Low Molecular Weight Oligomers Research Articles

Controlled organocatalyzed d,l-lactide ring-opening polymerizations: synthesis of low molecular weight oligomers.

A systematic approach to the synthesis of organocatalyzed oligo(d,l-lactide) demonstrates that choice of initiator, catalytic ratio, and reaction time yields well-controlled oligomers. Ring-opening polymerization of d,l-lactide with the initiator α-methyl propargyl alcohol, a secondary alcohol, used in excess of 4-dimethylaminopyridine catalyst mitigates cyclicization, transesterification, and catalyst-initiated side reactions. This approach enables the design of uniform lactide oligomers for controlled release applications, such as delivery systems for drugs, prodrugs, and molecular sensors.

Optimizing the Extraction of Procyanidins Oligomers through Decamer

Author(s): Mitchell, Alyson E; Robertson, Danielle; Koh, Eunmi | Abstract: The extraction of procyanidins from a food is influenced by food matrix, extraction solvent, sample particle size, sample to solvent ratio, as well as other factors. Many of these parameters can easily be controlled in a laboratory to improve or target the extraction of low or high molecular weight oligomers. As various oligomers have differing biological and functional qualities, preferred extraction of one group of oligomers may be a desired target. In the following study, we describe the influence of solvent polarity and composition, solvent-solute ratio and particle size on the extraction of procyanidin oligomers monomer through decamer. The solvents evaluated included dimethyl sulfoxide (DMSO), acetone and methanol.

Novel processing approach to polymer‐derived ceramic matrix composites

AbstractThe rheological properties of commercially available polycarbosilane, SMP‐10, were analyzed as a function of temperature, to guide development of thermal treatment processes for the improved yield and functionality of polymer ceramic precursors. The curing onset temperature for SMP‐10 was determined to be as low as 100°C for a heating rate of 1°C/min enabling a heat treatment process at 90°C, where low molecular weight oligomers volatilize from the liquid precursor prior to curing. By driving off the low molecular weight oligomers before fabrication of a composite, the mass yield of SMP‐10, from a room temperature liquid state was increased from 77% to 83%. The development of B‐staging processes, or a semicure of SMP‐10, were also demonstrated. B‐staging processes were then applied to polymer infiltration and pyrolysis processing and compared with traditional wet layup CMC processing. It was determined that B‐staging processes did not adversely affect ceramic matrix composite fabrication. B‐staged processing methods were determined to result in less waste, allow ply‐by‐ply control of matrix compositions, and enable time independent processing when compared to traditional wet layup processing methods.

Homoleptic Zr and Hf Complexes of Imino/Bis(imino)phenoxide Scaffolds: Synthesis, Structural Characterization and Their Catalytic Activity in the ROP of Cyclic Esters

AbstractA series of homoleptic iminophenoxide and bis(imino)phenoxide supported Zr and Hf complexes 1–10 has been synthesized and characterized by NMR, mass spectrometry and elemental analysis. Structural analysis of the selected complexes by single crystal X‐ray diffraction method revealed that the complexes are monomeric in their solid state with distorted dodecahedral geometries. These complexes are found to be potential single‐site catalysts for ring‐opening polymerization (ROP) of lactide (LA) and ϵ‐caprolactone (ϵ‐CL) and afforded controlled molecular weight (Mn) polyesters with narrow molecular weight distributions (MWDs) of 1.12‐1.28. Kinetic studies revealed that the polymerization rate have shown to be first order dependency on lactide. The low molecular weight oligomer analysis imparted that the polymerization proceeds through the coordination‐insertion mechanism.

Fatty Acid Concentration and Phase Transitions Modulate A\u03b2 Aggregation Pathways

Aggregation of amyloid β (Aβ) peptides is a significant event that underpins Alzheimer disease (AD) pathology. Aβ aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD and hence, there is increasing interest in understanding their formation and behavior. Aggregation is a nucleation-dependent process in which the pre-nucleation events are dominated by Aβ homotypic interactions. Dynamic flux and stochasticity during pre-nucleation renders the reactions susceptible to perturbations by other molecules. In this context, we investigate the heterotypic interactions between Aβ and fatty acids (FAs) by two independent tool-sets such as reduced order modelling (ROM) and ensemble kinetic simulation (EKS). We observe that FAs influence Aβ dynamics distinctively in three broadly-defined FA concentration regimes containing non-micellar, pseudo-micellar or micellar phases. While the non-micellar phase promotes on-pathway fibrils, pseudo-micellar and micellar phases promote predominantly off-pathway oligomers, albeit via subtly different mechanisms. Importantly off-pathway oligomers saturate within a limited molecular size, and likely with a different overall conformation than those formed along the on-pathway, suggesting the generation of distinct conformeric strains of Aβ, which may have profound phenotypic outcomes. Our results validate previous experimental observations and provide insights into potential influence of biological interfaces in modulating Aβ aggregation pathways.

