Ketone Functional Groups Research Articles

Tagging the Untaggable: A Difluoroalkyl-Sulfinate Ketone-Based Reagent for Direct C-H Functionalization of Bioactive Heteroarenes.

We have developed a new difluoroalkyl ketal sulfinate salt reagent suitable for direct derivatization of heteroarene C-H bonds. The reagent is capable of introducing a ketone functional group on heteroarene bioactive compounds via a one-pot reaction. Remarkably, in three examples the ketone analog and its parent drug had almost identical cytotoxicity. In a representative example, the ketone analog was bioconjugated with a delivery vehicle via an acid-labile semicarbazone linkage and with a photolabile protecting group to produce the corresponding prodrug. Controlled release of the drug-ketone analog was demonstrated in vitro for both systems. This study provides a general approach to obtain taggable ketone analogs directly from bioactive heteroarene compounds with limited options for conjugation. We anticipate that this sodium ketal-sulfinate reagent will be useful for derivatization of other heteroarene-based drugs to obtain ketone-taggable analogs with retained efficacy.

Insight into the Unexpectedly Rapid Degradation of Dihydroxyacetone-Based Hydrogels

Biodegradable hydrogels are an important class of biomaterials with a diverse range of applications. In some cases, a rapid hydrogel degradation rate is advantageous. Polycarbonate hydrogels based on dihydroxyacetone (DHA), a natural metabolite, have been reported to undergo surprisingly fast hydrolytic degradation. In the present work, insight into the key features of DHA that contribute to the observed degradation rates is gained. In vitro degradation (mass loss) of three different chemically cross-linked polycarbonate hydrogels is investigated to shed light on the role of the ketone functional group, as well as the carbon-chain length between the ketone and carbonate bonds. The ketone is found to be the major cause of rapid degradation. Also, mass loss is accelerated by increased temperature and pH, offering insight into potential tuning parameters and storage conditions. The results show that DHA is a promising monomeric unit for the design of rapidly degrading, biocompatible, and functional biomaterials.

Nickel-Catalyzed Hiyama-type Decarboxylative Coupling of Propiolic Acids and Organosilanes.

A Ni catalytic system was developed for the decarboxylative coupling reaction of alkynyl carboxylic acids with organosilanes. Ni(acac)2 and 1,10-phenanthroline showed the best result in the presence of CsF and CuF2 at 120 °C. This system tolerated the presence of alkyl, alkoxy, halogen, nitro, cyano, ketone, and ester functional groups. Moreover, the reaction with but-2-ynedioic acid and organosilane afforded the corresponding symmetrical diarylalkynes.

Deorphanizing Renal Olfactory Receptor 1393

Olfactory receptors (ORs) are G protein‐coupled receptors which serve to detect odorants in the nose. Recently, ORs have been shown to play novel roles beyond odorant detection in a number of tissues, and we previously determined that a subset of ORs are expressed in the kidney. One of these receptors is Olfr1393, an orphan receptor with no known ligand. In order to determine the physiological role of Olfr1393 within the kidney, it is important to understand its ligand profile. Unfortunately, most ORs are orphan receptors, due in large part to the inability to functionally express ORs in heterologous cell systems; ORs are retained in the ER and degraded when heterologously expressed. Luckily, with the assistance of chaperone proteins and a novel cleavable tag that we developed (Shepard, et al PLoS One 2013), we were able to express Olfr1393 on the cell surface of HEK293T cells. Thus, we undertook a large scale ligand screen using a cAMP‐dependent luciferase reporter assay. We began our unbiased screen using different odorant mixtures, each containing a variety of chemicals clustered by functional group such that the mixes, in sum, cover a wide “odorant space”. However, we did not observe any Olfr1393 activation using these libraries. The murine OR gene family (consisting of ~1000 ORs) is subdivided into subfamilies, grouped based on phylogenetic clustering and protein sequence identity, and ORs within a subfamily often share similar ligands. Olfr1393 belongs to the MOR256 subfamily, and several other MOR256 family members have been previously deorphanized. Thus, we screened Olfr1393 against known MOR256 odorants and found that Olfr1393 does respond to one of these chemicals – cyclohexanone. Using cyclohexanone as a guide, we broadened our search by using a multidimensional physiochemical metric for odorant prediction and identified a total of 8 different ligands. All 8 of these ligands are structurally similar, and can be broadly described as pre‐constrained rings containing either ketone or alcohol functional groups. Notably, if the ligand is modified even slightly (with the addition or removal of a functional group) it will no longer activate the receptor. Further unbiased screens ‐including the use of a 1280 compound chemical library ‐ did not reveal any additional ligands for Olfr1393 indicating the narrow range of its ligand profile. Efforts are currently underway to determine the physiological relevance of these 8 ligands using targeted metabolomics of murine urine and plasma; discovering the source of these ligands will contribute to the understanding that Olfr1393 plays in the kidney.Support or Funding InformationNIDDK

