Availability Of Functional Groups Research Articles

2-fluoro-5-maleimidobenzoic acid-linked albumin drug (MAD) delivery for selective systemic targeting of metastatic prostate cancer.

The SH-group at Cys-34 of human serum albumin (HSA) is a unique and accessible functional group that can be exploited for efficient linkage of a maleimide containing cytotoxic drug derivative to albumin. The specific maleimide chemistry used for production of the maleimide-linked albumin drug (MAD) is critical, however, to minimize the plasma concentration of "free" cytotoxic drug spontaneously released from albumin carrier thus decreasing dose-limiting host toxicity while enhancing the plasma half-life from minutes to days (ie, pharmacokinetic effect) and tissue concentration of the MAD in the extracellular cellular fluid at sites of cancer (ie, EPR effect). To accomplish this goal, a chemical synthesis was developed using 2-fluoro-5-maleimidobenzoic acid to stably link the potent cytotoxic chemically modified analogue of the naturally occurring sesquiterpene γ-lactone, thapsigargin, 8-O-(12-aminododecanoyl)-8-O-debutanoyl thapsigargin (12ADT), to Cys-34 of albumin to produce 12ADT-MAD. Using FITC-labeling, LC/MS analysis, and in vitro growth and clonogenic survival assays on a series of 6 human prostate cancer lines (LNCaP, LAPC-4, VCap, CWR22Rv 1, PC3, and Du145), we documented that 12ADT-MAD is endocytosed by prostate cancer cells where it is degraded into its amino acids liberating cysteinyl-maleimide-12ADT which is both chemically stable at the acidic pH of 5.5 present in the endosome while retaining its high killing ability (IC50 50 nM) via SERCA inhibition. Based upon these positive in vitro validation results, the in vivo efficacy versus host toxicity of this 12-ADT-MAD approach is presently being evaluated against a series of patient derived androgen responsive and castration resistant human xenografts in immune-deficient mice.

Magnetic sporopollenin-cyanopropyltriethoxysilane-dispersive micro-solid phase extraction coupled with high performance liquid chromatography for the determination of selected non-steroidal anti-inflammatory drugs in water samples

A facile dispersive-micro-solid phase extraction (D-μ-SPE) method coupled with HPLC for the analysis of selected non-steroidal anti-inflammatory drugs (NSAIDs) in water samples was developed using a newly prepared magnetic sporopollenin-cyanopropyltriethoxysilane (MS-CNPrTEOS) sorbent. Sporopollenin homogenous microparticles of Lycopodium clavatum spores possessed accessible functional groups that facilitated surface modification. Simple modification was performed by functionalization with 3-cyanopropyltriethoxysilane (CNPrTEOS) and magnetite was introduced onto the biopolymer to simplify the extraction process. MS-CNPrTEOS was identified by infrared spectrometrywhile the morphology and the magnetic property were confirmed by scanning electron microscopy (SEM) and vibrating sample magnetometer (VSM), respectively. To maximize the extraction performance of ketoprofen, ibuprofen, diclofenac and mefenamic acid using the proposed MS-CNPrTEOS, important D-μ-SPE parameters were comprehensively optimized. The optimum extraction conditions were sorbent amount, 40 mg; extraction time, 5 min; desorption time; 5 min; sample volume, 15 mL; sample pH 2.0; and salt addition, 2.5% (w/v). The feasibility of the developed method was evaluated using spiked tap water, lake water, river water and waste water samples. Results showed that ketoprofen and ibuprofen were linear in the range of 1.0–1000 μg L−1 whilst diclofenac and mefenamic acid were linear in the range 0.8–500 μg L−1. The results also showed good detection limits for the studied NSAIDs in the range of 0.21–0.51 μg L−1 and good recoveries for spiked water samples in the range of 85.1–106.4%. The MS-CNPrTEOS proved a promising dispersive sorbent and applicable to facile and rapid assay of NSAIDs in water samples.

Influence of hemicelluloses and lignin content on structure and sorption properties of flax fibers (Linum usitatissimum L.)