Elucidation of insulin assembly at acidic and neutral pH: Characterization of low molecular weight oligomers.

Deficiency in insulin secretion and function that characterize type 2 diabetes often requires administration of extraneous insulin, leading to injection-site amyloidosis. Insulin aggregation at neutral pH is not well understood. Although oligomer formation is believed to play an important role, insulin oligomers have not been fully characterized yet. Here, we elucidate similarities and differences between in vitro insulin aggregation at acidic and neutral pH for a range of insulin concentrations (2.5-100 μM) by using kinetic thioflavin T fluorescence, circular dichroism, atomic force and electron microscopy imaging. Importantly, we characterize the size distribution of insulin oligomers at different assembly stages by the application of covalent cross-linking and gel electrophoresis. Our results show that at the earliest assembly stage, oligomers comprise up to 40% and 70% of soluble insulin at acidic and neutral pH, respectively. While the highest oligomer order increases with insulin concentration at acidic pH, the opposite tendency is observed at neutral pH, where oligomers up to heptamers are formed in 10 μM insulin. These findings suggest that oligomers may be on- and off-pathway assemblies for insulin at acidic and neutral pH, respectively. Agitation, which is required to induce insulin aggregation at neutral pH, is shown to increase fibril formation rate and fibrillar mass both by an order of magnitude. Insulin incubated under agitated conditions at neutral pH rapidly aggregates into large micrometer-sized aggregates, which may be of physiological relevance and provides insight into injection-site amyloidosis and toxic pulmonary aggregates induced by administration of extraneous insulin.

Direct Arylation Polycondensation of 2,5-Dithienylsilole with a Series of Difluorobenzodiimine-Based Electron Acceptors

This paper describes the use of direct arylation polymerization (DArP) reaction to synthesize three new 2,5-dithienylsilole polymers with a series of difluorobenzodiimine-based electron acceptors: 5,6-difluoro[2,1,3]benzothiadiazole (DFBT), 5,6-difluoro[2,1,3]benzoselenadiazole (DFBSe), and 5,6-difluoro[2,1,3]benzotriazole (DFBTA). The Stille cross-coupling polycondensation reaction was performed to confirm the structural quality of the polymers; however, only low molecular weight oligomers were obtained. This result demonstrates the power of the DArP method to prepare polymers containing strong electron-deficient monomers. During our investigation, it was found that Fagnou’s condition did not produce polymers, whereas the condition reported by Ozawa and co-workers gave polymers with moderate molecular weights. This is the first known example of the synthesis of 2,5-dithienylsilole-containing polymers by the DArP. Our polymers have reduced band gaps (<2.0 eV), and P1 provided hole mobility values in the r...

Additive and Aging Effects on Methylalumoxane Oligomers

In the presence of the weak donor octamethyltrisiloxane (OMTS), methylalumoxane (MAO) undergoes ionization through [Me2Al]+ abstraction. The [Me2Al·OMTS]+[(MeAlO)x(Me3Al)yMe]− ion pairs formed can conveniently be studied by electrospray ionization mass spectrometry. The anion distribution changes with OMTS:Al ratio, with low molecular weight (MW) anions forming at high ratios due to oligomer degradation. Monitoring of room-temperature aging shows that MAO oligomers of low MW are slowly and systematically converted to species with higher MW through addition of (MeAlO) units, and intermediate oligomers are observed and assigned. This process occurs at room temperature but does not occur significantly over a period of months at low temperatures. Computational investigations of these species show large cagelike clusters with four-coordinate Al and three-coordinate O. All neutral structures have sites that could readily give up [Me2Al]+ to form the observed ions, though sites that can lose [Me2Al]+ without lea...

Analyzing Amyloid Beta Aggregates with a Combinatorial Fluorescent Molecular Sensor.

