Molecule Analogues Research Articles

Commentary: The promise of polymers

Commentary: The promise of polymers

Antibiotic Resistance: Current Perspectives.

Antibiotic resistance is one of the most serious challenges that the world is currently facing. The number of people succumbing to drug-resistant infections is increasing every day, but the rate of drug discovery has failed to match the requisite demands. Most of the currently known antibiotics target the three essential pathways of central dogma. However, bacteria have evolved multiple mechanisms to survive these antibiotics. Consequently, there is an urgent necessity to target auxiliary pathways for the discovery of new drugs. Metabolism-related and stress-associated pathways are ideal in this regard. The stringent response pathway regulated by the signaling nucleotides (p)ppGpp is an attractive target as inhibition of the pathway would in turn decrease the persistence and long-term survival of pathogenic bacteria. In this perspective, we focus on the recent design of small molecule analogues of (p)ppGpp that have yielded promising results in terms of growth and biofilm inhibition. Additionally, we discuss how targeting small RNAs and riboswitches, as well as antimicrobial peptides, would help combat drug-resistant infections in the near future.

An aptamer-based colorimetric sensor for streptomycin and its application in food inspection

An aptamer-based colorimetric biosensor was developed, which could be used to detect residual streptomycin from food quickly and cost-effectively. The ssDNA aptamer target for streptomycin was obtained using systemic evolution of ligands by exponential enrichment through affinity chromatography. A total of 19 candidates were obtained after 10 rounds of selection and were grouped into 3 families according to their similarity of sequence and structure. Among them, aptamer A15 showed the highest affinity for streptomycin tested by fluorescence intensity analysis with a dissociation constant of 6.07 nmol/L. Aptamer A15 also exhibited a higher streptomycin specificity with the lowest detectable limit of 25 nmol/L according to the value of A 620/A 520 ratio with AuNP-based colorimetric assay. The method was specific and sensitive for the detection of streptomycin from simply-treated milk and honey at 100 and 125 nmol/L, respectively, and is a promising approach to monitor antibiotics or other small molecules analogues in food inspection.

Multifunctional Analogs of Kynurenic Acid for the Treatment of Alzheimer's Disease: Synthesis, Pharmacology, and Molecular Modeling Studies.

We report the synthesis and pharmacological investigation of analogs of the endogenous molecule kynurenic acid (KYNA) as multifunctional agents for the treatment of Alzheimer's disease (AD). Synthesized KYNA analogs were tested for their N-methyl-d-aspartate (NMDA) receptor binding, mGluR5 binding and function, acetylcholinesterase (AChE) inhibition, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, interference with the amyloid β peptide (Aβ) fibrillation process, and protection against Aβ-induced toxicity in transgenic Caenorhabditis elegans strain GMC101 expressing full-length Aβ42. Molecular modeling studies were also performed to predict the binding modes of most active compounds with NMDAR, mGluR5, and Aβ42. Among the synthesized analogs, 3c, 5b, and 5c emerged as multifunctional compounds that act via multiple anti-AD mechanisms including AChE inhibition, free radical scavenging, NMDA receptor binding, mGluR5 binding, inhibition of Aβ42 fibril formation, and disassembly of preformed Aβ42 fibrils. Interestingly, 5c showed protection against Aβ42-induced toxicity in transgenic C. elegans strain GMC101. Moreover, 5b and 5c displayed high permeability in an MDR1-MDCKII cell-based model of the blood-brain barrier (BBB). Compound 3b emerged with specific activity as a micromolar AChE inhibitor, however it had low permeability in the BBB model. This study highlights the opportunities that exist to develop analogs of endogenous molecules from the kynurenine pathway for therapeutic uses.

Acute myeloid leukemia cells require 6-phosphogluconate dehydrogenase for cell growth and NADPH-dependent metabolic reprogramming.