In this work, alkali and oxidative treatments were employed to obtain flax fibers with different content of hemicelluloses and lignin, in order to study the influence of chemical composition on structure and sorption properties of flax fibers. The flax fibers were characterized using FTIR spectroscopy and FESEM microscopy, and by determination of chemical composition, carboxyl group content, electrokinetic and sorption properties. Adsorption of silver ions was used to evaluate flax fiber sorption properties, but also to obtain antimicrobial fibers whose antimicrobial activity was tested against Gram-negative bacteria Escherichia coli, Gram-positive bacteria Staphylococcus aureus and fungi Candida albicans. The progressive removal of hemicelluloses or lignin influenced the sorption properties through the increased liberation of elementary fibers and accessibility of functional surface groups of flax fibers. Removal of hemicelluloses led to increase of iodine sorption without significant change in functional groups content and electrokinetic properties. On the other hand, lignin removal led to an increase of functional groups content, namely carboxyl groups, which in turn influenced better moisture and silver ions sorption. Flax fibers with incorporated silver exhibit fair antimicrobial activity against Gram (−) E. coli, Gram (+) S. aureus and fungi C. albicans.

Aminopolymer Mobility and Support Interactions in Silica-PEI Composites for CO2 Capture Applications: A Quasielastic Neutron Scattering Study.

Composite gas sorbents, formed from an active polymer phase and a porous support, are promising materials for the separation of acid gases from a variety of gas streams. Significant changes in sorption performance (capacity, rate, stability etc.) can be achieved by tuning the properties of the polymer and the nature of interactions between polymer and support. Here we utilize quasielastic neutron scattering (QENS) and coarse-grained molecular dynamics (MD) simulations to characterize the dynamic behavior of the most commonly reported polymer in such materials, poly(ethylenimine) (PEI), both in bulk form and when supported in a mesoporous silica framework. The polymer chain dynamics (rotational and translational diffusion) are characterized using two neutron backscattering spectrometers that have overlapping time scales, ranging from picoseconds to a few nanoseconds. Two modes of motion are detected for the PEI molecule in QENS. At low energy transfers, a "slow process" on the time scale of ∼200 ps is found and attributed to jump-mediated, center-of-mass diffusion. A second, "fast process" at ∼20 ps scale is also found and is attributed to a locally confined, jump-diffusion. Characteristic data (time scale and spectral weight) of these processes are compared to those characterized by MD, and reasonable agreement is found. For the nanopore-confined PEI, we observe a significant reduction in the time scale of polymer motion as compared to the bulk. The impacts of silica surface functionalization and of polymer fill fraction in the silica pores (controlling the portion of polymer molecules in contact with the pore walls), are both studied in detail. Hydrophobic functionalization of the silica leads to an increase of the PEI mobility above that in native silanol-terminated silica, but the dynamics are still slower than those in bulk PEI. Sorbents with faster PEI dynamics are also found to be more efficient for CO2 capture, possibly because sorption sites are more accessible than those in systems with slower PEI dynamics. Thus, this work supports the existence of a link between the affinity of the support for PEI and the accessibility of active sorbent functional groups.

Structure-Activity Relationships in Salinomycin: Cytotoxicity and Phenotype Selectivity of Semi-synthetic Derivatives.

The ionophore salinomycin has attracted attention for its exceptional ability to selectively reduce the proportion of cells with stem-like properties in cancer cell populations of varying origin. Targeting the tumorigenicity of such cells is of interest as they are implicated in recurrence, metastasis, and drug resistance. Structural derivatives of salinomycin are thus sought after, both as tools for probing the molecular mechanism(s) underlying the observed phenotype effects, and for improving selectivity and activity against cancer stem cells. Synthetic strategies for modification of each of the directly accessible functional groups of salinomycin are presented and the resulting library of analogues was investigated to establish structure-activity relationships, both with respect to cytotoxicity and phenotype selectivity in breast cancer cells. 20-O-Acylated derivatives stand out by exhibiting both improved selectivity and activity. Mechanistically, the importance of the ionophore properties of salinomycin is highlighted by a significant loss of activity by modifications directly interfering with either of the two primary ion coordinating motifs in salinomycin, the C11 ketone and the C1 carboxylate.

Cyanobacterial Surface Display System Mediates Engineered Interspecies and Abiotic Binding.

