Low Molecular Analogues Research Articles

Comb-like polyelectrolytes with pyridinium and trimethylammonium cations: Micellar catalytic and antibacterial properties

Here we report of two different but related properties of comb-like polyelectrolytes, namely, poly-11-acryloyloxyundecylpyridinium bromide and poly-11-acryloyloxyundecyltrimethylammonium bromide. The micellar catalytic activity of polyelectrolytes in alkali hydrolyses reactions of 4-nitrophenyl ethers and their antibacterial activity against Escherichia coli and Staphylococcus aureus were the focus of this work. A comparative analysis on the declared properties of a comb-like polyelectrolyte vs monomer and a non-polymerizable surfactant were carried out. The influence of the ionic strength on the solubilization and the catalytic activity of comb-like polyelectrolytes were studied. The catalytic activity of comb-like polyelectrolytes is several times higher than that for low-molecular analogs. The largest differences are observed at low catalyst concentrations. Antibacterial activity of monomers and polymers against staphylococci and escherichia using drip method was revealed. Investigated polyelectrolytes have generally order of magnitude lower inhibitory concentrations in E. coli compared to their monomers. Only one of the polymers synthesized by us turned out to be active against staphylococci.

Low molecular weight heparan sulfate containing facial skin care for reducing inflammation and restoring aged-skin homeostasis.

Chronic exposure of the skin to environmental factors, including solar radiation and air pollution, promotes skin aging by inducing inflammation which damages the skin. Heparan sulfate (HS) is one of the glycosaminoglycans, which has a central role in modulating skin repair. In its appearance in the skin, HS is large and highly polar and therefore unable to penetrate the skin. As a component in a topical formulation, the modified to a low molecular weight heparan sulfate analog (LMW-HS) showed biological modulation activity. This review discusses the potential role of topical formulations containing LMW-HS in restoring aged-skin homeostasis and skin health. An expert panel of dermatologists who regularly treat clinical signs of facial photoaging explored the role of LMW-HS containing formulations for reducing inflammation and facial-aging signs. For this purpose, evidence from the conducted literature searches was used together with expert opinion and experience of the panel. Extrinsic factors contribute to skin aging through oxidative stress, stimulating inflammation involved in extracellular matrix degradation. Evidence showed that chemokines require heparan sulfate for their full range of functional activities during innate immunity. Studies showed the LMW-HS containing topical formulation to penetrate the skin within 48hours of once-daily application. LMW-HS used in the periorbital area improved discoloration and wrinkles at Week 2 with continuous improvement up to Week 12. The LMW-HS containing formulation showed improvements in skin condition when applied on photo-damaged skin, indicating its therapeutic potential.

Discovery and SAR of aryl hydroxy pyrimidinones as potent small molecule agonists of the GPCR APJ

This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response. A potent and low molecular weight aryl hydroxy pyrimidinone analog 30 was identified through optimization of an HTS hit and medicinal chemistry efforts to improve its properties.

The study of the effect of the low molecular analog of neuropeptide Y on behavioral reactions in rats

The study of the effect of the low molecular analog of neuropeptide Y on behavioral reactions in rats

Topical low molecular weight sulfated glycosaminoglycan analogs improve skin tightening and deep hydration in subjects with moderate to severe facial photodamage.

Topical low molecular weight sulfated glycosaminoglycan analogs improve skin tightening and deep hydration in subjects with moderate to severe facial photodamage.

Magnetic Resonance Imaging Reveals Distinct Roles for Tissue Transglutaminase and Factor XIII in Maternal Angiogenesis During Early Mouse Pregnancy.

