Ketone Moiety Research Articles

A general scheme for synthesis of substrate-based polyketide labels for acyl carrier proteins

A general strategy to enzymatically label acyl carrier proteins (ACPs) of polyketide synthases has been developed. Incorporation of a chloromethyl ketone or vinyl ketone moiety into polyketide chain elongation intermediate mimics allows for the synthesis of CoA adducts. These CoA adducts undergo enzymatic reaction with Sfp, a phosphopantetheinyl transferase, to afford labeled CurB carrier proteins.

Synthesis and properties of thermoplastic polyimides with ether and ketone moieties

AbstractA series of polyimides containing ether and ketone moieties were synthesized from 1,3‐bis(4‐fluorobenzoyl) benzene and several commercially available dianhydrides via a conventional two‐step polymerization. The inherent viscosities of Polyamide acids ranged from 0.46 to 0.73 dL/g. Thermal properties, mechanical properties, and thermalplasticity of the obtained polimide films were investigated by focusing on the chemical structures of their repeat units. These films were amorphous, flexible, and transparent. All films displayed low Tgs (184–225 °C) but also excellent thermal stability, the 5% weight loss temperature was up to 542 °C under nitrogen. The films showed outstanding mechanical properties with the modulus up to 3.0 GPa and the elongation at break in the range of 8–160%. The uniaxial stretching of PI‐a at high temperature was studied owing to its excellent flexibility. The PI‐a had an elongation at break up to 1600% at 245 °C and the uniaxially stretched film exhibited a much higher modulus (3.9 GPa) and strength (240 MPa) than undrawn film. The results indicated that PI‐a can potentially be used to prepare materials such as fiber, ultra‐thin film or ultra‐high modulus film. All the obtained films also demonstrated excellent thermoplasticity (drop of E′ at Tg > 103) which made the polyimides more suitable for melt processing. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2878–2884, 2010

Functional Characterization of TtnD and TtnF, Unveiling New Insights into Tautomycetin Biosynthesis

The biosynthetic gene cluster for tautomycetin (TTN), a highly potent and selective protein phosphatase (PP) inhibitor isolated from Streptomyces griseochromogenes, has recently been cloned and sequenced. To better understand the transformations responsible for converting the post-polyketide synthase product into the exciting anticancer and immunosuppressive chemotherapeutic candidate TTN, we produced and characterized new analogues resulting from inactivation of two genes, ttnD and ttnF, in S. griseochromogenes. Inactivation of ttnD and ttnF, which encode for putative decarboxylase and dehydratase enzymes, respectively, afforded mutant strains SB13013 and SB13014. The DeltattnD mutant SB13013 accumulated four new TTN analogues, TTN D-1, TTN D-2, TTN D-3, and TTN D-4, whereas the DeltattnF mutant accumulated only one new TTN analogue, TTN F-1. The accumulation of these new TTN analogues defines the function of TtnD and TtnF and the timing of their chemistries in relation to installation of the C5 ketone moiety within TTN. Notably, all new analogues possess a structurally distinguishing carboxylic acid moiety, revealing that TtnD apparently cannot catalyze decarboxylation in the absence of TtnF. Additionally, cytotoxicity and PP inhibition assays reveal the importance of the functional groups installed by TtnDF and, consistent with earlier proposals, the C2''-C5 fragment of TTN to be a critical structural determinant behind the important and unique PP-1 selectivity displayed by TTN.

Identification of new non-carboxylic acid containing inhibitors of aldose reductase

Non-carboxylic acid containing bioisosteres of (5-arylidene-2,4-dioxothiazolidin-3-yl)acetic acids, which are active as aldose reductase (ALR2) inhibitors, were designed by replacing the carboxylic group with the trifluoromethyl ketone moiety. The in vitro evaluation of the ALR2 inhibitory effects of these trifluoromethyl substituted derivatives led to the identification of two inhibitors effective at low micromolar doses. It was further confirmed that a carboxylic chain on N-3 of the thiazolidinedione scaffold is a determining requisite to obtain the highest efficacy levels; however, it is not essential for the interaction with the target enzyme and it can be replaced by different polar groups, thus obtaining less ionised or unionised inhibitors.

