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A new synthetic approach to thiolactones that employs an efficient acyl thiol-ene (ATE) or acyl thiol-yne (ATY) cyclization to convert unsaturated thiocarboxylic acid derivatives into thiolactones under very mild conditions is described. The high overall yields, fast kinetics, high diastereoselectivity, excellent regiocontrol, and broad substrate scope of these reaction processes render this a very useful approach for diversity-oriented synthesis and drug discovery efforts. A detailed computational rationale is provided for the observed regiocontrol. [ABSTRACT FROM AUTHOR]

A direct acyl radical addition to 2H-indazoles has been achieved for the first time, where the less-aromatic quinonoid 2H-indazoles readily accepted radical species to the C-3 position. Motivated by the lack of direct acylation strategy for 2H-indazoles, the current method utilizes the radical acceptability of 2H-indazoles, discovering an ambient temperature reaction to provide facile access to a diverse array of 3-acyl-2H-indazoles with three points of structural diversification in 25%-83% yields. [ABSTRACT FROM AUTHOR]

An unusual strategy toward novel substituted benzo[b]thiophenes has been developed. The generation of arynes in the presence of acyl ketene dithioacetals resulted in a cascade reaction involving [3 + 2] cycloaddition, and a dealkylative arylation of a thioether moiety to afford 2,3-disubstuted benzo[b]thiophenes. This route represents an expeditious approach to benzothiophenes that employs acyl ketene dithioacetals as dipoles. [ABSTRACT FROM AUTHOR]

A palladium/norbornene-catalyzed ortho acylation for the efficient synthesis of functionalized alkyl aryl ketones is reported. Studies on the electronic and steric properties of mixed aryl anhydrides indicated that the cross-coupling favored with the electron-enriched aryl acyl group. DFT calculation on the oxidative addition of Pd(II) with 2,4,6-(Cl)3C6H2CO2C(O)Ph suggested that 2,4,6-(Cl)3C6H2C(O)-O bond cleavage was more kinetically disfavored than that of the PhC(O)-O bond by 11.7 kJ/mol. [ABSTRACT FROM AUTHOR]

Concepts of solid-state NMR spectroscopy and applications to fluid membranes are reviewed in this paper. Membrane lipids with 2H-labeled acyl chains or polar head groups are studied using [sup 2]H NMR to yield knowledge of their atomistic structures in relation to equilibrium properties. This review demonstrates the principles and applications of solid-state NMR by unifying dipolar and quadrupolar interactions and highlights the unique features offered by solid-state [sup 2]H NMR with experimental illustrations. For randomly oriented multilamellar lipids or aligned membranes, solidstate [sup 2]H NMR enables direct measurement of residual quadrupolar couplings (RQCs) due to individual C-2H-labeled segments. The distribution of RQC values gives nearly complete profiles of the segmental order parameters S[sup (i)]CD as a function of acyl segment position (i). Alternatively, one can measure residual dipolar couplings (RDCs) for natural abundance lipid samples to obtain segmental SCH order parameters. A theoretical mean-torque model provides acyl-packing profiles representing the cumulative chain extension along the normal to the aqueous interface. Equilibrium structural properties of fluid bilayers and various thermodynamic quantities can then be calculated, which describe the interactions with cholesterol, detergents, peptides, and integral membrane proteins and formation of lipid rafts. One can also obtain direct information for membrane-bound peptides or proteins by measuring RDCs using magic-angle spinning (MAS) in combination with dipolar recoupling methods. Solid-state NMR methods have been extensively applied to characterize model membranes and membrane-bound peptides and proteins, giving unique information on their conformations, orientations, and interactions in the natural liquid-crystalline state. [ABSTRACT FROM AUTHOR]

N-Acylsaccharin represents a facile acyl group transfer agent to heteroarenes in the presence of Pd(II)/NHC complexes appended with a pyrene unit. Catalytic acylation of heteroarenes was enhanced by the noncovalent interaction between the pyrene unit and substrates. High functional group tolerance, broad substrate scope, and moderate to good yields of 2-acylated azoles are added features of this method. [ABSTRACT FROM AUTHOR]