The early embryo implantation is characterized by enhanced uterine vascular permeability at the site of blastocyst attachment, followed by extracellular-matrix remodeling and angiogenesis. Two TG (transglutaminase) isoenzymes, TG2 (tissue TG) and FXIII (factor XIII), catalyze covalent cross-linking of the extracellular-matrix. However, their specific role during embryo implantation is not fully understood. Approach and Results: For mapping the distribution as well as the enzymatic activities of TG2 and FXIII towards blood-borne and resident extracellular-matrix substrates, we synthetized selective and specific low molecular weight substrate analogs for each of the isoenzymes. The implantation sites were challenged by genetically modifying the trophoblast cells in the outer layer of blastocysts, to either overexpress or deplete TG2 or FXIII, and the angiogenic response was studied by dynamic contrast-enhanced-magnetic resonance imaging. Dynamic contrast-enhanced-magnetic resonance imaging revealed a decrease in the permeability of decidual vasculature surrounding embryos in which FXIII were overexpressed in trophoblast cell. Reduction in decidual blood volume fraction was demonstrated when either FXIII or TG2 were overexpressed in embryonic trophoblast cell and was elevated when trophoblast cell was depleted of FXIII. These results were corroborated by histological analysis. In this study, we report on the isoenzyme-specific roles of TG2 and FXIII during the early days of mouse pregnancy and further reveal their involvement in decidual angiogenesis. Our results reveal an important magnetic resonance imaging-detectable function of embryo-derived TG2 and FXIII on regulating maternal angiogenesis during embryo implantation in mice.Visual Overview: An online visual overview is available for this article.

Real-Time, in Vivo Correlation of Molecular Structure with Drug Distribution in the Brain Striatum Following Convection Enhanced Delivery.

The blood-brain barrier (BBB) represents a major obstacle in delivering therapeutics to brain lesions. Convection-enhanced delivery (CED), a method that bypasses the BBB through direct, cannula-mediated drug delivery, is one solution to maintaining increased, effective drug concentration at these lesions. CED was recently proven safe in a phase I clinical trial against diffuse intrinsic pontine glioma (DIPG), a childhood cancer. Unfortunately, the exact relationship between drug size, charge, and pharmacokinetic behavior in the brain parenchyma are difficult to observe in vivo. PET imaging of CED-delivered agents allows us to determine these relationships. In this study, we label different modifications of the PDGFRA inhibitor dasatinib with fluorine-18 or via a nanofiber-zirconium-89 system so that the effect of drug structure on post-CED behavior can accurately be tracked in vivo, via PET. Relatively unchanged bioactivity is confirmed in patient- and animal-model-derived cell lines of DIPG. In naïve mice, significant individual variability in CED drug clearance is observed, highlighting a need to accurately understand drug behavior during clinical translation. Generally, the half-life for a drug to clear from a CED site is short for low molecular weight dasatinib analogs that bare different charge; 1-3 (1, 32.2 min (95% CI: 27.7-37.8), 2, 44.8 min (27.3-80.8), and 3, 71.7 min (48.6-127.6) minutes) and is much longer for a dasatinib-nanofiber conjugate, 5, (42.8-57.0 days). Positron emission tomography allows us to accurately measure the effect of drug size and charge in monitoring real-time drug behavior in the brain parenchyma of live specimens.

PAMAM Dendrimers Attached to Collagen via a Malondialdehyde Linker

AbstractFunctionalization of polyamidoamine dendrimers (PAMAM) for use as macromolecular drug carriers with aldehydes was performed using aminoacetaldehyde dimethylacetal (AADA) and malondialdehyde (MDA). AADA was used to obtain low molecular weight product upon reaction with dimethyl succinate and PAMAM G‐0.5. The structure of succinate bis‐(dimethylacetal)acetamide was elucidated by X‐ray crystallography. This product, as well as the product of condensation of PAMAM G‐0.5 with AADA, were resistant to hydrolysis. MDA reacted with iso‐butylamine and polyamidoamine PAMAM G0 dendrimers to give 3‐[N‐(2‐methylpropyl)amino]prop‐2‐enal and PAMAM G0 with four arms ending with prop‐2‐enal groups. The compounds were characterized by NMR, MS and/or elemental analysis. PAMAM G3 was also converted to aldehyde‐terminated dendrimer with excess MDA, however, the product was water insoluble. The low molecular weight water soluble analogue prop‐2‐enal terminated PAMAM G0 dendrimer was tested for toxicity on normal human fibroblasts and glioblastoma cell cultures. The toxicity of prop‐2‐enal terminated PAMAM G0 was comparable with that of amine ending PAMAM G0. Finally, fluorescein‐labeled PAMAM G3 was covalently attached to a collagen scaffold via a MDA linker as demonstrated by confocal microcopy. This rapid method of covalent attachment of PAMAM‐drug conjugates to MDA‐activated collagen opens new pathways for delivery of drugs into tissue.

Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer

P-glycoprotein (P-gp) is a drug transporter that effluxes chemotherapeutic drugs and is implicated in the development of resistance of cancer cells to chemotherapeutic drugs. To date, no drug has been approved to inhibit P-gp and restore chemotherapy efficacy. Moreover, majority of the reported inhibitors have high molecular weight and complex structures, making it difficult to understand the basic structural requirement for P-gp inhibition. In this study, two structurally simple, low molecular weight piperine analogs Pip1 and Pip2 were designed and found to better interact with P-gp than piperine in silico. A one step, acid-amine coupling reaction between piperic acid and 6,7-dimethoxytetrahydroisoquinoline or 2-(3,4-dimethoxyphenyl)ethylamine afforded Pip1 and Pip2, respectively. In vitro testing in drug resistant P-gp overexpressing KB (cervical) and SW480 (colon) cancer cells showed that both analogs, when co-administered with vincristine, colchicine or paclitaxel were able to reverse the resistance. Moreover, accumulation of P-gp substrate (rhodamine 123) in the resistant cells, a result of alteration of the P-gp efflux, was also observed. These investigations suggest that the natural product analog – Pip1 ((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H)-yl)penta-2,4-dien-1-one) – is superior to piperine and could inhibit P-gp function. Further studies are required to explore the full potential of Pip1 in treating drug resistant cancer.

Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors

The FLT3 kinase represents an attractive target to effectively treat AML. Unfortunately, no FLT3 targeted therapeutic is currently approved. In line with our continued interests in treating kinase related disease for anti-FLT3 mutant activity, we utilized pioneering synthetic methodology in combination with computer aided drug discovery and identified low molecular weight, highly ligand efficient, FLT3 kinase inhibitors. Compounds were analyzed for biochemical inhibition, their ability to selectively inhibit cell proliferation, for FLT3 mutant activity, and preliminary aqueous solubility. Validated hits were discovered that can serve as starting platforms for lead candidates.

Driving Forces in Pressure-Induced Protein Transitions.

The molecular mechanisms underlying pressure-induced protein denaturation can be analyzed based on the pressure-dependent differences in the apparent volume occupied by amino acids inside the protein and when exposed to water in an unfolded conformation. This chapter presents a volumetric analysis of the peptide group and the 20 naturally occurring amino acid side chains in the interior of the native state, the micelle-like interior of the pressure-induced denatured state, and in the unfolded conformation modeled by low-molecular analogs of proteins. The transfer of a peptide group from the protein interior to water becomes increasingly favorable as pressure increases. This observation classifies solvation of peptide groups as a major driving force in pressure-induced protein denaturation. Polar side chains do not appear to exhibit significant pressure-dependent changes in their preference for the protein interior or solvent. The transfer of nonpolar side chains from the protein interior to water becomes more unfavorable as pressure increases. An inference can be drawn that a sizeable population of nonpolar side chains remains buried inside a solvent-inaccessible core of the pressure-induced denatured state. At elevated pressures this core, owing to the absence of structural constraints, may become packed almost as tightly as the interior of the native state. The presence and partial disappearance of large intraglobular voids is another driving force facilitating pressure-induced protein denaturation. Volumetric data presented here have implications for the kinetics of protein folding and shed light on the nature of the folding transition state ensembles.

Specific interactions of low molecular weight analogues of carnauba wax and polyethylene glycol binders of ceramic injection moulding feedstocks

This paper is devoted to understanding of the molecular interactions between components of Ceramic Injection Moulding (CIM) binders – carnauba wax (CW) and polyethylene glycol (PEG). Due to the complexity of interactions mechanisms the binders were substituted by their basic low-molecular analogues, which were then investigated using the combination of FTIR and calorimetry. Calorimetric analysis derived the self-interaction energies and association energies for the respective pairs. FTIR spectra were collected in the range of 400 to 4000cm−1 for the analogue blends, where the shift of C=O and O–H stretch bounding peaks were assumed as the evidence of the presence of the partial interactions between the components. Combining obtained data a linear relation of these two independent analyses was found. The results proved reliable quantification of interactions between CW and PEG low molecular substitutes implying the partial miscibility of the respective polar polymers.