Rapid access to morphinones: removal of 4,5-ether bridge with Pd-catalyzed triflate reduction

A new synthetic method for the removal of the 4, 5-bridged ether moiety of several opioids has been developed. This process offers a faster, simpler synthetic route to obtain the morphinone scaffold in high yields without the need for protection of the ketone moiety.

Phase‐Transfer‐Catalyzed Asymmetric Alkylation of α‐Benzoyloxy‐β‐keto Esters: Stereoselective Construction of Congested 2,3‐Dihydroxycarboxylic Acid Esters

Highly enantioselective phase-transfer-catalyzed alkylation of tert-butyl 2-benzoyloxy-3-oxobutanoate was realized by the use of an N-spiro chiral quaternary ammonium salt, as a complementary approach to the asymmetric hydroxylation of alpha-alkyl-beta-keto esters. The synthetic utility of the alkylated compounds is highlighted by the diastereoselective reduction and alkylation of the remaining ketone moiety to give various enantiomerically enriched congested 2,3-dihydroxycarboxylic acid esters.

Efficient and Selective Extraction of Fe3+ by Mono- and Di-Azocalix[4]arene Derivatives

Nine series of chromogenic mono- (A1-A2) and di- (B1-B7) substituted azocalix[4] arene analogues containing more than one azo group were described. Different chelating agents like ester and ketone moieties were grafted on the lower rim position of azocalix[4]arenes. The selective extraction properties of Fe3+ cation were studied by liquid-liquid extraction. This extraction process was carried out by using compounds A1-A2 and B1-B7. The results proved that coupling of phenylazo groups onto the upper rim of azocalix[4]arenes yielded greater efficiency and selectivity for carrying the Fe3+ cation in the extraction process at pH 2.2.

Furan Ring‐Opening/Indole Ring‐Closure: Pictet–Spengler‐Like Reaction of 2‐(o‐Aminophenyl)furans with Aldehydes

AbstractA new simple approach to 3‐(2‐acylvinyl)‐2‐(hetero)arylindoles has been developed. The method is based on the acid‐catalysed interaction of 2‐(2‐aminophenyl)furans with(hetero)aromatic aldehydes. The reactions proceed under very mild conditions and lead to indoles containing a reactive α,β‐unsaturated ketone moiety, which is suitable for further transformations, in moderate to good yields.

ChemInform Abstract: Synthesis of Functionalized Indoles with an α‐Stereogenic Ketone Moiety Through an Enantioselective Friedel—Crafts Alkylation with (E)‐1,4‐Diaryl‐2‐butene‐1,4‐diones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Cucurbitane-Type Triterpenes with Anti-proliferative Effects on U937 Cells from an Egyptian Natural Medicine, Bryonia cretica: Structures of New Triterpene Glycosides, Bryoniaosides A and B

The 90% aqueous ethanol extract of an Egyptian natural medicine, the roots of Bryonia cretica L., was found to exhibit a strong inhibitory effect on the proliferation of human leukemia U937 cells. By bioassay-guided fractionation, we isolated two new cucurbitane-type triterpene glycosides, bryoniaosides A and B, were isolated from the roots of Bryonia cretica L. together with 16 known cucurbitane-type triterpenes and glycosides. The chemical structures of bryoniaosides A and B were determined on the basis of chemical and spectroscopic evidence. Effects of principal cucurbitane-type triterpenes (cucurbitacins B, D, E, and J, 23,24-dihydrocucurbitacins B and E, and hexanorcucurbitacin D) on proliferation of the cells were examined. Cucurbitacins B and E showed the greater cytotoxic effects with IC(50) values of 9.2 and 16 nM after 72 h, and their IC(50) values were equivalent to that of camptothecin. An alpha,beta-conjugated ketone moiety at the 22-24-positions and an acetoxy group at the 25-position are essential for the strong activity.