The acyl substitution reactions between 1-hydroxy-7-aza-benzotriazole (HOAt)/1-hydroxy-benzotriazole (HOBt) ester reagents and nucleophilic side chains on peptides have been demonstrated in the gas phase via ion/ion reactions. The HOAt/HOBt ester reagents were synthesized in solution and ionized via negative nano-electrospray ionization. The anionic reagents were then reacted with doubly protonated model peptides containing amines, guanidines, and imidazoles in the gas phase. The complexes formed in the reaction cell were further probed with ion trap collision induced dissociation (CID) yielding either a covalently modified analyte ion or a proton transfer product ion. The covalent reaction yield of HOAt/HOBt ester reagents was demonstrated to be higher than the yield with N-hydroxysuccinimide (NHS) ester reagents over a range of equivalent conditions. Density functional theory (DFT) calculations were performed with a primary amine model system for both triazole-ester and NHS-ester reactants, which indicated a lower transition state barrier for the former reagent, consistent with experiments. The work herein demonstrates that the triazole-ester reagents are more reactive, and therefore less selective, than the analogous NHS-ester reagent. As a consequence, the triazole-ester reagents are the first to show efficient reactivity with unprotonated histidine residues in the gas phase. For all nucleophilic sites and all reagents, covalent reactions are favored under long time, low amplitude activation conditions. This work presents a novel class of reagents capable of gas-phase conjugation to nucleophilic sites in analyte ions via ion/ion chemistry. [ABSTRACT FROM AUTHOR]

N-Acyliminium ions are powerful reactive species for the formation of carbon--carbon and carbon--heteroatom bonds. Strategies relying on intramolecular reactions of N-acyliminium intermediates, also referred to as N-acyliminium ion cyclization reactions, have been employed for the construction of structurally diverse scaffolds, ranging from simple bicyclic skeletons to complex polycyclic systems and natural-product-like compounds. This review aims to provide an overview of cyclization reactions of N-acyliminium ions derived from various precursors for the assembly of structurally diverse scaffolds, covering the literature over the past 12 years (from 2004 to 2015). [ABSTRACT FROM AUTHOR]

The simple acetylation or acrylation of poly(ethylene glycol) (PEG) terminus leads to the aggregation of PEG chains into spherical nanoparticles in water at room temperature and very low concentrations. The experiment results suggest that this aggregation happens by the variation of the local conformation of the O–CH2–CH2–O segments of PEG chains caused by the introduced acyl group, which disturbs the originally strict hydrogen bond mode between the O–CH2–CH2–O groups and the water molecules. The simple modified PEG nanoparticles are excellent carriers for drug delivery. As examples, the cross-linkable 1d-based drug delivery systems, cPEG@SN-38 and targeted cPEG@SN-38, are successfully established by their high drug loading content (18 wt %/wt) and enhanced anticancer efficacy both in vitro and in vivo while obviating the inherent toxicity of the employed chemotherapeutics. This strategy that revolves around the simple modification of the generally regarded as safe (GRAS) modules to fabricate drug carriers represents a new direction for the drug delivery systems with clinical potential. [ABSTRACT FROM AUTHOR]

Lipid A molecules consist of a diglucosamine sugar core with a number of appended acyl chains that vary in their length and connectivity. Because of the challenging nature of characterizing these molecules and differentiating between isomeric species, an energy-resolved MS/MS strategy was undertaken to track the fragmentation trends and map genealogies of product ions originating from consecutive cleavages of acyl chains. Generalizations were developed based on the number and locations of the primary and secondary acyl chains as well as variations in preferential cleavages arising from the location of the phosphate groups. Secondary acyl chain cleavage occurs most readily for lipid A species at the 3′ position, followed by primary acyl chain fragmentation at both the 3′ and 3 positions. In the instances of bisphosphorylated lipid A variants, phosphate loss occurs readily in conjunction with the most favorable primary and secondary acyl chain cleavages. [ABSTRACT FROM AUTHOR]