Inhibitors of Serine Proteinases from Blood Coagulation Cascade - View on Current Developments

The importance of Factor Xa and thrombin in thrombosis and haemostasis is widely appreciated in the last years. This understanding logically leads to the concept of Factor Xa and thrombin inhibition as viable and attractive target for the antithrombotic therapy. The following review collects and summarizes information on numerous anticoagulant peptides, proteins, chemical compounds and low molecular weight fragment analogues of natural peptides isolated from hematophagous. Unfortunately, not much data from clinical trials of direct Factor Xa and thrombin inhibitors is available in the present moment. The current information reveals that Factor Xa and thrombin inhibition is a promising approach for prevention and treatment of hemostatic impairments. The synthesis of a low molecular weight synthetic peptide mimetics could be a key point in the fight against many diseases related to haemostatic disorders.

A Novel Pathway of Photoinduced Decomposition of Sphingolipids

A possibility of a novel photodestruction process has been shown for sphingolipids and their low-molecular analogues, including the stage of Norrish Type-I decomposition of excited molecules of the starting compounds followed by fragmentation of nitrogen-centered radicals via rupture of the C-C and O-H bonds. Realization of such transformation during photolysis of ceramide, sphingomyelin and galactocerebroside results in formation of 2-hexadecenal, which possess a wide spectrum of biological activity.

Interfacial concentrations of chloride and bromide in zwitterionic micelles with opposite dipoles: Experimental determination by chemical trapping and a theoretical description

Interfacial concentrations of chloride and bromide ions, with Li+, Na+, K+, Rb+, Cs+, trimethylammonium (TMA+), Ca2+, and Mg2+ as counterions, were determined by chemical trapping in micelles formed by two zwitterionic surfactants, namely N-hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (HPS) and hexadecylphosphorylcholine (HDPC) micelles. Appropriate standard curves for the chemical trapping method were obtained by measuring the product yields of chloride and bromide salts with 2,4,6-trimethyl-benzenediazonium (BF4) in the presence of low molecular analogs (N,N,N-trimethyl-propane sulfonate and methyl-phosphorylcholine) of the employed surfactants. The experimentally determined values for the local Br− (Cl−) concentrations were modeled by fully integrated non-linear Poisson Boltzmann equations. The best fits to all experimental data were obtained by considering that ions at the interface are not fixed at an adsorption site but are free to move in the interfacial plane. In addition, the calculation of ion distribution allowed the estimation of the degree of ion coverage by using standard chemical potential differences accounting for ion specificity.

A study on hybrid oligomeric type II photoinitiator

AbstractPreparing tailor-made hybrid photoinitiator (PI) for specific applications continues to gain momentum. The hybrid PIs comprising both H-abstraction chromophore and coinitiator moiety are the candidate materials with energy-saving and environment-protection in the photo-curing field. So two oligomeric photoinitiators (OMKs) containing benzophenone (BP) and aliphatic tert-amines chromophore in the main-chain (OMK-2) or side-chain (OMK-1) were synthesized and characterized respectively. Photophysical investigation showed that the absorption maxima of OMKs were around 340 nm, red shifted about 5-10 nm compared to BP. Their initiation efficiencies were found to be higher than that of BP and 4,4’-bis(dimethylamino)benzophenone(MK) respectively. The reaction proceeds via a simple electron-transfer/proton-transfer mechanism. Dynamic NMR data reveal that H-abstraction reacts predominantly via alpha H of aliphatic tertamines, as might be expected on the basis of the lower ionization potential and bond dissociation energy of aliphatic amines compared to aromatic amines. The reaction mechanism of H-abstraction was confirmed by using radical scavenger 2,2,6,6-tetramethylpiperidin-1-oxy(TEMPO), which acts as a probe under photolysis reaction conditions. The volatility and migration were tested under simulated conditions, the result show that OMKs exhibited very low volatility and significantly reduced migration compared to the low molecular analogs. Results showed that the OMKs are the promising candidate as higher efficient PIs with low volatile organic compounds (VOCs) emission and reduced migration. They are suitable for environmental-friendly formulations.

