Starting from the neutral antagonist 4, the effects of indole core modification on the pharmacodynamic profile of the ligands were investigated. Several N1 side chains afforded potent and CB2-selective neutral antagonists, notably derivatives 26 (R1 = n-propyl, R2 = H) and 35 (R1 = 4-pentynyl, R2 = H). Addition of a methyl group at C2 improved the selectivity for the CB2 receptor. Moreover, C2 indole substitution may control the CB2 activity as shown by the functionality switch in 35 (antagonist) and 49 (R1 = 4-pentynyl, R2 = CH3, partial agonist).

New class of trianionic constrained geometry ligands: Representative complexes of zirconium

Acid-catalyzed condensation of fluorenylacetaldehyde diethylacetal (1) or indenylacetaldehyde diethylacetal (2) with 3-methylindole yields fluorenylbis(3-methylindolyl)ethane (3) or indenylbis(3-methylindolyl)ethane (4), respectively. Compounds 3 and 4 were used to demonstrate the coordination modes of this new class of ligands to zirconium. Transamination of Zr(NEt2)4 with 3 (H3L) yields (HL)Zr(NEt2)2(THF) (5) in which doubly deprotonated 3 chelates zirconium via two N-indolide moieties. The fluorenyl group remains protonated and uncoordinated. Transamination of Zr(NEt2)4 with 4 (H3L´) yields L´Zr(NEt2) (6) in which triply deprotonated 4 coordinates to zirconium via an η5-indenyl and both N-indolide moieties in a constrained geometry fashion. The molecular structures of 3·THF, 5·3THF, and 6·0.5C7H8 were confirmed by X-ray crystallography.

Marine Exopolysaccharide Complexed With Scandium Aimed as Theranostic Agents.

(1) Background: Exopolysaccharide (EPS) derivatives, produced by Alteromonas infernus bacterium, showed anti-metastatic properties. They may represent a new class of ligands to be combined with theranostic radionuclides, such as 47Sc/44Sc. The goal of this work was to investigate the feasibility of such coupling. (2) Methods: EPSs, as well as heparin used as a drug reference, were characterized in terms of molar mass and dispersity using Asymmetrical Flow Field-Flow Fractionation coupled to Multi-Angle Light Scattering (AF4-MALS). The intrinsic viscosity of EPSs at different ionic strengths were measured in order to establish the conformation. To determine the stability constants of Sc with EPS and heparin, a Free-ion selective radiotracer extraction (FISRE) method has been used. (3) Results: AF4-MALS showed that radical depolymerization produces monodisperse EPSs, suitable for therapeutic use. EPS conformation exhibited a lower hydrodynamic volume for the highest ionic strengths. The resulting random-coiled conformation could affect the complexation with metal for high concentration. The LogK of Sc-EPS complexes have been determined and showing that they are comparable to the Sc-Hep. (4) Conclusions: EPSs are very promising to be coupled with the theranostic pair of scandium for Nuclear Medicine.

Antimycobacterial activity of total extracts from Solanum torvum Swartz. (Solanaceae)

Aims and objectives: Tuberculosis (TB) caused by Mycobacterium tuberculosis complex remains a leading cause of morbidity and mortality worldwide. The zoonotic infectious condition represents a never-ending challenge towards which drug discovery efforts are needed. The current study was designed to evaluate the in vitro antimycobacterial activity of ethanolic extracts from roots, stem bark, leaves and unripe fruits derived from Solanum torvum, a shrub traditionally used against respiratory tract illnesses, including tuberculosis. Methods: The phenotypic colorimetric micro plate alamar blue assay (MABA) was used to study the antimycobacterial activity of the ethanolic extracts against six mycobacterial strains. Each experiment was run in triplicate. Data generated was analyzed using descriptive statistics to obtain mean minimum inhibitory concentration values. Results: The roots, stem bark, leaves and unripe fruits exhibited minimum inhibitory concentration values of 1.250 mg/mL, 0.078 mg/mL, 1.250 mg/mL and 0.625 mg/mL against the pathogenic mycobacterial strain, M. tuberculosis H37Rv (ATCC 27294) respectively. Conclusions: In conclusion, Solanum torvum stem bark has demonstrated moderate activity against the pathogenic Mycobacterium tuberculosis strain. This observation validates the ethno pharmacological use of the plant species against tuberculosis. Further studies are required to isolate, elucidate the structure and characterize the antimycobacterial compounds responsible for the observed activity. These will potentially contribute towards bioprospecting for a new class of ligands with activity against sensitive and drug resistant strains of M. tuberculosis.

Nuclear Hormone Receptors and Their Ligands: Metabolites in Control of Transcription.