Adsorption of levofloxacin onto an iron-pillared montmorillonite (clay mineral): Kinetics, equilibrium and mechanism

Antibiotics have been recognized as a class of emerging pollutant. In this study, Fe-pillared montmorillonite (Fe-P-Mt) was prepared and characterized by XRF, XRD, BET, and UV–vis-DRS analyses. Adsorption of levofloxacin (LVX), a fluoroquinolone antimicrobial agent, onto Fe-P-Mt was investigated as a function of contact time, LVX concentration, pH, temperature, and ionic strength by using a batch adsorption method. FT-IR spectroscopy was used to reveal the interaction of LVX and Fe-P-Mt at the molecular level. The obtained results showed that the adsorption of LVX on Fe-P-Mt followed the pseudo-second-order kinetics, and the adsorption isotherms conformed to the Langmuir model with a maxima adsorption capacity of 48.61mg·g−1 at 25°C. The solution pH exerted a strong influence on LVX adsorption. The maximum adsorption was found to occur around pH7. The addition of NaCl had a minor effect on LVX adsorption, whereas the presence of NaH2PO4 depressed LVX adsorption due to its stronger affinity to Fe species. The thermodynamic parameters indicated that the adsorption process was endothermic and spontaneous. The mean free energies of adsorption calculated from a D–R model, on the other hand, suggested a chemisorption process. FT-IR spectroscopic analysis further revealed that LVX was adsorbed onto Fe-P-Mt via the coordination of ketone and carboxylate functional groups with an Fe atom to form a mononuclear bidentate complex. This study indicates that pillaring montmorillonite with iron species could significantly influence its adsorption behavior and mechanism toward fluoroquinolone antimicrobial agents.

Synthesis and functionalization of vinylsulfide and ketone-containing aliphatic copolyesters from fatty acids

A series of novel aliphatic copolyesters bearing vinylsulfide and ketone functional groups were synthesized via lipase catalyzed polycondensation of vegetable oil derivatives. The vinylsulfide-containing hydroxyacid (VSHA) from 10-undecenoic fatty acid and the ketone-containing hydroxyester (KHE) from methyl oleate were used to obtain random copolymers and further sequential and single-step strategies involving the reactions with thiol and oxyamine were investigated. Good agreement between product and feed stoichiometries was achieved in both reactions for sequential modification, and the order of addition seems not to be a significant parameter. One pot functionalization allows for the single step modification, but not quantitative reactions were achieved.

Rigidified malononitrile- and ketone-merocyanines in rigid environments

<p class="03Abstract">Two merocyanine dyes containing a malononitrile or a ketone functional group as electron-acceptors, and a piperidine group as electron-donor were synthetized and crystallized as pigments. The electron-donor and -acceptor moieties are linked <em>via</em> an octahydroanthracene skeleton, forming an electronic push-pull molecular system. The crystal structure of the malononitrile compound was solved <em>ab initio</em> from X-ray powder diffraction data, complementing the reported structure of the ketone pigment. Both compounds show similar molecular structures in the solid state, yet with completely different crystal packing schemes. The crystal structures were analysed with inspecting the Hirshfeld surfaces. IR spectroscopy was applied to complement the crystallographic study. The absorption characteristics of both pigments emerge from the push-pull chemical structure, which was visualized by plotting the electrostatic potentials, calculated using molecular geometries as observed in the solid state. The solid state UV-vis spectra showed peak broadening and bathochromic spectral shift as compared to the spectra recorded in solution, depending on the polarity of the solvent molecules: The largest shifts of the spectra of solid state pigments were observed with respect to the spectra recorded in toluene solution, whether the smallest to those in ethanol. </p>

Structure–Activity Relationships in the Domain of Odorants Having Marine Notes

AbstractContinuing our investigations into marine note odorants, we herein describe several new scaffolds. Among them, 2,3‐dihydrobenzofuran‐2‐carbaldehyde is particularly interesting. The results demonstrate that the seven‐membered ring with a ketone functional group of the Calone 1951® family can be replaced by a five‐membered ring carrying an aldehyde function. In addition, this work has allowed us to discover the valuable 2‐methoxy‐4‐methylphenyl methyl carbonate (20b), which is very close to vanillin, and 2‐methoxy‐2,4‐dimethyl‐1,3‐benzodioxole (29d), which belongs to the isoeugenol/dihydroeugenol olfactive family.