Acute myeloid leukemia (AML) cells are highly dependent on glycolytic pathways to generate metabolic energy and support cell growth, hinting at specific, targetable vulnerabilities as potential novel targets for drug development. Elevated levels of NADPH, a central metabolic factor involved in redox reactions, are common in myeloid leukemia cells, but the significance or biochemical basis underlying this increase is unknown. Using a small molecule analog that efficiently inhibits NADPH-producing enzymes, we found that AML cells require NADPH homeostasis for cell growth. We also found that inhibiting NADPH production through knockdown of 6-phosphogluconate dehydrogenase (6PGD) within the pentose phosphate pathway was sufficient to reduce cell growth and lactate production, a measure of metabolic reprogramming. Further, inhibition of 6PGD activity reduced NADH levels and enzymatic activity of the oxidized NADH-dependent sirtuin-1. Targeting 6PGD and NADPH production was sufficient to block growth of AML cell lines resistant to the chemotherapeutics daunorubicin and cytarabine. Importantly, stromal cell-mediated resistance to targeted inhibition of oncogenic FLT3 kinase activity by quizartinib was circumvented by 6PGD knockdown. Overall, these data suggest that the dependency of AML cells on NADPH to permit increased glycolytic flux creates a potential vulnerability of possible therapeutic benefit, since much of the enhanced production of NADPH is dependent on the activity of a single enzyme, 6PGD.

Dendritic cells provide a therapeutic target for synthetic small molecule analogues of the parasitic worm product, ES-62

ES-62, a glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae, subverts host immune responses towards anti-inflammatory phenotypes by virtue of covalently attached phosphorylcholine (PC). The PC dictates that ES-62 exhibits protection in murine models of inflammatory disease and hence a library of drug-like PC-based small molecule analogues (SMAs) was synthesised. Four sulfone-containing SMAs termed 11a, 11e, 11i and 12b were found to reduce mouse bone marrow-derived dendritic cell (DC) pathogen-associated molecular pattern (PAMP)-induced pro-inflammatory cytokine production, inhibit NF-κB p65 activation, and suppress LPS-induced up-regulation of CD40 and CD86. Active SMAs also resulted in a DC phenotype that exhibited reduced capacity to prime antigen (Ag)-specific IFN-γ production during co-culture with naïve transgenic TCR DO.11.10 T cells in vitro and reduced their ability, following adoptive transfer, to prime the expansion of Ag-specific T lymphocytes, specifically TH17 cells, in vivo. Consistent with this, mice receiving DCs treated with SMAs exhibited significantly reduced severity of collagen-induced arthritis and this was accompanied by a significant reduction in IL-17+ cells in the draining lymph nodes. Collectively, these studies indicate that drug-like compounds that target DCs can be designed from parasitic worm products and demonstrate the potential for ES-62 SMA-based DC therapy in inflammatory disease.

Patent highlights December 2016-January 2017.

Patent highlights December 2016-January 2017.

Development of a novel near-infrared fluorescent theranostic combretastain A-4 analogue, YK-5-252, to target triple negative breast cancer

The treatment of triple negative breast cancer (TNBC) is a significant challenge to cancer research. The lack of hormone receptors limits the treatment options available to patients with this diagnosis, forcing them to endure prolonged radiation and chemotherapy. Anti-angiogenesis is a chemotherapeutic strategy that targets the vasculature of tumors. Combretastatin A-4 (CA-4) is a well-known vasculature-disrupting agent, which has been shown to effectively kill a variety of cancers through inhibition of tubulin polymerization. Due to its toxicity, small molecule analogues of CA-4 have been sought out. We have designed a novel dual action CA-4 prodrug, YK-5-252, which releases the drug through a disulfide bond cleavage mechanism and contains a near-infrared (NIR) fluorophore, which allows fluorescence monitoring of cleavage. This disulfide linkage causes CA-4 to become effective only when released by glutathione (GSH) reducing the toxicity of the drug while simultaneously releasing the NIR fluorophore. Therefore the prodrug, YK-5-252, represents a novel CA-4 analogue which has reduced toxicity and can be used for theranostics imaging.