Cyanobacteria are uniquely suited for the development of sustainable bioproduction platforms but are currently underutilized in scaled applications in part due to a lack of genetic tools. Here, we develop a surface display system in the cyanobacterial model Synechococcus elongatus PCC7942 via expression of modified versions of the outer membrane porin SomA. Importantly, we demonstrate accessibility of heterologous functional groups on the recombinant porin to the external environment in living cells. We show that this requires the removal of occluding factors that include lipopolysaccharides and a putative surface layer protein. Displayed epitopes on SomA can be utilized to mediate physical adhesion between living cyanobacteria and abiotic surfaces or an engineered Saccharomyces cerevisiae partner strain. We show that >80% of cyanobacterial cells attach to functionalized magnetic beads, allowing for magnet-assisted recovery. This work showcases the development of a functional surface display system in cyanobacteria with wide-ranging applications.

Effect of heat and moisture on surface titratability and pore size distribution of Victorian brown coals

Separating brown coal from its water in an energy-efficient manner is a major challenge, which if successful would substantially improve its combustion efficiency. Many dewatering processes are being investigated, most of which involve heat and pressure to reduce the porosity and number of water-binding surface groups in brown coal. Here we report the results of studies into the effect of temperature and moisture levels on the properties of the brown coal produced. The accessibility of surface functional groups to water was measured using an aqueous titration technique and pore size distribution was measured using mercury porosimetry. We found that heating dry brown coals substantially reduces the accessibility of titratable surface groups on brown coals and that loss of carboxylic acid functional groups on heating is insufficient to explain this effect. Mercury porosimetry indicates that blockage of pores on the size scales reachable by this measurement is unlikely to explain this loss of accessibility, and so the mechanism responsible for this pore blockage is acting on <5nm pores. This effect of heating is less marked if the coal had been heated in the presence of water. This indicates that this blocking process is strongly influenced by the local environment. The porosity of the dried coal decreased with increasing heat treatment temperature.

Determination of DNA Hypermethylation Using Anti‐cancer Drug‐Temozolomide

AbstractAn electrochemical drug‐DNA biosensor was developed for the detection of interaction between the anti‐cancer drug, Temozolomide (TMZ), and DNA sequences by using Differential Pulse Voltammetry at the graphite electrode surfaces. TMZ is a pro‐drug and an alkylating agent that crosses the blood‐brain barrier, so it is mainly used for brain cancers treatment. In this study, we aim to develop a‐proof‐of‐concept study to investigate the effect of TMZ on formerly methylated DNA sequences since TMZ shows its anti‐cancer activity by methylating the DNA. Interaction between TMZ and DNA causes localized distortion of DNA away from an idealized B‐form, resulting in a wider major groove and greater steric accessibility of functional groups in the base of the groove. According to the results, TMZ behaves as a ‘hybridization indicator’ because of its different electrochemical behavior to different strands of DNA. After interaction with TMZ, hybrid (double stranded DNA‐dsDNA) signals decreased dramatically whereas probe (single stranded DNA‐ssDNA) and control signals remain almost unchanged. The signal differences enabled us to distinguish ssDNA and dsDNA without using a label or tag. It is the first study to demonstrate the interaction between the TMZ and dsDNA created from probe and target. We use specific oligonucleotides sequences instead of using long dsDNA sequences.

Synthesis of polypropylene/cellulosic fiber composites using Ziegler-Natta catalyst byin situpolymerization

Composites of polypropylene/natural fiber were obtained synthesizing polypropylene in the presence of chemically treated fibers. For this, vegetal cellulose fibers were introduced in the polymerization medium of propylene using Ziegler-Natta catalyst. The fibers were treated to increase their compatibility with the polypropylene matrix and decrease the accessibility of functional groups to the catalyst active sites. At first, mild acid hydrolysis was performed, followed by chemical treatments with triethylaluminum and stearic alcohol. The results showed that the chemical treatments increased the crystallinity index to 73–77% in comparison with the original fiber (57.6%). The catalyst activity and its stereospecificity maintained high when fiber was treated with triethylaluminium and that with stearic alcohol. The composites contained amounts of fiber in a range of 3.1–5.8%. The fibers did not induce crystallization of PP crystallites different from the most common α-form. Fibers were fibrillated to nanometric diameter, although micrometric length. POLYM. ENG. SCI., 56:71–78, 2016. © 2015 Society of Plastics Engineers

Facile Functionalization of PDMS Elastomer Surfaces Using Thiol–Ene Click Chemistry