The enzymology of 135 assembly lines containing primarily cis-acyltransferase modules is comprehensively analyzed, with greater attention paid to less common phenomena. Diverse online transformations, in which the substrate and/or product of the reaction is an acyl chain bound to an acyl carrier protein, are classified so that unusual reactions can be compared and underlying assembly-line logic can emerge. As a complement to the chemistry surrounding the loading, extension, and offloading of assembly lines that construct primarily polyketide products, structural aspects of the assembly-line machinery itself are considered. This review of assembly-line phenomena, covering the literature up to 2017, should thus be informative to the modular polyketide synthase novice and expert alike. [ABSTRACT FROM AUTHOR]

The first chemical study of the common species Terrazoanthus onoi, present off the coast of Ecuador, led to the identification of a new family of 2-aminoimidazole alkaloids named terrazoanthines A-C (1-3). Homologues 1 and 2 feature an unprecedented 6-(imidazol-5-yl)benzo[d]imidazole. Acyl substitution pattern and complete configurational assignments were deduced from comparison between experimental and theoretical 13C NMR and ECD data, respectively. These compounds may represent key derivatives in the biosynthesis of zoanthoxanthins. [ABSTRACT FROM AUTHOR]

Fluorescence microscopy is an important technique for studying lipid membranes and is increasingly being used for examining liquid ordered-liquid disordered phase coexistence. Liquid-liquid phase coexistence is a phenomenon of biological interest because it led to the lipid raft hypothesis, which postulates the existence of lateral heterogeneities in cell membranes. Observation of membrane heterogeneity relies on differential distribution of fluorescent membrane markers, but this can also modify the phase behavior, complicating the observation. We have used 2H NMR to measure the physical changes to 35:35:30 (mol/mol) DOPC/DPPC-D62/chol membranes introduced by fluorescent probes Laurdan and naphthopyrene. We measured miscibility transition temperature (Tmix) and DPPC-D62 chain order for a range of probe concentrations. We found that up to 0.5 mol% of the equipartitioning probe Laurdan does not influence DPPC-D62 acyl chain order or phase behavior. In contrast, 2.0 mol% Laurdan slightly increases the fraction of DPPC-D62 in the liquid disordered phase below the Tmix and increases Tmix by 1 °C. Conversely, the nominally liquid ordered phase preferring probe naphthopyrene slightly perturbs the membrane even at concentrations as low as 0.3 mol%. This suggests that the strength of fluorescent probe partitioning between liquid ordered and liquid disordered phases correlates with the degree of perturbation to membrane phase behavior. [ABSTRACT FROM AUTHOR]

The hepatotoxicity of acetaminophen (APAP) is generally attributed to the formation of a reactive quinoneimine metabolite (NAPQI) that depletes glutathione and covalently binds to hepatocellular proteins. To explore the importance of the N-acyl group in APAP metabolism and toxicity, we synthesized 12 acyl side chain homologues of acetaminophen (APAP) and its 3'-regioisomer (AMAP), including the respective N-(4-pentynoyl) analogues PYPAP and PYMAP. Rat hepatocytes converted APAP, AMAP, PYPAP, and PYMAP extensively to O-glucuronide and O-sulfate conjugates in varying proportions, whereas glutathione or cysteine conjugates were observed only for APAP and PYPAP. PYPAP and PYMAP also underwent N-deacylation followed by O-sulfation and/or N-acetylation to a modest extent. The overall rates of metabolism in hepatocytes varied approximately 2-fold in the order APAP < AMAP ≈ PYPAP < PYMAP. Rat liver microsomes supplemented with NADPH and GSH converted APAP and PYPAP to their respective glutathione conjugates (formed via a reactive quinoneimine intermediate). With PYPAP only, a hydroxylated GSH conjugate was also observed. Thus, differences in biotransformation among these analogues were modest and mostly quantitative in nature. Cytotoxicity was evaluated in cultured hepatocytes by monitoring cell death using time-lapse photomicrography coupled with Hoechst 33342 and CellTox Green dyes to facilitate counting live cells vs dead cells, respectively. Progress curves for cell death and the areas under those curves showed that toxicity was markedly dependent on compound, concentration, and time. AMAP was essentially equipotent with APAP. Homologating the acyl side chain from C-2 to C-5 led to progressive increases in toxicity up to 80-fold in the para series. In conclusion, whereas N- or ring-substitution on APAP decrease metabolism and toxicity, homologating the N-acyl side chain increases metabolism about 2-fold, preserves the chemical reactivity of quinoneimine metabolites, and increases toxicity by up to 80-fold. [ABSTRACT FROM AUTHOR]