Co‐Assembly and Self‐Sorting Effects in Gels of Blends of Polyurethane Model Compounds

AbstractWe present studies on two‐component organo‐gels of small molecule analogues of polyurethanes. Whereas the two‐component organo‐ or polymer gels reported in the literature so far involve two types of polymers or polymer/ small molecules, this paper deals with blends of homologous pairs of biscarbamates, which differ only in the number of CH2 groups in the side chain. The mixture of any two biscarbamates self‐sort when crystallized from the melt or solution. We also showed before that these molecules, with a side chain shorter than (CH2)6 do not form gels by themselves as a single component. However, in this work, it was found that a blend of biscarbamates with side chains (CH2)3 and (CH2)15 (denoted as C3/ C15 henceforth) formed a homogeneous gel with benzonitrile as the solvent. A small ratio of the C15 component is sufficient to depress the precipitation of C3 and form a gel, leading to co‐assembly in these gels. Such an effect was also seen in the gelation of blends of C8 and C9, which differ by just one CH2 group in the side chains (Δx=1). With the gels of C7/C9 blends (Δx=2), an ageing effect was seen in that the as‐prepared gel did not show any self‐sorting, but the aged gel did. Self‐sorting was observed in the two‐component gels of biscarbamates with Δx > 2. We believe that this is the first case of two‐component organo‐gels of homologous pairs in which co‐assembly and self‐sorting phenomena were observed.

Phosphorus garners an organic starring role

Over time, chemists have synthesized an incredible array of molecules that combine carbon, hydrogen, nitrogen, and oxygen. Second row periodic table elements such as phosphorus and sulfur have made important guest appearances in compounds, but they tend not to form heavy analogs of common CHNO organic molecules. A research team based at ETH Zurich has reported a rare exception by preparing the phosphorus analog of cyanuric acid. A six-membered heterocyclic ring, cyanuric acid, C3N3(OH)3, and its derivatives are often used as polymer cross-linking agents and to make industrial chemicals such as herbicides and dyes. Riccardo Suter, Zoltan Benkő, and Hansjorg Grutzmacher, who led the discovery team, believe the phosphorus analog, the triphosphabenzene 2,4,6-tri(hydroxy)-1,3,5-triphosphinine, C3P3(OH)3, could play a similar role to make phosphorus-containing plastics and could serve as a valuable ligand for metal catalysts (Angew. Chem. Int. Ed. 2016, DOI: 10.1002/anie.201610156). The researchers thought they...

Colloidal molecules assembled from binary spheres under an AC electric field.

Colloidal particles are envisioned as analogues of atoms and molecules, however they often lack the complexities present in their counterparts. In this work, we report the assembly of colloidal molecules from a binary mixture of polystyrene spheres (1, 1.6, 2, and 4 μm) under an alternating current electric field. The rich family of assembled oligomers typically consists of a large sphere that is closely surrounded by a number of smaller petal particles, driven by the dipolar attraction between large and small particles. In deionized water, the number of satellite particles, i.e., the coordination number increases with the increasing size ratio of the constituent particles. For a given size ratio, the coordination number decreases with the increasing frequency of the applied field. These trends have also been correctly captured by computing the electric energy of different oligomers based on induced dipolar and double-layer interactions. By suspending the particles in polyvinylpyrrolidone aqueous solution, we can further tune the bond length of the oligomers independent of their coordination numbers. The addition of polyvinylpyrrolidone also allows us to lock the assembled colloidal molecules so that they remain intact after the electric field is turned off. Our method provides a robust way to produce a family of colloidal molecules with well-defined geometry and high yield.