Using NMR Spectroscopy To Probe the Chemo- and Diastereoselectivity in the NaBH4 Reduction of Benzoin Acetate and Benzoin Benzoate

A pedagogically useful discovery-based undergraduate organic chemistry lab experiment probing the chemo- and diastereoselectivity in the NaBH4 reduction of two chiral ketoesters (benzoin acetate and benzoin benzoate) has been developed. This experiment complements a previously described and highly popular discovery-based experiment that probes the stereoselectivity in the NaBH4 reduction of the chiral ketone (±)-benzoin. Using reactions described in standard textbooks, students convert (±)-benzoin to the ketoester derivatives (±)-benzoin acetate and (±)-benzoin benzoate. In contrast to benzoin that has a single reducible ketone functional group, the ketoester derivatives have two reducible functional groups. In addition, the structural modifications made to the hydroxyl group of the benzoin molecule lead to an increase in the effective steric bulk of the OH group of benzoin, affording a larger acetoxy group and an even larger benzoxy group. Using NMR spectroscopy, students probe not only the chemoselectiv...

Miscibility and Hydrogen Bonding in Blends of Poly(4-vinylphenol)/Poly(vinyl methyl ketone)

The miscibility and phase behavior of poly(4-vinylphenol) (PVPh) with poly(vinyl methyl ketone) (PVMK) was investigated by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). It was shown that all blends of PVPh/PVMK are totally miscible. A DSC study showed the apparition of a single glass transition (Tg) over their entire composition range. When the amount of PVPh exceeds 50% in blends, the obtained Tgs are found to be significantly higher than those observed for each individual component of the mixture, indicating that these blends are capable of forming interpolymer complexes. FTIR analysis revealed the existence of preferential specific interactions via hydrogen bonding between the hydroxyl and carbonyl groups, which intensified when the amount of PVPh was increased in blends. Furthermore, the quantitative FTIR study carried out for PVPh/PVMK blends was also performed for the vinylphenol (VPh) and vinyl methyl ketone (VMK) functional groups. These results were also established by scanning electron microscopy study (SEM).

Stabilization of Cobalt Catalysts by Embedment for Efficient Production of Valeric Biofuel

We herein report, for the first time, a bifunctional base-metal catalyst (Co@HZSM-5) that acts as an efficient alternative to noble-metal catalysts (e.g., Pt, Ru) for the conversion of levulinic acid into valeric biofuel under batch and fixed-bed reactor conditions. The cobalt nanoparticles were embedded in HZSM-5 crystals and catalyzed the sequential hydrogenations of the ketone and alkene functional groups; meanwhile, the acidic zeolite catalyzed the ring opening of the γ-valerolactone intermediate. Although base metals (e.g., Co) are abundant and inexpensive, their sintering and/or leaching under liquid-phase conditions always lead to the irreversible deactivation of the catalyst. In this system, the embedment structure stabilizes the nanoparticles, and Co@HZSM-5 could be used up to eight times. This work provides a practical clue toward the stabilization of base-metal catalysts and will inspire the development of large-scale biorefinery.

Cells producing their own nemesis: understanding methylglyoxal metabolism.

Methylglyoxal, which is technically known as 2-oxopropanal or pyruvaldehyde, shows typical reactions of carbonyl compounds as it has both an aldehyde and a ketone functional group. It is an extremely cytotoxic physiological metabolite, which is generated by both enzymatic and nonenzymatic reactions. The deleterious nature of the compound is due to its ability to glycate and crosslink macromolecules like protein and DNA, respectively. However, despite having toxic effects on cellular processes, methylglyoxal retains its efficacy as an anticancer drug. Indeed, methylglyoxal is one of the well-known anticancer therapeutic agents used in the treatment. Several studies on methylglyoxal biology revolve around the manifestations of its inhibitory effects and toxicity in microbial growth and diabetic complications, respectively. Here, we have revisited the chronology of methylglyoxal research with emphasis on metabolism of methylglyoxal and implications of methylglyoxal production or detoxification on bacterial pathogenesis and disease progression.