The development of efficient catalytic methods for N-C bond cleavage in amides remains an important synthetic challenge. The first Pd-catalyzed Suzuki-Miyaura cross-coupling of N-acylsaccharins with boronic acids by selective N-C bond activation is reported. The reaction enables preparation of a variety of functionalized diaryl and alkyl-aryl ketones with broad functional group tolerance and in good to excellent yields. Of general interest, N-acylsaccharins serve as new, highly reactive, bench-stable, economical, amide-based, electrophilic acyl transfer reagents via acyl-metal intermediates. Mechanistic studies strongly support the amide N-C(O) bond twist as the enabling feature of N-acylsaccharins in the N-C bond cleavage. [ABSTRACT FROM AUTHOR]

To better understand the interactions of saturated ceramides with unsaturated glycerophospholipids in bilayer membranes, we measured how palmitoyl ceramide (PCer) and dihydroceramide (dihydro-PCer, lacking the trans 4 double bond of the sphingoid base of ceramide) can interact with phosphatidylcholines (PCs) with palmitic acid in the sn-1 position and increasingly unsaturated acyl chains in the sn-2 position. The PCs were 16:0/18:1 (POPC), 16:0/18:2 (PLPC), 16:0/20:4 (PAPC), and 16:0(22:6 (PDPC). We also included di-18:1-PC (DOPC) to compare it with POPC. Because the ceramides were expected to segregate laterally to an ordered ceramide-rich phase, we determined the formation of the ordered phase using lifetime analysis of trans-parinaric acid (tPA) fluorescence. The presence of ordered domains, as indicated by tPA lifetime analysis, was verified by an analysis of tPA anisotropy as a function of temperature. The interaction between PCer and POPC was clearly more favored than interactions with DOPC, as seen from a more thermostable gel phase in POPC than in DOPC at equal ceramide content. The concentration needed for PCer gel phase formation was also lower in POPC than in the DOPC bilayers, suggesting that POPC had better miscibility in the ordered phase. The increased unsaturation of the sn-2 acyl chains of the PCs had more clear effects of dihydro-PCer segregation than on PCer segregation, and the dihydro-PCer gel phase became more thermostable as the unsaturation in the PC increased. We conclude that the interactions between ceramides and PCs were complex and affected both by the trans 4 double bond of PCer by the palmitoyl acyl in the sn-1 position and by the overall degree of unsaturation of the sn-2 acyl chain of the PCs. [ABSTRACT FROM AUTHOR]

A tandem Sonogashira coupling/cyclization/aromatization sequence of β-halo vinyl sulfones/ketones with terminal alkynes has been developed for the construction of benzene rings. Polysubstituted functionalized benzenes containing a sulfonyl or an acyl group could be obtained in up to 95% yield. [ABSTRACT FROM AUTHOR]

Unambiguous identification of isomeric lipids by mass spectrometry represents a significant analytical challenge in contemporary lipidomics. Herein, the combination of collision-induced dissociation (CID) with ozone-induced dissociation (OzID) on an ion-trap mass spectrometer is applied to the identification of triacylglycerol (TG) isomers that vary only by the substitution pattern of fatty acyl (FA) chains esterified to the glycerol backbone. Isolated product ions attributed to loss of a single FA arising from CID of [TG + Na]+ ions react rapidly with ozone within the ion trap. The resulting CID/OzID spectra exhibit abundant ions that unequivocally reveal the relative position of FAs along the backbone. Isomeric TGs containing two or three different FA substituents are readily differentiated by diagnostic ions present in their CID/OzID spectra. Compatibility of this method with chromatographic separations enables the characterization of unusual TGs containing multiple short-chain FAs present in Drosophila. [ABSTRACT FROM AUTHOR]