Different amyloid beta (Aβ) aggregates can be discriminated by a combinatorial fluorescent molecular sensor. The unique optical fingerprints generated by the unimolecular analytical device provide a simple means to differentiate among aggregates generated from different alloforms or through distinct pathways. The sensor has also been used to track dynamic changes that occur in Aβ aggregation states, which result from the formation of low molecular weight oligomers, high molecular weight oligomers, protofibrils, and fibrils.

Crowding Agents Direct Amyloid Beta into Membrane-Active Oligomers

Oligomeric Amyloid-β (1-42) peptides are considered to be the most toxic species connected to the occurrence of Alzheimer disease. However, not all aggregation conditions promote oligomer formation in vitro, raising the question whether oligomer formation in vivo also requires a specific suitable cellular environment. In this study we find that the presence of osmolytes such as glucose and sucrose Aβ (1-42) strongly favors oligomer formation. We characterized oligomers by dynamic light scattering, atomic force microscopy, immuno transmission electron microscopy and fluorescence cross correlation spectroscopy techniques. We found that Aβ (1-42) spontaneously and rapidly forms low molecular weight oligomers in the presence of sugars. Slightly acidic pH (6.7-7) greatly favors oligomer formation when compared to the extracellular physiological pH (7.4). Circular dichroism demonstrated that in presence of crowding agents Aβ (1-42) oligomers did not adopt a β-sheet structure, whereas in the absence of these agents Aβ (1-42) formed β-sheets. Unstructured oligomeric Aβ (1-42) interacted with membrane bilayers of giant unilamellar vesicles (GUV). We recently found that interaction with neuronal membranes initiates aggregation of Aβ (1-42) and neuronal uptake. Our data suggest that crowding agents in the extracellular space facilitate the formation of membrane-active Aβ (1-42) oligomers.

Doubly Dynamic Self‐Healing Materials Based on Oxime Click Chemistry and Boronic Acids

The dynamic covalent characteristics of oxime and boronate ester bonds have been explored. A small excess of a competing aldehyde under acidic conditions resulted in oxime polymer degradation from high molecular weights (30 kDa) to low molecular weight oligomers (2.2 kDa). The dynamic nature of oxime bonds imparts oxime cross-linked hydrogels with self-healing properties and the incorporation of phenyl boronic acid groups into the hydrogel network provides a platform for hydrogel functionalization. The addition of a polyphenol (tannic acid) proves a facile means to incorporate a second, dynamic covalent cross-linking network through boronate ester formation which, owing to the increase in the degree of cross-linking, is found to be nearly double the hydrogel strength (storage modulus increased from 4.6 to 8.5 kPa). Finally, the tannic acid cross-linking network is selectively degraded returning the hydrogel storage modulus to its initial value and providing a means for the synthesis of materials with tunable mechanical properties.

Strain-specific Fibril Propagation by an A\u03b2 Dodecamer

Low molecular weight oligomers of amyloid-β (Aβ) have emerged as the primary toxic agents in the etiology of Alzheimer disease (AD). Polymorphism observed within the aggregation end products of fibrils are known to arise due to microstructural differences among the oligomers. Diversity in aggregate morphology correlates with the differences in AD, cementing the idea that conformational strains of oligomers could be significant in phenotypic outcomes. Therefore, it is imperative to determine the ability of strains to faithfully propagate their structure. Here we report fibril propagation of an Aβ42 dodecamer called large fatty acid-derived oligomers (LFAOs). The LFAO oligomeric strain selectively induces acute cerebral amyloid angiopathy (CAA) in neonatally-injected transgenic CRND8 mice. Propagation in-vitro occurs as a three-step process involving the association of LFAO units. LFAO-seeded fibrils possess distinct morphology made of repeating LFAO units that could be regenerated upon sonication. Overall, these data bring forth an important mechanistic perspective into strain-specific propagation of oligomers that has remained elusive thus far.