Specific features of molecular mobility of paramagnetic probe in chiral biomimetic solutions

Molecular mobility of a nitroxyl radical (as a paramagnetic probe) in methylcyclohexane (MCH) solutions of chiral biomimetic gelators—trifluoroacetylated amino alcohols (synthetic analogues of biological molecules)—has been studied by monitoring thermally induced changes in EPR spectra. The phase state of the systems has been examined by the low-temperature scanning calorimetry method. There has been found an unusual concentration and temperature dependence of probe species mobility in diluted solutions (10–2–10–3 M) of trifluoroacetylated amino alcohols with a molecular weight of no more than 200. From the temperature-induced changes in EPR spectra of the paramagnetic probe in the temperature range 170–290 K, the rotation activation energies of probe species in biomimetic solutions and in the neat solvent. The minimum radical rotation activation energy (2.1 kcal/mol) is observed in the most concentrated gelator solution, whereas in neat MCH, this energy is 3.7 kcal/mol.

Colloidal Magnetic Heterostructured Nanocrystals with Asymmetric Topologies: Seeded-Growth Synthetic Routes and Formation Mechanisms

Colloidal inorganic nanocrystals, free-standing crystalline nanostructures generated and processed in solution phase, represent an important class of advanced nanoscale materials owing to the flexibility with which their physical–chemical properties can be controlled through synthetic tailoring of their compositional, structural and geometric features and the versatility with which they can be integrated in technological fields as diverse as optoelectronics, energy storage/ conversion/production, catalysis and biomedicine. In recent years, building upon mechanistic knowledge acquired on the thermodynamic and kinetic processes that underlie nanocrystal evolution in liquid media, synthetic nanochemistry research has made impressive advances, opening new possibilities for the design, creation and mastering of increasingly complex “colloidal molecules”, in which nanocrystal modules of different materials are clustered together via solid-state bonding interfaces into free-standing, easily processable multifunctional nanocomposite systems. This Review will provide a glimpse into this fast-growing research field by illustrating progress achieved in the wet-chemical development of last-generation breeds of all-inorganic heterostructured nanocrystals (HNCs) in asymmetric non-onionlike geometries, inorganic analogues of polyfunctional organic molecules, in which distinct nanoscale crystalline modules are interconnected in hetero-dimer, hetero-oligomer and anisotropic multidomain architectures via epitaxial heterointerfaces of limited extension. The focus will be on modular HNCs entailing at least one magnetic material component combined with semiconductors and/or metals, which hold potential for generating enhanced or unconventional magnetic properties, while offering diversified or even new chemical-physical properties and functional capabilities. The available toolkit of synthetic strategies, all based on the manipulation of seeded-growth techniques, will be described, revisited and critically interpreted within the framework of the currently understood mechanisms of colloidal heteroepitaxy.

Surface patterning of nanoparticles with polymer patches.

Patterning of colloidal particles with chemically or topographically distinct surface domains (patches) has attracted intense research interest. Surface-patterned particles act as colloidal analogues of atoms and molecules, serve as model systems in studies of phase transitions in liquid systems, behave as 'colloidal surfactants' and function as templates for the synthesis of hybrid particles. The generation of micrometre- and submicrometre-sized patchy colloids is now efficient, but surface patterning of inorganic colloidal nanoparticles with dimensions of the order of tens of nanometres is uncommon. Such nanoparticles exhibit size- and shape-dependent optical, electronic and magnetic properties, and their assemblies show new collective properties. At present, nanoparticle patterning is limited to the generation of two-patch nanoparticles, and nanoparticles with surface ripples or a 'raspberry' surface morphology. Here we demonstrate nanoparticle surface patterning, which utilizes thermodynamically driven segregation of polymer ligands from a uniform polymer brush into surface-pinned micelles following a change in solvent quality. Patch formation is reversible but can be permanently preserved using a photocrosslinking step. The methodology offers the ability to control the dimensions of patches, their spatial distribution and the number of patches per nanoparticle, in agreement with a theoretical model. The versatility of the strategy is demonstrated by patterning nanoparticles with different dimensions, shapes and compositions, tethered with various types of polymers and subjected to different external stimuli. These patchy nanocolloids have potential applications in fundamental research, the self-assembly of nanomaterials, diagnostics, sensing and colloidal stabilization.