Optimization of a Headspace SPME GC–MS Methodology for the Analysis of Processed Almond Beverages

Optimization of a headspace–solid phase microextraction (HS-SPME) technique for analyzing the volatile profile of almond beverages was performed. An ultra-high temperature (UHT)-treated almond beverage prepared at the pilot plant was used as a model for this kind of vegetable beverage. For the analysis a 2-mL almond beverage, aliquot was used in the presence of salt (NaCl) at saturation levels. Heating of sample was carried out at 60 °C for 60 min with a stirring rate of 700 rpm using a divinylbenzene (DVB)/Carboxen™ (CAR)/polydimethylsiloxane (PDMS) fibre. The most abundant volatile compounds found were benzaldehyde and hexanal. Most volatiles belong to the aldehyde, ketone and alcohol functional groups. Volatiles derived from thermal treatments such as furans and pyrazines were detected in lesser extent. This technique may be useful to characterize and detect changes in the volatile profile of almond beverages arising from the technological treatments applied in their production.

A structure–reactivity relationship driven approach to the identification of a color test protocol for the presumptive indication of synthetic cannabimimetic drugs of abuse

The number of analyses of synthetic cannabimimetic drugs of abuse by forensic laboratories in the United States grew rapidly from 2010 to 2012 and then declined somewhat in 2013. In 2010, according to the National Forensic Laboratory Information System (NFLIS), 3,287 reports by federal, state and local forensic laboratories were identified as containing synthetic cannabinoids. In 2011 and 2012, the numbers increased to 23,693 and 42,503, respectively. 27,119 reports were identified in 2013. Several commonly encountered structural sub-classes of these synthetic designer drugs, namely the naphthoylindoles, benzoylindoles, phenylacetylindoles, and cyclopropoylindoles contain a ketone functional group. The Duquenois-Levine color test for the presumptive identification of classical cannabinoids such as Δ9-tetrahydrocannabinol is negative for the synthetic cannabimimetics. The van Urk color test for the presumptive identification of indole containing drugs of abuse is also negative for these compounds. The use of 2,4-dinitrophenylhydrazine as an alternative color test reagent (targeting the keto moiety rather than the indole) for presumptive identification of these classes of drugs was investigated.

Latex Clearing Protein—an Oxygenase Cleaving Poly( cis -1,4-Isoprene) Rubber at the cis Double Bonds

Gordonia polyisoprenivorans strain VH2, a potent rubber-degrading actinomycete, harbors two latex clearing proteins (Lcps), which are known to be essential for the microbial degradation of rubber. However, biochemical information on the exact role of this protein in the degradation of polyisoprene was lacking. In this study, the gene encoding Lcp1VH2 was heterologously expressed in strains of Escherichia coli, the corresponding protein was purified, and its role in rubber degradation was examined by measurement of oxygen consumption as well as by chromatographic and spectroscopic methods. It turned out that active Lcp1VH2 is a monomer and is responsible for the oxidative cleavage of poly(cis-1,4-isoprene) in synthetic as well as in natural rubber by the addition of oxygen (O2) to the cis double bonds. The resulting oligomers possess repetitive isoprene units with aldehyde (CHO-CH2-) and ketone (-CH2-CO-CH3) functional groups at the termini. Two fractions with average isoprene contents of 18 and 10, respectively, were isolated, thus indicating an endocleavage mechanism. The activity of Lcp1VH2 was determined by applying a polarographic assay. Alkenes, acyclic terpenes, or other rubber-like polymers, such as poly(cis-1,4-butadiene) or poly(trans-1,4-isoprene), are not oxidatively cleaved by Lcp1VH2. The pH and temperature optima of the enzyme are at pH 7 and 30°C, respectively. Furthermore, it was demonstrated that active Lcp1VH2 is a Cu(II)-containing oxygenase that exhibits a conserved domain of unknown function which cannot be detected in any other hitherto-characterized enzyme. The results presented here indicate that this domain might represent a new protein family of oxygenases.

ChemInform Abstract: Enantiospecific Total Synthesis of N‐Methylwelwitindolinone D Isonitrile.

ChemInform Abstract: Enantiospecific Total Synthesis of N‐Methylwelwitindolinone D Isonitrile.