Formation of low molecular weight oligomers from chitin and chitosan stimulated by plasma-assisted processes

The controlled degradation of solid powders of chitin and chitosan stimulated by electron-beam plasma (EBP) was experimentally studied. Crab shell chitin and chitosan were used as original substances. The non-equilibrium low temperature EBP was generated by injecting an electron beam into a gaseous medium. Chitooligosaccharides with Mw=800–2000Da and polydispersion 1.5–2.5 were formed due to the EBP-treatment of chitin and chitosan. The β-1,4 glycosidic bounds in original polymers degrade under the action of active oxygen species produced in the EBP. Low molecular weight products of chitosan inhibited the growth of various yeast-like and filamentous fungi at minimum inhibitory concentration 500mcg/ml. By optimizing the treatment conditions and using special techniques of reaction volume formation the 95% yield of chitooligosaccharides was obtained after 2min whereas the conventional chemical hydrolysis usually takes several days. The EBP-stimulated hydrolysis is promising for effective polysaccharides degradation and can be competitive with traditional technologies.

Equilibrium condition and stabilization kinetics of lactic acid oligomers in aqueous solutions

Lactic acid is one of the most important compounds in the field of bio‐renewable chemicals. Lactic acid is present in nature but can also be produced by chemical synthesis or by fermentation of biomass. It can be used as raw material for the production of biodegradable and environmentally friendly polymers or copolymers, such as poly lactic acid (PLA).In this work, the equilibrium distribution of monomer and low molecular weight oligomers of lactic acid in aqueous solutions at different overall concentrations of lactic acid (from 0.09 g/g to 0.94 g/g) and temperatures (423 K and 453 K), was investigated.In addition, a kinetic study of monomer and oligomer esterification reactions, of a lactic acid aqueous solution at about 0.09 g/g, was carried out at 423, 433, 443, and 453 K. The values of the kinetic constants were successfully correlated through Arrhenius’ law.

In vitro monitoring of amyloid β-peptide oligomerization by Electrospray differential mobility analysis: An alternative tool to evaluate Alzheimer's disease drug candidates

Alzheimer's disease (AD) is a neurodegenerative disorder linked to protein aggregation, like more than twenty other human pathologies. One major protein incriminated in AD is the 42-residue amyloid-β peptide (Aβ1–42) which aggregates to form neurotoxic oligomers and fibrils. While, low molecular weight oligomers have been evidenced as neurotoxic species, only scarce methods raise the challenge to monitor the beginning of the aggregation process, called oligomerization. We propose here an innovative and fast monitoring of the time-dependent Aβ1–42 oligomerization pattern by electrospray differential mobility analysis (ES-DMA). We developed a non-denaturing method based on ES-DMA to afford a real-time and direct characterization of the early, metastable and neurotoxic species. This technique provided their size distribution over time. At the beginning of the in vitro oligomerization process of Aβ1–42, the size distribution is characterized by two populations with modal diameters around 3.5 and 4nm, corresponding to Monomer and Small oligomers. After few hours, larger species around 10nm are observed. The results were correlated to those obtained by capillary electrophoresis. We also demonstrated the ability of our method to evaluate Aβ1–42 kinetics modulators. Thereby, ES-DMA provides new insights on Aβ1–42 oligomerization in the presence of sugar-based peptidomimetic analogs which were recently described as modulators of Aβ1–42 self-assembly and neurotoxicity inhibitors.

Large Soluble Oligomers of Amyloid β-Protein from Alzheimer Brain Are Far Less Neuroactive Than the Smaller Oligomers to Which They Dissociate.

Oligomers of amyloid β-protein (oAβ) are tought to play an important role in Alzheimer's disease (AD), but there is confusion and controversy about what types and sizes of oligomers have disease-relevant activity. Using size-exclusion chromatography and three distinct measures of bioactivity, we show that the predominant forms of Aβ in aqueous extracts of AD brain are high molecular weight (HMW) and relatively inactive. Importantly, under certain conditions, the abundant HMW oAβ can dissociate into low molecular weight species, and these low molecular weight oligomers are significantly more bioactive on synapses and microglia than the HMW species from which they are derived. We conclude that conditions that destabilize HMW oAβ or retard the sequestration of smaller, more bioactive components are important drivers of Aβ toxicity.