The reversible acetylation of lysines is one of the best characterized epigenetic modifications. Its involvement in many key physiological and pathological processes has been documented in numerous studies. Lysine deacetylases (KDACs) and acetyltransferases (KATs) maintain the acetylation equilibrium at histones but also many other proteins. Besides acetylation, also other acyl groups are reversibly installed at the side chain of lysines in proteins. Because of their involvement in disease, KDACs and KATs were proposed to be promising drug targets, and for KDACs, indeed, five inhibitors are now approved for human use. While there is a similar level of evidence for the potential of KATs as drug targets, no inhibitor is in clinical trials. Here, we review the evidence for the diverse roles of KATs in disease pathology, provide an overview of structural features and the available modulators, including those targeting the bromodomains of KATs, and present an outlook. [ABSTRACT FROM AUTHOR]

Sirtuins are NAD+-dependent protein deacylases that cleave off acetyl but also other acyl groups from the ε-amino group of lysines in histones and other substrate proteins. Dysregulation of human Sirt2 (hSirt2) activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, which makes the modulation of hSirt2 activity a promising strategy for pharmaceutical intervention. The sirtuin rearranging ligands (SirReals) have recently been discovered by us as highly potent and isotype-selective hSirt2 inhibitors. Here, we present a well-defined structure-activity relationship study, which rationalizes the unique features of the SirReals and probes the limits of modifications on this scaffold regarding inhibitor potency. Moreover, we present a crystal structure of hSirt2 in complex with an optimized SirReal derivative that exhibits an improved in vitro activity. Lastly, we show cellular hyperacetylation of the hSirt2 targeted tubulin caused by our improved lead structure. [ABSTRACT FROM AUTHOR]

The interdigitated phase of the lipid bilayer results when acyl chains from opposing monolayers fully interpenetrate such that the terminal methyl groups of the respective lipid chains are located at the interfacial region on the opposite sides of the bilayer. Usually, chain interdigitation is not encountered in a symmetric chain phosphatidylcholine (PC) membrane but can be induced under certain special conditions. In this article, we elucidate the contribution of small amphiphatic molecules in altering the physical properties of a symmetric chain PC bilayer membrane, which results in acyl chain interdigitation. Using small-angle X-ray scattering (SAXS), we have carried out a systematic investigation of the physical interactions of three naphthalene derivatives containing hydroxyl groups: ß-naphthol, 2,3-dihydroxynaphthalene, and 2,7-dihydroxynaphthalene, with dipalmitoylphosphatidylcholine (DPPC) bilayers. On the basis of the diffraction patterns, we have determined the temperature-composition phase diagrams of these binary mixtures. The present study not only enables us to gain insight into the role played by small molecules in altering the packing arrangement of the acyl chains of the constituting PC lipids of the bilayer but also brings to light some important features that have not yet been reported hitherto. One such feature is the stabilization of the enigmatic asymmetric ripple phase over a wide temperature and concentration range. The results presented here strongly point toward a clear correlation between chain interdigitation and the stability of the ripple phase. [ABSTRACT FROM AUTHOR]

Headgroup-functionalized lipids arebeing developed as ligand tethers for high selectivity separationson polypropylene capillary-channeled polymer fiber stationary phases.Surface modification is affected under ambient conditions from aqueoussolution. This basic methodology has promise in many areas where robustmodifications are desired on hydrophobic surfaces. In order to understandthe mode of adsorption of the lipid tail to the polypropylene surface,lipids labeled with the environmentally sensitive 7-nitro-2-1,3-benzoxadiazol-4-yl(NBD) fluorophore were used, with NBD covalently attached to the headgroup(NBD-PE) or the acyl chain (acyl NBD-PE) of the lipid. When modifiedwith the acyl NBD-PE, fluorescence imaging of the fiber at excitationwavelengths increasing from 470 to 510 nm caused a 32 nm shift inemission toward the red edge of the absorption band, indicating thatthe NBD molecule (and thus the lipid tail) is motionally restricted.Fluorescence imaging on fibers modified with NBD-PE or the free NBD-Cldye molecule yields no change in the emission response. The resultsof these imaging studies provide evidence that the acyl chain portionsof the lipids intercalate into free volume of the polypropylene fiberstructure, yielding a robust means of surface modification and thepotential for high ligand densities. [ABSTRACT FROM AUTHOR]