Rhodium-Catalyzed 1,2-Addition of Sb-Phenyl-1,5-azastibocines to Functionalized Aldehydes

Simple and efficient addition of a phenyl group to aldehydes was accomplished by the rhodium-catalyzed reaction of Sb-phenyl-1,5-azastibocines. Because of the soft nucleophilic character of 1,5-azastibocines, arylation of functionalized aldehydes having ketone, ester, and halogen moieties can be achieved to afford aryl alcohols. The reaction can be carried out under aerobic conditions, in striking contrast to the reactions with hard nucleophiles such as organolithium and Grignard reagents.

Cyclization of Arylacetoacetates to Indene and Dihydronaphthalene Derivatives in Strong Acids. Evidence for Involvement of Further Protonation of O,O-Diprotonated β-Ketoester, Leading to Enhancement of Cyclization

The chemical features, such as substrate stability, product distribution, and substrate generality, and the reaction mechanism of Brønsted superacid-catalyzed cyclization reactions of aromatic ring-containing acetoacetates (beta-ketoesters) were examined in detail. While two types of carbonyl cyclization are possible, i.e., keto cyclization and ester cyclization, the former was found to take place exclusively. The reaction constitutes an efficient method to synthesize indene and 3,4-dihydronapthalene derivatives. Acid-base titration monitored with (13)C NMR spectroscopy showed that the acetoacetates are fully O(1),O(3)-diprotonated at H(0) = -11. While the five-membered ring cyclization of the arylacetoacetates proceeded slowly at H(0) = -11, a linear increase in the rate of the cyclization was found with increasing acidity in the high acidity region of H(0) = -11.8 to -13.3. Therefore, the O(1),O(3)-diprotonated acetoacetates exhibited some cyclizing reactivity, but they are not the reactive intermediates responsible for the acceleration of the cyclization in the high acidity region. The reactive cationic species might be formed by further protonation (or protosolvation) of the O(1),O(3)-diprotonated acetoacetates; i.e., they may be tricationic species. Thermochemical data on the acid-catalyzed cyclization of the arylacetoacetates showed that the activation energy is decreased significantly as compared with that of the related acid-catalyzed cyclization reaction of a compound bearing a single functional group, such as a ketone. These findings indicate that intervention of the trication contributes to the activation of the cyclization of arylacetoacetates in strong acid, and the electron-withdrawing nature of the O-protonated ester functionality significantly increases the electrophilicity of the ketone moiety.

Conformational Analyses and MO Studies of f152A1 and Its Analogues as Potent Protein Kinase Inhibitors

f152A1 was isolated from a fermentation broth of Curvularia verruculosa and characterized as a potent inhibitor of TNFalpha transcription, with anti-inflammatory activity. f152A1 and several analogues displayed inhibitory activity against the MAP kinases ERK2 and MEK1 in in vitro kinase assays. Through SAR studies on f152A1 and analogues prepared via total synthesis, we have identified structural features that contribute to inhibitory activity. To rationalize these results and to aid in the discovery process, a combination of high temperature molecular dynamics and MOPAC AM1 semiempirical molecular orbital method studies was used in studies that yielded a postulated active conformation, M1(8). This active conformation M1(8) reflects a high degree of conformational similarity among f152A1 and its more potent analogues. In view of the highly reactive cis-enone moiety in the flexible 14-membered resorcylic acid lactone ring of f152A1, the chemical reactivities of the enone moieties in various analogues were assessed by molecular orbital calculations. The enone reactivity analyses suggested that these inhibitors were prone to Michael addition at the alpha,beta-unsaturated ketone moiety and might chemically react with cysteine residues in the ATP-binding site of MAP kinases. Reactivity of the cis-enone moiety and the M1(8) conformation make important contributions to the inhibitory activity of MAP kinases.