Derivatization Technique to Increase the Spectral Selectivity of Two-Dimensional Fourier Transform Infrared Focal Plane Array Imaging: Analysis of Binder Composition in Aged Oil and Tempera Paint

The interpretation of standard Fourier transform infrared spectra (FT-IR) on oil-based paint samples often suffers from interfering bands of the different compounds, namely, binder, oxidative aging products, carboxylates formed during aging, and several pigments and fillers. The distinction of the aging products such as ketone and carboxylic acid functional groups pose the next problem, as these interfere with the triglyceride esters of the oil. A sample preparation and derivatization technique using gaseous sulfur tetrafluoride (SF4), was thus developed with the aim to discriminate overlapping signals and achieve a signal enhancement on superposed compounds. Of particular interest in this context is the signal elimination of the broad carboxylate bands of the typical reaction products developing during the aging processes in oil-based paints, as well as signal interference originating from several typical pigments in this spectral range. Furthermore, it is possible to distinguish the different carbonyl-containing functional groups upon selective alteration. The derivatization treatment can be applied to both microsamples and polished cross sections. It increases the selectivity of the infrared spectroscopy technique in a fundamental manner and permits the identification and two-dimensional (2D) localization of binder components in aged paint samples at the micrometer scale. The combination of SF4 derivatization with high-resolution 2D FT-IR focal plane array (FPA) imaging delivers considerable advances to the study of micro-morphological processes involving organic compounds.

Tuning Gelation Time and Morphology of Injectable Hydrogels Using Ketone–Hydrazide Cross-Linking

Injectable, covalently in situ forming hydrogels based on poly(N-isopropylacrylamide) have been designed on the basis of mixing hydrazide-functionalized nucleophilic precursor polymers with electrophilic precursor polymers functionalized with a combination of ketone (slow reacting) and aldehyde (fast reacting) functional groups. By tuning the ratio of aldehyde:ketone functional groups as well as the total number of ketone groups in the electrophilic precursor polymer, largely independent control over hydrogel properties including gelation time (from seconds to hours), degradation kinetics (from hours to months), optical transmission (from 1 to 85%), and mechanics (over nearly 1 order of magnitude) can be achieved. In addition, ketone-functionalized precursor polymers exhibit improved cytocompatibility at even extremely high concentrations relative to polymers functionalized with aldehyde groups, even at 4-fold higher functional group densities. Overall, increasing the ketone content of the precursor copolymers can result in in situ-gellable hydrogels with improved transparency and biocompatibility and equivalent mechanics and stimuli-responsiveness while only modestly sacrificing the speed of gel formation.

Polyketoesters from oleic acid. Synthesis and functionalization

In this study, we exploited the reactivity of the methyl oleate enone derivative for the conversion of this renewable raw material to ketone-containing hydroxyesters. The radical-mediated thiol–ene addition to the conjugated double bonds has been investigated and low yields were obtained due to secondary reactions. The thiol-Michael addition under acidic and basic/nucleophilic conditions was also examined. While using vanadyl triflate (VO(OTf)2), a slight excess of thiol was necessary to complete the reaction, by using both basic/nucleophilic catalysts 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), quantitative conversion was achieved under stoichiometric conditions in shorter reaction times. The obtained hydroxyester, carrying sulphide and ketone functional groups, was used to obtain polyesters by Novozyme-435 enzymatic polymerization. The coupling between the ketone group of the repeating unit and a model oxyamine has been used to demonstrate the polyketoester functionalization via oxime formation.

Single Molecule FRET Studies of the NMDA Receptor using Unnatural Amino Acids

The NMDA receptor is one class of ionotropic glutamate receptors, which are the primary mediators of excitatory neurotransmission in the central nervous system. As such, function and dysfunction of these receptors has been implicated in such physiological and pathological processes as learning and memory, strokes, Alzheimer disease, and Parkinson disease. Studies into the similarly structured AMPA-type glutamate receptor have revealed a relationship between the extent of closure of the agonist-binding domain cleft and activation of the channel, showing a structural mechanism for transduction of signal from binding of ligand to receptor activation. However, neither crystal structures nor more dynamics-based studies using ensemble FRET/LRET show such a correlation when examining the agonist-binding domain of the glycine-binding subunit of the NMDA receptor. Here, we use single molecule FRET to examine more closely the range of conformation states probed by the isolated agonist-binding domain. To perform this, we had to overcome the problem of immutable native cysteines, which resulted in non-specific labeling when using the conventional maleimide-conjugated fluorophores that are regularly used in protein-based FRET studies. Thus, we introduced the unnatural amino acid p-acetylphenylalanine, which contains a unique ketone functional group, at the sites which we wished to test, allowing for specific labeling of the protein. Doing this, we see that while the protein exhibits a peak probability around 33A when bound both to full agonist glycine and partial agonist ACPC, the protein bound to partial agonist probes a slightly broader range of states than full agonist. From these data, we can infer that while the agonist-binding domain may show similar average extents of cleft closure, irresolvable by crystallography or ensemble LRET, full agonists more narrowly restrict the range of conformational states probed to conformations that allow for channel activation.