Acylation of lysine is an important protein modification regulating diverse biological processes. It was recently demonstrated that members of the human Sirtuin family are capable of catalyzing long chain deacylation, in addition to the well-known NAD+-dependent deacetylation activity [Feldman, J. L., Baeza, J., and Denu, J. M. (2013) J. Biol. Chem. 288, 31350–31356]. Here we provide a detailed kinetic and structural analysis that describes the interdependence of NAD+-binding and acyl-group selectivity for a diverse series of human Sirtuins, SIRT1–SIRT3 and SIRT6. Steady-state and rapid-quench kinetic analyses indicated that differences in NAD+ saturation and susceptibility to nicotinamide inhibition reflect unique kinetic behavior displayed by each Sirtuin and depend on acyl substrate chain length. Though the rate of nucleophilic attack of the 2'-hydroxyl on the C1'-O-alkylimidate intermediate varies with acyl substrate chain length, this step remains rate-determining for SIRT2 and SIRT3; however, for SIRT6, this step is no longer rate-limiting for long chain substrates. Cocrystallization of SIRT2 with myristoylated peptide and NAD+ yielded a co-complex structure with reaction product 2'-O-myristoyl-ADP-ribose, revealing a latent hydrophobic cavity to accommodate the long chain acyl group, and suggesting a general mechanism for long chain deacylation. Comparing two separately determined co-complex structures containing either a myristoylated peptide or 2'-O-myristoyl-ADP-ribose indicates there are conformational changes at the myristoyl–ribose linkage with minimal structural differences in the enzyme active site. During the deacylation reaction, the fatty acyl group is held in a relatively fixed position. We describe a kinetic and structural model to explain how various Sirtuins display unique acyl substrate preferences and how different reaction kinetics influence NAD+ dependence. The biological implications are discussed. [ABSTRACT FROM AUTHOR]

2-Substituted N-acyl-piperidine is a widespread and important structural motif, found in approximately 500 currently available structures, and present in nearly 30 pharmaceutically active compounds. Restricted rotation of the acyl substituent in such molecules can give rise to two distinct chemical environments. Here we demonstrate, using NMR studies and density functional theory modeling of the lowest energy structures of 5-acyl-6,7-dihydrothieno[3,2-c]pyridine derivatives, that the amide E:Z equilibrium is affected by non-covalent interactions between the amide oxygen and adjacent aromatic protons. Structural predictions were used to design molecules that promote either the E- or Z-amide conformation, enabling preparation of compounds with a tailored conformational ratio, as proven by NMR studies. Analysis of the available X-ray data of a variety of published N-acyl-piperidine-containing compounds further indicates that these molecules are also clustered in the two observed conformations. This finding emphasizes that directed conformational isomerism has significant implications for the design of both small molecules and larger amide-containing molecular architectures. [ABSTRACT FROM AUTHOR]