Nuclear hormone receptors are a family of transcription factors regulated by small molecules derived from the endogenous metabolism or diet. There are forty-eight nuclear hormone receptors in the human genome, twenty of which are still orphans. In this review, we make a brief historical journey from the first observations by Berthold in 1849 to the era of orphan receptors that began with the sequencing of the Caenorhabditis elegans genome in 1998. We discuss the evolution of nuclear hormone receptors and the putative ancestral ligands as well as how the ligand universe has expanded over time. This leads us to define four classes of metabolites—fatty acids, terpenoids, porphyrins and amino acid derivatives—that generate all known ligands for nuclear hormone receptors. We conclude by discussing the ongoing efforts to identify new classes of ligands for orphan receptors.

Quantifying the Selectivity of Protein-Protein and Small Molecule Interactions with Fluorinated Tandem Bromodomain Reader Proteins.

Multidomain bromodomain-containing proteins regulate gene expression via chromatin binding, interactions with the transcriptional machinery, and by recruiting enzymatic activity. Selective inhibition of members of the bromodomain and extra-terminal (BET) family is important to understand their role in disease and gene regulation, although due to the similar binding sites of BET bromodomains, selective inhibitor discovery has been challenging. To support the bromodomain inhibitor discovery process, here we report the first application of protein-observed fluorine (PrOF) NMR to the tandem bromodomains of BRD4 and BRDT to quantify the selectivity of their interactions with acetylated histones as well as small molecules. We further determine the selectivity profile of a new class of ligands, 1,4-acylthiazepanes, and find them to have ≥3-10-fold selectivity for the C-terminal bromodomain of both BRD4 and BRDT. Given the speed and lower protein concentration required over traditional protein-observed NMR methods, we envision that these fluorinated tandem proteins may find use in fragment screening and evaluating nucleosome and transcription factor interactions.

The PPAR Ω Pocket: Renewed Opportunities for Drug Development.

The past decade of PPARγ research has dramatically improved our understanding of the structural and mechanistic bases for the diverging physiological effects of different classes of PPARγ ligands. The discoveries that lie at the heart of these developments have enabled the design of a new class of PPARγ ligands, capable of isolating central therapeutic effects of PPARγ modulation, while displaying markedly lower toxicities than previous generations of PPARγ ligands. This review examines the emerging framework around the design of these ligands and seeks to unite its principles with the development of new classes of ligands for PPARα and PPARβ/δ. The focus is on the relationships between the binding modes of ligands, their influence on PPAR posttranslational modifications, and gene expression patterns. Specifically, we encourage the design and study of ligands that primarily bind to the Ω pockets of PPARα and PPARβ/δ. In support of this development, we highlight already reported ligands that if studied in the context of this new framework may further our understanding of the gene programs regulated by PPARα and PPARβ/δ. Moreover, recently developed pharmacological tools that can be utilized in the search for ligands with new binding modes are also presented.

Amino Acids Bearing Aromatic or Heteroaromatic Substituents as a New Class of Ligands for the Lysosomal Sialic Acid Transporter Sialin.

Sialin, encoded by the SLC17A5 gene, is a lysosomal sialic acid transporter defective in Salla disease, a rare inherited leukodystrophy. It also enables metabolic incorporation of exogenous sialic acids, leading to autoantibodies against N-glycolylneuraminic acid in humans. Here, we identified a novel class of human sialin ligands by virtual screening and structure-activity relationship studies. The ligand scaffold is characterized by an amino acid backbone with a free carboxylate, an N-linked aromatic or heteroaromatic substituent, and a hydrophobic side chain. The most potent compound, 45 (LSP12-3129), inhibited N-acetylneuraminic acid 1 (Neu5Ac) transport in a non-competitive manner with IC50 ≈ 2.5 μM, a value 400-fold lower than the KM for Neu5Ac. In vitro and molecular docking studies attributed the non-competitive character to selective inhibitor binding to the Neu5Ac site in a cytosol-facing conformation. Moreover, compound 45 rescued the trafficking defect of the pathogenic mutant (R39C) causing Salla disease. This new class of cell-permeant inhibitors provides tools to investigate the physiological roles of sialin and help develop pharmacological chaperones for Salla disease.