A variety of methods have been developed for polydimethylsiloxane (PDMS) elastomer surface functionalization, particularly for the improvement of hydrophilicity. However, in addition to difficulties in avoiding undesired physical changes to the modified surface, including surface cracking, "hydrophobic recovery" frequently leads hydrophilically modified surfaces to completely return over time to their hydrophobic nature, with accompanying loss of accessible functional groups. Thiol-ene chemistry provides a mild and robust technology for synthetic elaboration. We demonstrate the introduction of thiol groups onto the PDMS surface via base-catalyzed equilibration of MTS ((MeO)3Si(CH2)3SH). Thiols in the product elastomer were shown to be located primarily at the air interface using EDX, XPS, and fluorescence labeling initially, and after extended periods of time: total thiol concentrations at the surface and in the bulk were established by complementary chemical titrations with DTDP (4,4'-dithiodipyridine) and iodine titrations in different solvents. The surface density of thiols was readily controlled by reaction conditions: the rate of hydrophobic recovery, which led to incomplete loss of accessible functional groups, was determined. Thiol-ene click chemistry was then used to introduce a variety of hydrophilic moieties onto the surface including a silicone surfactant and maleic anhydride, respectively. In the latter case, molecular functionalization with both small (fluorescent labels) and polymeric nucleophiles (poly(ethylene glycol), chitosan) could be subsequently induced by simple ring-opening nucleophilic attack leading to permanently functional surfaces.

Comparative study of adsorption of Pb(II) on native garlic peel and mercerized garlic peel

A comparative study using native garlic peel and mercerized garlic peel as adsorbents for the removal of Pb(2+) has been proposed. Under the optimized pH, contact time, and adsorbent dosage, the adsorption capacity of garlic peel after mercerization was increased 2.1 times and up to 109.05 mg g(-1). The equilibrium sorption data for both garlic peels fitted well with Langmuir adsorption isotherm, and the adsorbent-adsorbate kinetics followed pseudo-second-order model. These both garlic peels were characterized by elemental analysis, Fourier transform infrared spectrometry (FT-IR), and scanning electron microscopy, and the results indicated that mercerized garlic peel offers more little pores acted as adsorption sites than native garlic peel and has lower polymerization and crystalline and more accessible functional hydroxyl groups, which resulted in higher adsorption capacity than native garlic peel. The FT-IR and X-ray photoelectron spectroscopy analyses of both garlic peels before and after loaded with Pb(2+) further illustrated that lead was adsorbed on the through chelation between Pb(2+) and O atom existed on the surface of garlic peels. These results described above showed that garlic peel after mercerization can be a more attractive adsorbent due to its faster sorption uptake and higher capacity.

Investigations Into Amphiphilic Chitosan: Properties and Availability of Original and Newly Introduced Functional Groups

The accessibility of functional groups of 3,6-O-chitosansulfate in water is studied using conductometric and polyelectrolyte titration techniques. These studies reveal the good accessibility of protonated amino groups following conductometric titrations and pH dependency on the accessibility of negatively charged sulfate groups following polyelectrolyte titrations. In addition, the influence of negatively charged sulfate groups, introduced onto polymer backbone by synthesis, is analyzed regarding the well-known antimicrobial activities of chitosan. The assessment of the mortality rates of Gram-negative, Gram-positive bacteria, and pathogenic fungi reveal that sulfate groups in chitosan lead to a tremendous loss in antimicrobial activity compared with nonmodified chitosan.

Humic and hymatomelanic acids interaction with lanthanide ions

The interactions of lanthanide ions, REE(III), with semiquinone radicals naturally occurring in humic (HA) and hymatomelanic (HY) acids of different origin were studied mainly by EPR spectroscopy. Quantitative EPR analysis proved that only the semiquinone free radical concentration in both, HA and HY, was affected by interaction with some of the lanthanide ions, whereas the EPR g parameters of the formed radical–REE(III) complexes remained unchanged. The radical concentration was practically unaffected by the REE(III) ions with 4f1–4f6 electron configurations and in some degree increased by REE(III) ions with 4f8–4f14 configuration. The lanthanide playing an exceptional role was Gd(III) (4f7), which diminished strongly the free radicals concentration. The quenching ability of Gd(III) was stronger towards the radicals provided by HA than by HY, what was assigned to higher content in HA of both, oxygen-containing functional groups and conjugated aromatic rings, leading to more efficient Gd(III)–radical interaction. The semiquinone free radicals of HA and HY originated from the compost were more reactive than those from peat, as the humic acids from mature compost with less bulk density have more accessible functional groups.