Studying epigenetic complexes and their inhibitors with the proteomics toolbox.

Some epigenetic modifier proteins have become validated clinical targets. With a few small molecule inhibitors already approved by national health administrations and many more in the pharmaceutical industry pipelines, there is a need for technologies that can promote full comprehension of the molecular action of these drugs. Proteomics, with its relatively unbiased nature, can contribute to a thorough understanding of the complexity of the megadalton complexes, which write, read and erase the histone code, and it can help study the on-target and off-target effect of the drugs designed to modulate their action. This review on the one hand gathers the published affinity probes able to decipher small molecule targets and off-targets in a close-to-native environment. These are small molecule analogues of epigenetic drugs conceived as protein target enrichment tools after they have engaged them in cells or lysates. Such probes, which have been designed for deacetylases, bromodomains, demethylases, and methyltransferases not only enrich their direct protein targets but also their stable interactors, which can be identified by mass spectrometry. Hence, they constitute a tool to study the epigenetic complexes together with other techniques also reviewed here: immunoaffinity purification with antibodies against native protein complex constituents or epitope tags, affinity matrices designed to bind recombinantly tagged protein, and enrichment of the complexes using histone tail peptides as baits. We expect that this toolbox will be adopted by more and more researchers willing to harness the spectacular advances in mass spectrometry to the epigenetic field.

Preparation and affinity identification of glutamic acid-urea small molecule analogs in prostate cancer.

In recent years, study concerning activity inhibitors of prostate-specific membrane antigen (PSMA) has been concentrated on the glutamic urea (Glu-urea-R) small molecule and its analogs. The present study aimed to synthesize 4 analogs of Glu-urea-R and identify the affinities of these compounds to PSMA. The compounds were synthesized from raw materials, and the experimental procedures of the present study were in accordance with standard techniques under anhydrous and anaerobic conditions. Glu-urea-Lysine (Glu-urea-Lys), Glu-urea-Ornithine (Glu-urea-Orn), Glu-urea-Glutamine (Glu-urea-Gln) and Glu-urea-Asparagine (Glu-urea-Asn) were successfully synthesized, and their structures were confirmed to be as desired using nuclear magnetic resonance spectroscopy and mass spectrometry. An affinity assay was performed to detect the affinity between the various compounds and PSMA expressed from the prostate cancer LNCap cell line. Glu-urea-Gln had the highest affinity to PSMA, followed by Glu-urea-Asn, Glu-urea-Orn and Glu-urea-Lys. In conclusion, the present study demonstrated that Glu-urea-R specifically binds PSMA expressed in the LNCap cell line and inhibits its activity.

Testing small molecule analogues of the Acanthocheilonema viteae immunomodulator ES-62 against clinically relevant allergens.

Summary ES‐62 is a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae that protects against ovalbumin (OVA)‐induced airway hyper‐responsiveness in mice by virtue of covalently attached anti‐inflammatory phosphorylcholine (PC) residues. We have recently generated a library of small molecule analogues (SMAs) of ES‐62 based around its active PC moiety as a starting point in novel drug development for asthma and identified two compounds – termed 11a and 12b – that mirror ES‐62's protective effects. In this study, we have moved away from OVA, a model allergen, to test the SMAs against two clinically relevant allergens – house dust mite (HDM) and cockroach allergen (CR) extract. We show that both SMAs offer some protection against development of lung allergic responses to CR, in particular reducing eosinophil infiltration, whereas only SMA 12b is effective in protecting against eosinophil‐dependent HDM‐induced allergy. These data therefore suggest that helminth molecule‐induced protection against model allergens may not necessarily translate to clinically relevant allergens. Nevertheless, in this study, we have managed to demonstrate that it is possible to produce synthetic drug‐like molecules based on a parasitic worm product that show therapeutic potential with respect to asthma resulting from known triggers in humans.