Fabrication and Characterization of Polyaniline Based Nano-Composite with Their Physico-Chemical and Environmental Applications

A series of organic–inorganic conducting nano polymer-matrix composite cation-exchanger have been synthesized via sol–gel method and characterized through FTIR, XRD, TGA-DTA, SEM, and TEM studies. The structural studies confirm the semi-crystalline nature of the material but the morphology of the exchanger gets changed after incorporation of inorganic moiety. The particle size of the nano-composite was found to be 19.2 nm. The observed band gap for the different samples was found to be in the range of 3.70–4.61 eV which shows that nano-composite material covers semiconducting range but the resistivity of samples is highly dependent on the percentage of inorganic part in the composite. Further the oxidative degradation of the polymer backbone begins after the removal of trapped water successively followed by dopant and low molecular weight oligomers. During the antimicrobial screening, the nano-composite was found to be active against different strains of bacteria and fungi. Gel electrophoresis and molecular docking studies were carried out to check the interaction and mechanism of inhibition of microbial growth, respectively by studying the effect of the nano-composite with DNA-Topoisomerase-1.

Structural characterization of allomelanin from black oat

The brown to black coloration found in plants is due to the melanins, which have been relatively poorly investigated among the plant pigments. The aim of this work was to study the dark pigment extracted from the black oat hull with respect to composition and structure. Ultraviolet–visible (UV–Vis) spectroscopy, electron paramagnetic resonance (EPR) spectroscopy, matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) and Fourier transform infrared (FT-IR) spectroscopy were applied for the characterization of the pigment. UV–Vis spectroscopy revealed that the extracted material displays a broadband, structureless absorption profile a common feature of melanins. MALDI-TOF MS measurements demonstrated that oat melanin is a homopolymer built up from p-coumaric acid and consists mainly of low molecular weight (527–1499 Da) oligomers of 3–9 monomer units. The tetramer oligomer proved to be dominant. The results of the FT-IR analysis indicated that oat melanin is a fully conjugated aromatic system containing tetrasubstituted aromatic rings linked by CC coupling. The in vitro preparation of melanin from p-coumaric acid by horseradish peroxidase was performed for comparison. The resulting polymer consisted of oligomers of 4–9 monomer units similarly to those in oat melanin. However, the building blocks proved to be connected to each other via COC linkages in contrast with the CC linkages in oat melanin.

Melt polycondensation approach for reduction degradable helical polyester based on l‐cystine

ABSTRACTMelt polycondensation approach is developed for new classes of reduction responsive disulfide containing functional polyesters based on l‐cystine amino acid resources under solvent free process. l‐Cystine was converted into multi‐functional ester‐urethane monomer and subjected to thermoselective transesterification at 120 °C with commercial diols in the presence of Ti(OBu)4 to produce polyesters with urethane side chains. The polymers were produced in moderate to high molecular weights and the polymers were found to be thermally stable up to 250 °C. The β‐sheet hydrogen bonding interaction among the side chain urethane unit facilitated the self‐assembly of the polyester into amyloid‐like fibrils. The deprotection of urethane unit into amine functionality modified the polymers into water soluble cationic polyester spherical nanoparticles. The reduction degradation of disulfide bond was studied using DTT as a reducing agent and the high molecular weight polymers chains were found be chopped into low molecular weight oligomers. The cytotoxicity of cationic disulfide nanoparticle was studied in MCF‐7 cells and they were found to be biocompatible and non‐toxic to cells upto 50 μg/mL. The custom designed reduction degradable and highly biocompatible disulfide polyesters from l‐cystine are useful for futuristic biomedical applications. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 2864–2875

Low Molecular Weight Oligomers with Aromatic Backbone as Efficient Nonviral Gene Vectors.

A series of oligomers were synthesized via ring-opening polymerization. Although the molecular weights of these oligomers are only ∼2.5 kDa, they could efficiently bind and condense DNA into nanoparticles. These oligomers gave comparable transfection efficiency (TE) to PEI 25 kDa, while their TE could even increase with the presence of serum, and up to 65 times higher TE than PEI was obtained. The excellent serum tolerance was also confirmed by TEM, flow cytometry, and BSA adsorption assay. Moreover, structure-activity relationship studies revealed some interesting factors. First, oligomers containing aromatic rings in the backbone showed better DNA binding ability. These materials could bring more DNA cargo into the cells, leading to much better TE. Second, the isomerism of the disubstituted phenyl group on the oligomer backbone has large effect on the transfection. The ortho-disubstituted ones gave at least 1 order of magnitude higher TE than meta- or para-disubstituted oligomers. Gel electrophoresis involving DNase and heparin indicated that the difficulty to release DNA might contribute to the lower TE of the latter. Such clues may help us to design novel nonviral gene vectors with high efficiency and biocompatibility.