Predicting the physicochemical profile of diastereoisomeric histidine‐containing dipeptides by property space analysis

This study aimed at measuring the lipophilicity and ionization constants of diastereoisomeric dipeptides, interpreting them in terms of conformational behavior, and developing statistical models to predict them. A series of 20 dipeptides of general structure NH(2)-L-X-(L or D)-His-OMe was designed and synthetized. Their experimental ionization constants (pK(1), pK(2) and pK(3)) and lipophilicity parameters (log P(N) and log D(7.4)) were measured by potentiometry. Molecular modeling in three media (vacuum, water, and chloroform) was used to explore and sample their conformational space, and for each stored conformer to calculate their radius of gyration, virtual log P (preferably written as log P(MLP), meaning obtained by the molecular lipophilicity potential (MLP) method) and polar surface area (PSA). Means and ranges were calculated for these properties, as was their sensitivity (i.e., the ratio between property range and number of rotatable bonds). Marked differences between diastereoisomers were seen in their experimental ionization constants and lipophilicity parameters. These differences are explained by molecular flexibility, configuration-dependent differences in intramolecular interactions, and accessibility of functional groups. Multiple linear equations correlated experimental lipophilicity parameters and ionization constants with PSA range and other calculated parameters. This study documents the differences in lipophilicity and ionization constants between diastereoisomeric dipeptides. Such configuration-dependent differences are shown to depend markedly on differences in conformational behavior and to be amenable to multiple linear regression.

Internal Functionalization of Three‐Dimensional Covalent Organic Frameworks

Thinking inside the COF: Internally functionalized, boroxine-linked, three-dimensional, covalent organic frameworks (COFs) can be synthesized by co-crystallizing a truncated, trifunctional monomer with the parent tetrafunctional building block. The functionalized COFs possess accessible functional groups and a distinct interior microenvironment. In the picture the orange sphere corresponds to an alkyl chain or an allyl group in the pore interior.

Copper-free click chemistry on polymersomes: pre- vs. post-self-assembly functionalisation

The optimal accessibility of functional groups on polymeric nanosized vesicles was investigated with copper-free clickable probes as a model system. Cu-free clickable polymersomes were developed either through co-assembly of end group modified amphiphilic block copolymers or by introduction of the reactive moieties on preformed vesicles. For the co-assembly approach, the highest degree of availability was obtained for the most hydrophilic functional group, whereas hydrophobic species were unable to react as efficiently since they were seemingly buried in the membrane. Post-self-assembly introduction led to good results for all three examined moieties whereby surface saturation was reached above a certain percentage of immobilised probes. Finally, we demonstrated that protrusion of functional entities from the membrane corona via a longer hydrophilic segment of the block-copolymer significantly enhances the accessibility.

Chromium(VI) reactions of polysaccharide biopolymers

This study investigated the reaction mechanisms of toxic hexavalent chromium (Cr(VI)) with polysaccharide biopolymers, including cellulose, hemicellulose and chitin, to understand their roles in determining the Cr(VI) removal efficiencies of biomaterials containing these polymers. The Cr(VI) removal rates and capacities at pH 2 followed the order of hemicellulose>chitin≫cellulose. The Cr(VI) removals by these biopolymers were primarily due to the reduction of Cr(VI) to Cr(III). The hydroxyl groups of these biomaterials were the predominant reactive sites for Cr(VI) reduction, and the oxidation of the hydroxyl groups by Cr(VI) led to the formation of carboxyl groups. In addition to the reactivity of functional groups toward Cr(VI), the accessibility of functional groups in different biopolymers may also determine the reduction rates of Cr(VI) by the biopolymers.