Ghrelin O-acyltransferase (GOAT) is an integral membrane acyltransferase responsible for catalyzing a serine-octanoylation posttranslational modification within the peptide hormone ghrelin. Ghrelin requires this octanoylation for its biological activity in stimulating appetite and in regulating other physiological pathways involved in energy balance. Blocking ghrelin acylation using GOAT inhibitors is a new potential avenue to treat health conditions impacted by ghrelin signaling, such as obesity and diabetes. Designing novel and potent GOAT inhibitors as potential therapeutics requires insight into the interactions between the ghrelin and octanoyl coenzyme A substrates and the GOAT active site. Through structure-activity investigation of ghrelin-mimetic peptide substrates and inhibitors, we have analyzed the amino acid selectivity of the enzyme as well as the functional groups involved in substrate recognition by human GOAT (hGOAT). This analysis reveals that hGOAT both prefers and tolerates a distinct set of chemical properties at each position within the N-terminal sequence of ghrelin and that sequence elements downstream of the ghrelin N-terminal sequence contribute to ghrelin binding to hGOAT. We also found that the hGOAT active site exhibits a marked preference for binding an eight-carbon acyl chain, which potentially explains the biological observation of ghrelin octanoylation in light of the acyl donor promiscuity reported for GOAT. Bioinformatics analysis, guided by our reactivity data, supports the conclusion that ghrelin is a unique substrate for hGOAT within the human proteome, providing further justification for the ghrelin-hGOAT system as a desirable drug target. By defining an array of substrate-enzyme interactions used by hGOAT to bind, recognize, and acylate ghrelin, this study yields novel insight into the character of the hGOAT active site that can serve as a guide toward the rational design of hGOAT inhibitors. [ABSTRACT FROM AUTHOR]

Ceramides(Cer) are the central molecules in sphingolipid metabolismthat participate in cellular signaling and also prevent excessivewater loss by the skin. Previous studies showed that sphingosine-basedCer with a long 16C chain (CerNS16) and very long 24C-chain ceramides(CerNS24) differ in their biological actions. Increased levels oflong CerNS16 at the expense of the very long CerNS24 have been foundin atopic dermatitis patients, and this change correlated with theskin barrier properties. To probe the membrane behavior of the longCerNS16 and the very long chain CerNS24, we studied their interactionswith fatty acids and cholesterol in model stratum corneum membranesusing infrared spectroscopy. Using Cer with deuterated acyls and/ordeuterated fatty acids, we showed differences in lipid mixing, packing,and thermotropic phase behavior between long and very long Cer. Thesedifferences were observed in the presence of lignoceric acid or aheterogeneous fatty acid mixture (C16–C24), in the presenceor absence of cholesterol sulfate, and at 5–95% humidity. Inthese membranes, very long CerNS24 prefers an extended (splayed-chain)conformation in which the fatty acid is associated with the very longCer chain. In contrast, the shorter CerNS16 and fatty acids are mostlyphase separated. [ABSTRACT FROM AUTHOR]

A concisesynthesis of peptides that contain E- or Z-dehydroisoleucine (ΔIle) residues isreported. The key reaction is an unusual antidehydrationof β-tert-hydroxy amino acid derivatives thatis mediated by the Martin sulfurane. A subsequent tandem Staudingerreduction–O → N acyl transfer process forges an amidebond to the ΔIle residue with minimal E/Zalkene isomerization. Density functional calculationsattribute the stereospecific dehydration to a highly asynchronousE2 antiprocess. [ABSTRACT FROM AUTHOR]

We have investigated the conformational preferences of a series of cyclitol derivatives, namely mono- and diesters of 1,2:5,6-di-O-isopropylidene-myo-inositol and 1,2:5,6-di-O-cyclohexylidene-myo-inositol, in both solid and solution states. The solid-state conformations were determined by single-crystal X-ray analysis. The solution-state conformations were determined by using NMR. The experimental ³JHH values were applied in the Haasnoot-Altona equation to calculate the dihedral angle (φ) between the respective vicinal protons. By fixing the dihedral angle between different sets of vicinal protons, the molecules were energy-minimized by MM2 method to visualize their conformation in solution. As the solvent polarities can influence the conformational preference, we have determined the conformations of these molecules in various solvents of different polarities such as benzene-d6, chloroform-d, acetonitrile-d3, acetone-d6, methanol-d4, and DMSO-d6. All of the compounds adopted boat conformations in solution irrespective of the solvents, acyl groups, or alkylidene protecting groups. This conformation places H6 and O3 of the cyclitol ring in proximity, such that an intramolecular CH⋯O hydrogen bond between them stabilizes this otherwise unstable conformation. However, in the solid state, several intermolecular CH⋯O hydrogen bonds force these molecules to adopt the chair conformation. This study uncovers the role of weak noncovalent interactions in influencing the molecular conformations differentially in different states. [ABSTRACT FROM AUTHOR]