Aldimine‐Thioether‐Phenolate Based Mono‐ and Bimetallic Zinc Complexes as Catalysts for the Reaction of CO2 with Cyclohexene Oxide

A synthetic strategy for the preparation of a new class of ligands is introduced. The bis(aldimine‐thioether‐phenolate) ligands bear two anionic oxygen donors from phenolate moieties, two neutral sulfur donors and two neutral nitrogen donors belonging, respectively, to thioether and aldimine functionalities. The so designed OSNNSO ligands show two coordinative pockets and thus should be able to host two metallic centers. Instead, the aldimine‐thioether‐phenolate OSN ligands are tridentate ligands which may form monometallic complexes. Two OSNNSO and one OSN ligands of this class, have been synthesized. Satisfyingly, by direct reaction of the ligands with one or two equivalents of the zinc precursor, the corresponding bimetallic Zn(II) complexes were prepared from the bis(aldimine‐thioether‐phenolate) ligands, while the monometallic zinc complex was prepared from the tridentate ligand. These zinc amido complexes act as single component catalysts in the reaction of CO2 with cyclohexene oxide by furnishing polycyclohexene carbonate, while adding PPNCl as cocatalyst to the reaction medium, cyclohexene carbonates were obtained as the main products.

Structure, optical and magnetic properties of a novel homometallic coordination polymers: Experimental and Computational studies

Single crystal of 1D homometallic coordination polymer involving cobalt metal ion and P2Mo5 Strandberg type polyoxometallate cluster (C6H10N2)2[Co(H2O)4P2Mo5O23].6H2O, is prepared in aqueous solution and characterized by X-ray diffraction (XRD), UV-vis diffuse reflectance, fluorescence and magnetism. Single crystal X-ray diffraction analysis reveals that this compound crystallizes in the triclinic system with space group P ,bar{1}. The 3-(ammoniomethyl)pyridine C6H8N2 organic fragment is used merely as stabilizer for the promotion of topological structure. DRS data indicate that the synthesized material can be identified as a ferromagnetic semiconductor with optical bands gaps energy of 1.81 and 2.74 eV, respectively. The large value of refractive index observed in the visible region make the simple a promising candidate for visible optical communication devices and fluorescent emisson result provides that the complex belongs to a blue luminescent compounds. Moreover, magnetic measurements and electronic structure calculations show that P2Mo5 Strandberg polyoxoanion can be reported as a new class of ligand that is candidate to construct metal-inorganic framworks with long distance ferromagnetic superechange between Co(II) centers. The evidence from this study suggests that the syntesized polymer can become a great multifunctional material openning the door for the developpement of new coordination polymers based on Strandberg type polyxoxmetalate with potential applications.

Membrane-binding peptides for extracellular vesicles on-chip analysis

ABSTRACT Small extracellular vesicles (sEVs) present fairly distinctive lipid membrane features in the extracellular environment. These include high curvature, lipid-packing defects and a relative abundance in lipids such as phosphatidylserine and ceramide. sEV membrane could be then considered as a “universal” marker, alternative or complementary to traditional, characteristic, surface-associated proteins. Here, we introduce the use of membrane-sensing peptides as new, highly efficient ligands to directly integrate sEV capturing and analysis on a microarray platform. Samples were analysed by label-free, single-particle counting and sizing, and by fluorescence co-localisation immune staining with fluorescent anti-CD9/anti-CD63/anti-CD81 antibodies. Peptides performed as selective yet general sEV baits and showed a binding capacity higher than anti-tetraspanins antibodies. Insights into surface chemistry for optimal peptide performances are also discussed, as capturing efficiency is strictly bound to probes surface orientation effects. We anticipate that this new class of ligands, also due to the versatility and limited costs of synthetic peptides, may greatly enrich the molecular toolbox for EV analysis.

Virtual screening identification and chemical optimization of substituted 2-arylbenzimidazoles as new non-zinc-binding MMP-2 inhibitors

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endoproteases known to exert multiple regulatory roles in tumor progression and invasiveness. This encouraged over the years the approach of MMP, and particularly MMP-2, targeting for anticancer treatment. Early generations of MMP inhibitors, based on aspecific zinc binding groups (ZBGs) assembled on (pseudo)peptide scaffolds, have been discontinued due to the clinical emergence of toxicity and further drawbacks, giving the way to inhibitors with alternative zinc-chelator moieties or not binding the catalytic zinc ion.In the present paper, we continue the search for new non-zinc binding MMP-2 inhibitors: exploiting previously identified compounds, a virtual screening (VS) campaign was carried out and led to the identification of a new class of ligands. The structure-activity relationship (SAR) of the benzimidazole scaffold was explored by synthesis of several analogues whose inhibition activity was tested with enzyme inhibition assays. By performing the molecular simplification approach, we disclosed different sets of single-digit micromolar inhibitors of MMP-2, with up to a ten-fold increase in inhibitory activity and ameliorated selectivity towards off-target MMP-8, compared to selected lead compound. Molecular dynamics calculations conducted on complexes of MMP-2 with docked privileged structures confirmed that analyzed inhibitors avoid targeting the zinc ion and dip inside the S1′ pocket. Present results provide a further enrichment of our insights for the design of novel MMP-2 selective inhibitors.