Potentiometric titration of humic acids

The acid-base properties of humic acids from the brown coal of the Aleksandriiskoe deposit (Ukraine) were investigated. The possibility of determining COOH and OH groups in humic acid macromolecules by different experimental methods was analyzed. It was found that the results of potentiometric titration depend on the method of titration (homogeneous or heterogeneous), the concentration of humic substances in the system, and the time taken to establish an equilibrium value of pH in the titrate. It was shown that the amount of accessible functional groups (COOH and OH) in humic acid macromolecules, which can be determined by a potentiometric method, is greater in homogeneous titration and at low concentrations of humic substances in solution. It was established that the total amount of acid groups determined by a barium method is higher than that measured with the use of potentiometric titration. The concentration of carboxyl groups determined by an acetate method is much lower than the results of potentiometric titration and the barium method. It was shown that the potentiometric titration of homogeneous systems (sodium humate + HCl) is preferable in the analysis of the acid-base properties of humic acids.

Structural analysis of alpha-helical proteins from wool using cysteine labelling and mass spectrometry

A simple reduction/labelling/extraction protocol has been developed to fractionate cortical matrix proteins from filament proteins in wool. Through differential labelling of cysteine residues their relative accessibility in the wool fibre has been investigated. This has allowed the preliminary development of a map of the chemical functionality that is accessible within wool fibres under native conditions. Protein analyses of wool subjected to mechanical action, wet chemical permonosulphate/sulphite treatment and dry argon plasma treatment revealed that none of these detectably improved the accessibility of functional groups at the wool cortex. It is anticipated that this analytical method can be extended to improve the sensitivity and scope with which chemical functionality within native fibres can be mapped and lead to a better understanding of the potential limits/opportunities for fibre modification.

Combination therapy with the albumin-binding prodrug of doxorubicin (INNO-206) and doxorubicin achieves complete remissions and improves tolerability in an ovarian A2780 xenograft model

We recently reported on the in superior in vivo antitumor efficacy of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (INNO-206, formerly DOXO-EMCH), an albumin-binding prodrug of doxorubicin with acid-sensitive properties (see Fig. 1), in three tumor models in this journal, i.e. in three xenograft models (breast carcinoma M3366, ovarian carcinoma A2780, and small cell lung cancer H209) as well as in an orthotopic pancreatic carcinoma model (AsPC-1) [1] Previously, INNO-206 has shown significantly improved activity over doxorubicin in two xenograft breast cancer models and an orthotopic murine renal cell carcinoma model [2] and recently against resistant and non resistant myeloma (see http//:www.cytrx.com). INNO-206 binds rapidly to circulating serum albumin and releases doxorubicin selectively at the tumor site due to incorporation of an acid-sensitive hydrazone bond. The accumulation of INNO-206 in tumor tissue combined with a favorable biodistribution [3] is due to the pathophysiology of tumor tissue, characterized by a high metabolic turnover, angiogenesis, hypervasculature, a defective vascular architecture and an impaired lymphatic drainage, the so-called EPR (enhanced and retention) effect [4]. As a carrier for INNO-206, we selected albumin, which is emerging as a versatile protein carrier for drug targeting and for improving the pharmacokinetic profile of peptideor protein-based drugs [5]. Albumin is a potential carrier for tumor targeting because it accumulates in solid tumors. In addition, we discovered that the HS-group of cysteine-34 of albumin is a unique and accessible functional group of a plasma protein for in situ prodrug conjugation considering that free thiol groups are absent from most circulating serum proteins except for albumin, which makes this group by far the most abundant thiol group in human plasma After injection directly into the blood stream, INNO-206 binds in situ to the cysteine-34 position of circulating albumin and is then transported in its albumin-bound form to the tumor site. INNO-206 is a prodrug of the anticancer agent doxorubicin in which doxorubicin is derivatized at its C-13 keto-position with a thiol-binding spacer molecule, i.e. 6-maleimidocaproic acid hydrazide. It contains an acidsensitive hydrazone linker that allows doxorubicin to be released either extracellularly in the slightly acidic environment often present in tumor tissue (pH range 6.0-6.8) [6] or intracellularly in acidic endosomal (pH 5.0-6.5) or lysosomal (pH 4.0-5.0) compartments after cellular uptake of the albumin conjugate by the tumor cell. INNO-206 was selected as an investigational product for clinical evaluation after toxicology studies in mice, rats, and dogs had shown a 2.5to 5-fold increase in the maximum tolerated dose (MTD) when compared to conventional doxoElectronic supplementary material The online version of this article (doi:10.1007/s10637-011-9686-5) contains supplementary material, which is available to authorized users.