Viscoelastic Sensing of Conformational Changes in Plasminogen Induced upon Binding of Low Molecular Weight Compounds

Plasminogen is a precursor to the fibrinolytic enzyme plasmin and is known to undergo large conformational changes when subjected to low molecular lysine analogues such as tranexamic acid (TA) or ε-amino-n-caproic acid (EACA). Here, we demonstrate how well-controlled surface immobilization of biotinylated plasminogen allows for monitoring of the interaction between TA and EACA with plasminogen. The interaction was studied by the quartz crystal microbalance with dissipation monitoring (QCM-D) technique as well as by surface plasmon resonance (SPR) based sensing. QCM-D measures changes in acoustically coupled mass (by detection of changes in the resonance frequency of the crystal, Δf) and is sensitive to changes in mass adsorbed on the sensor surface including how liquid medium is associated with this material. Through the dissipation factor (i.e., changes in the energy dissipation of the crystal oscillation, ΔD), QCM-D is also sensitive to the viscoelastic properties of material adsorbed to the sensor surface. Upon binding of TA or EACA, changes in the plasminogen structure were recorded as distinct, although small, ΔD responses which were used to determine affinity constants. By comparing native and truncated plasminogen, we conclude that the observed dissipation shifts were caused by conformational changes in the proteins leading to changes in the viscoelastic properties of the protein layer on the surface. These results demonstrate a novel application of the QCM-D technique, paving the way for a whole new approach to screening of this target for novel lead structures.

Design, Synthesis and Structure–Activity Relationship of New 109–116 Fragment Analogues of Antistasin and Ghilantens

A series of new low molecular weight peptide inhibitors, antistasin and ghilantens fragment analogues was designed and synthesized by manual solid phase peptide synthesis. These compounds only differ either by the amino acid placed in position 109 (different basic amino acids) and 115 position (Val or Ile) or 116 position Pro (as free acid or as amide). The anticoagulant activity of the different synthesized peptide mimetics was measured. Further the IC50 was obtained by means of Activated Partial Thromboplastin Time measurement. Using Mihaelis–Menthen equation the mixed type of inhibition toward thrombin and Factor Xa is determined.

Inhibitors of slit protein interactions with the heparan sulphate proteoglycan glypican‐1: Potential agents for the treatment of spinal cord injury

1. The heparan sulphate proteoglycan glypican-1 is a major high-affinity ligand of the Slit proteins. 2. Messenger RNA for both Slit-2 and glypican-1 is strongly upregulated and coexpressed in the reactive astrocytes of injured adult brain, suggesting a possible function of Slit proteins and glypican-1 in the adult central nervous system as significant components of the inhibitory environment that prevents axonal regeneration after injury. 3. Based on the hypothesis that adverse effects on axonal regeneration may be due to a glypican-Slit complex or the retention of glypican-binding C-terminal proteolytic processing fragments of Slit at the injury site, we used ELISA to examine a number of small molecules and low molecular weight heparin analogues for their ability to inhibit glypican-Slit interactions. 4. Our studies have led to the identification of several potent inhibitors with a favourable therapeutic profile that can now be tested in a spinal cord injury model. Among the most promising of these are a low molecular weight heparin produced by periodate oxidation and having no significant anticoagulant activity, the chemically sulphonated yeast-derived phosphomannan PI-88 and a number of randomly derivatized water-soluble sulphated dextrans.

Modulation of the Mitochondrial Cytochrome bc1 Complex Activity by Chromanols and Related Compounds

Tocopherols (alpha-, beta-, gamma-, and delta-Toc) and tocopheryl quinones (alpha-, beta-, gamma-, and delta-TQ) were recently suggested to modulate mitochondrial electron transfer in mammals. Intriguingly, Tocs and stigmatellin, a potent inhibitor of the mitochondrial cytochrome (cyt) bc(1) complex, possess a common structural feature: the chroman core. Therefore, we studied the interference of Tocs as well as synthetic model compounds (low molecular weight TQ analogues and tetramethyl chromanones) at the mitochondrial cyt bc(1) complex. Enzymatic experiments revealed that besides the inhibitor stigmatellin, among natural vitamin E-related derivatives, gamma-TQ/delta-TQ and, among synthetic compounds, TMC2O (6-hydroxy-4,4,7,8-tetramethyl-chroman-2-one) were most effective in decreasing the cyt bc(1) activities. Stopped-flow photometric and low-temperature electron paramagnetic resonance spectroscopic experiments showed for TMC2O an inhibition of electron transfer to cyt c(1) and a modulation of the environment of the Rieske iron-sulfur protein (ISP). Docking experiments suggest a binding interaction of the 6-OH group and 1-O atom/2-C( horizontal lineO) group of TMC2O with Glu-271 (cyt b) and His-161 (ISP) in the cyt bc(1) complex, respectively. This binding pose is similar but not identical to the potent inhibitor stigmatellin. The data suggest that chroman-2-ones are possible templates for modulatory molecules for the cyt bc(1) target.