Domino Multicomponent Michael-Michael-Aldol Reactions under Phase-Transfer Catalysis: Diastereoselective Synthesis of Pentasubstituted Cyclohexanes

A simple, efficient, and environmental friendly domino multicomponent reaction to construct new cyclohexane derivatives with five new stereocenters, one of them quaternary, under phase-transfer catalysis is reported. This novel one-pot reaction allows the transformation of very simple starting materials into pentasubstituted cyclohexane derivatives bearing hydroxy, nitro, and ketone moieties and involving the formation of three new C-C bonds. All compounds have been formed in a completely diastereoselective way and have been isolated in high yields.

Molecular Tuning of Phenylene-Vinylene Derivatives for Two-Photon Photosensitized Singlet Oxygen Production

Substituent-dependent features and properties of the sensitizer play an important role in the photosensitized production of singlet oxygen, O(2)(a(1)Delta(g)). In this work, we systematically examine the effect of molecular changes in the sensitizer on the efficiency of singlet oxygen production using, as the sensitizer, oligophenylene-vinylene derivatives designed to optimally absorb light in a nonlinear two-photon process. We demonstrate that one cannot always rely on rule-of-thumb guidelines when attempting to construct efficient two-photon singlet oxygen sensitizers. Rather, as a consequence of behavior that can deviate from the norm, a full investigation of the photophysical properties of the system is generally required. For example, it is acknowledged that the introduction of a ketone moiety to the sensitizer chromophore often results in more efficient production of singlet oxygen. However, we show here that the introduction of a carbonyl into a given phenylene-vinylene can, rather, have adverse effects on the yield of singlet oxygen produced. Using these molecules, we show that care must also be exercised when using qualitative symmetry-derived arguments to predict the relationship between one-and two-photon absorption spectra.

Calcium Complexation by Corticosteroids

Cortisone and hydrocortisone form calcium complexes of 2:1 steroid/Ca(2+) stoichiometry in solution, with formation constants of 201 +/- 1.7 and 184 +/- 1.7 M(-2), respectively-roughly half the value seen for a simple aromatic alpha-hydroxy ketone, phenacyl alcohol (341 +/- 10.0 M(-2)). X-ray crystallographic analysis demonstrates maintenance of this 2:1 stoichiometry in the solid state for the phenacyl alcohol and cortisone complexes, while the hydrocortisone complex crystallizes with a 1:1 stoichiometry in the form of linear chains, with the alpha-hydroxy ketone ligand and C(3) (A-ring) carbonyl groups binding two different calcium ions. In each complex, both in solution and in the solid state, the alpha-hydroxy ketone moiety serves as a bidentate chelator for calcium. Extensive hydrogen-bonded networks are present in each structure, linking various hydroxyl groups, coordinated and noncoordinated hydrate molecules, and the chloride counterions, in essence representing supramolecular complexation of the hydrated chloride anion.

Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol

Ethnopharmacological relevance Zingiber officinale Rosc. (Zingiberaceae) has been traditionally used in Ayurvedic, Chinese and Tibb-Unani herbal medicines for the treatment of various illnesses that involve inflammation and which are caused by oxidative stress. Although gingerols and shogaols are the major bioactive compounds present in Zingiber officinale, their molecular mechanisms of actions and the relationship between their structural features and the activity have not been well studied. Aim of the study The aim of the present study was to examine and compare the antioxidant and anti-inflammatory activities of gingerols and their natural analogues to determine their structure–activity relationship and molecular mechanisms. Materials and methods The in vitro activities of the compounds [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol were evaluated for scavenging of 1,1-diphenyl-2-picyrlhydrazyl (DPPH), superoxide and hydroxyl radicals, inhibition of N-formyl-methionyl-leucyl-phenylalanine ( f-MLP) induced reactive oxygen species (ROS) production in human polymorphonuclear neutrophils (PMN), inhibition of lipopolysaccharide induced nitrite and prostaglandin E 2 production in RAW 264.7 cells. Results In the antioxidant activity assay, [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol exhibited substantial scavenging activities with IC 50 values of 26.3, 19.47, 10.47 and 8.05 μM against DPPH radical, IC 50 values of 4.05, 2.5, 1.68 and 0.85 μM against superoxide radical and IC 50 values of 4.62, 1.97, 1.35 and 0.72 μM against hydroxyl radical, respectively. The free radical scavenging activity of these compounds also enhanced with increasing concentration ( P < 0.05). On the other hand, all the compounds at a concentration of 6 μM have significantly inhibited ( P < 0.05) f-MLP-stimulated oxidative burst in PMN. In addition, production of inflammatory mediators (NO and PGE 2) has been inhibited significantly ( P < 0.05) and dose-dependently. Conclusions 6-Shogaol has exhibited the most potent antioxidant and anti-inflammatory properties which can be attributed to the presence of α,β-unsaturated ketone moiety. The carbon chain length has also played a significant role in making 10-gingerol as the most potent among all the gingerols. This study justifies the use of dry ginger in traditional systems of medicine.

Synthesis of Functionalized Indoles with an α‐Stereogenic Ketone Moiety Through an Enantioselective Friedel–Crafts Alkylation with (E)‐1,4‐Diaryl‐2‐butene‐1,4‐diones

AbstractChiral complexes of BINOL‐based ligands with hafnium tert‐butoxide catalyze the enantioselective Friedel–Crafts alkylation of indoles with (E)‐1,4‐diaryl‐2‐butene‐1,4‐diones at room temperature, with good yields and ee up to 94%. Hafnium(IV) was found to be a more effective Lewis acid than other frequently used metal ions such as titanium(IV) or zirconium(IV). Unlike the enantioselective Friedel–Crafts alkylation of indoles with α,β‐unsaturated compounds where the stereogenic center is generated in the β‐position to a carbonyl group, the Friedel–Crafts alkylation with 2‐butene‐1,4‐diones described here generates an α‐stereogenic center with respect to one of the carbonyl groups. This can be regarded as an inversion of the normal reactivity pattern or umpolung. The enantioselective Friedel–Crafts alkylation of indoles with (E)‐4‐oxo‐4‐phenylbutenoates using a zirconium(IV)‐BINOL catalyst is also reported. This reaction takes place regioselectively at the carbon in the β‐position to the ketone carbonyl group, generating an α‐ester stereogenic center.

Direct Construction of 1,3-Diaxial Diol Derivatives by C−H Hydroxylation

Direct hydroxylation of tertiary C-H bonds for construction of 1,3-diaxial diol derivatives was achieved by devising a new detachable dioxirane precursor containing a trifluoromethyl ketone moiety and ethylene tether. Oxone treatment of the ketones led to the corresponding dioxiranes, enabling hydroxy group installment into cyclohexane and steroid derivatives in a regio- and stereoselective manner through intramolecular oxygen insertion.

Synthesis, Antibacterial and Analgesic Activities of 4‐[1‐Oxo‐3‐(substituted aryl)‐2‐propenyl]‐3‐(4‐methylphenyl) sydnones

A series of sydnone derivatives containing styryl ketone moiety, 4‐[1‐oxo‐3‐(substituted aryl)‐2‐propenyl]‐3‐(4‐methylphenyl)sydnones (6a‐i) has been synthesized and characterized by spectral data. The synthesized compounds have been screened for preliminary antibacterial activity by cup plate method and analgesic activity by the method of acetic acid induced writhing in mice. The chloro and nitro derivatives showed good antibacterial activity against both gram positive and gram negative bacteria while the chloro and furyl derivatives exhibited highest analgesic effect among the series.