Deficiency of the TLR4 analogue RP105 aggravates vein graft disease by inducing a pro-inflammatory response.

Venous grafts are often used to bypass occlusive atherosclerotic lesions; however, poor patency leads to vein graft disease. Deficiency of TLR4, an inflammatory regulator, reduces vein graft disease. Here, we investigate the effects of the accessory molecule and TLR4 analogue RadioProtective 105 (RP105) on vein graft disease. RP105 deficiency resulted in a 90% increase in vein graft lesion area compared to controls. In a hypercholesterolemic setting (LDLr−/−/RP105−/− versus LDLr−/− mice), which is of importance as vein graft disease is usually characterized by excessive atherosclerosis, total lesion area was not affected. However we did observe an increased number of unstable lesions and intraplaque hemorrhage upon RP105 deficiency. In both setups, lesional macrophage content, and lesional CCL2 was increased. In vitro, RP105−/− smooth muscle cells and mast cells secreted higher levels of CCL2. In conclusion, aggravated vein graft disease caused by RP105 deficiency results from an increased local inflammatory response.

N-Alkyl Interstitial Spacers and Terminal Pendants Influence the Alkaline Stability of Tetraalkylammonium Cations for Anion Exchange Membrane Fuel Cells

Current performance targets for anion exchange membrane (AEM) fuel cells call for greater than 95% alkaline stability for 5000 h at temperatures of up to 120 °C. Using this target temperature of 120 °C, we provide an incisive 1H nuclear magnetic resonance-based alkaline degradation method to identify the degradation products of n-alkyl spacer tetraalkylammonium cations in various AEM polymers and small molecule analogues. The operative alkaline degradation mechanisms and rates on benzyltrimethylammonium-, n-alkyl interstitial spacer-, and n-alkyl terminal chain-cations are compared in several architectures. Our findings indicate that benzyltrimethylammonium and n-alkyl terminal pendant cations are significantly more labile than an n-alkyl interstitial spacer cation. Additionally, we found that the alkaline stability of an n-alkyl interstitial spacer cation is enhanced when it is combined with an n-alkyl terminal pendant. At 120 °C, an inverse trend was observed in the overall stability of AEM poly(styrene...

Improved Hierarchical Ordering in Supramolecules via Symmetrically Bifunctionalized Organic Semiconductor

Block copolymer (BCP)-based supramolecular systems provide a versatile approach to manipulate functional structures spanning several nanometers to macroscopic length scales. Most studies to date focused on supramolecules containing asymmetrically end-functionalized small molecules, and it remains challenging to obtain molecular control over small molecule ordering within the BCP microdomain. Here we designed symmetrically end-functionalized bis-phenol quarterthiophene (BP4T) small molecules and systematically investigated how the end-group chemistry of the small molecules affects the supramolecular assembly process and the resulting morphology. Bifunctionalized small molecules can bridge two adjacent polymer blocks and lead to macroscopically aligned hierarchical assemblies at much higher degree of ordering than previously observed for asymmetrically functionalized small molecule analogues. The supramolecular morphology is very sensitive to the stoichiometry between the BP4T and polymer repeat unit because of the specific molecular organization within BCP microdomain. Furthermore, similar thermoresponsiveness of supramolecule, i.e., ∼40% change in the supramolecular periodicity during the heating and cooling cycles, can be obtained at BP4T loading stoichiometry of 0.5, much smaller than that of asymmetrically functionalized small molecule. These results clearly demonstrate that supramolecular assemblies can be readily manipulated by engineering the small molecule chemistry. Present studies provide basic design principles and an effective route to fabricate well-defined hierarchical assemblies for functional and stimuli-responsive nanomaterials.