Positioningof peptides with respect to membranes is an importantparameter for biological and biophysical studies using model systems.Our experiments using five different membrane peptides suggest thatthe time-dependent fluorescence shift (TDFS) of Laurdan can help whendistinguishing between peripheral and integral membrane binding andcan be a useful, novel tool for studying the impact of transmembranepeptides (TMP) on membrane organization under near-physiological conditions.This article focuses on LAH4, a model α-helical peptidewith high antimicrobial and nucleic acid transfection efficiencies.The predominantly helical peptide has been shown to orient in supportedmodel membranes parallel to the membrane surface at acidic and, ina transmembrane manner, at basic pH. Here we investigate its interactionwith fully hydrated large unilamellar vesicles (LUVs) by TDFS andfluorescence correlation spectroscopy (FCS). TDFS shows that at acidicpH LAH4does not influence the glycerol region while atbasic pH it makes acyl groups at the glycerol level of the membraneless mobile. TDFS experiments with antimicrobial peptides alamethicinand magainin 2, which are known to assume transmembrane and peripheralorientations, respectively, prove that changes in acyl group mobilityat the glycerol level correlate with the orientation of membrane-associatedpeptide molecules. Analogous experiments with the TMPs LW21 and LATshow similar effects on the mobility of those acyl groups as alamethicinand LAH4at basic pH. FCS, on the same neutral lipid bilayervesicles, shows that the peripheral binding mode of LAH4is more efficient in bilayer permeation than the transmembrane mode.In both cases, the addition of LAH4does not lead to vesicledisintegration. The influence of negatively charged lipids on thebilayer permeation is also addressed. [ABSTRACT FROM AUTHOR]

The addition of saturated fatty acids(FA) to phosphatidylcholinelipids (PC) that have saturated acyl chains has been shown to promotethe formation of lyotropic liquid-crystalline phases with negativemean curvature. PC/FA mixtures may exhibit inverse bicontinuous cubicphases (Im3m, Pn3m) or inverse topology hexagonal phases (HII), depending on the length of the acyl chains/fatty acid.Here we report a detailed study of the phase behavior of binary mixturesof dioleoylphosphatidylcholine (DOPC)/oleic acid (OA) and dioleoylphosphatidylethanolamine(DOPE)/oleic acid at limiting hydration, constructed using small-angleX-ray diffraction (SAXD) data. The phase diagrams of both systemsshow a succession of phases with increasing negative mean curvaturewith increasing OA content. At high OA concentrations, we have observedthe occurrence of an inverse micellar Fd3mphase in both systems. Hitherto, this phase had not beenreported for phosphatidylethanolamine/fatty acid mixtures, and assuch it highlights an additional route through which fatty acids mayincrease the propensity of bilayer lipid membranes to curve. We alsopropose a method that uses the temperature dependence of the latticeparameters of the HIIphases to estimate the spontaneousradii of curvature (R0) of the binarymixtures and of the component lipids. Using this method, we calculatedthe R0values of the complexes comprisingone phospholipid molecule and two fatty acid molecules, which havebeen postulated to drive the formation of inverse phases in PL/FAmixtures. These are −1.8 nm (±0.4 nm) for DOPC(OA)2and −1.1 nm (±0.1 nm) for DOPE(OA)2. R0values estimated in this way allowthe quantification of the contribution that different lipid speciesmake to membrane curvature elastic properties and hence of their effecton the function of membrane-bound proteins. [ABSTRACT FROM AUTHOR]

Polyprenylated polycyclic acylphloroglucinols (PPAP) are a constantly growing class of natural products that exhibit a common bicyclo[3.3.1]nonatrione core and consist of currently more than 200 members. A subclassification among the various natural products of this class includes the position of the exocyclic acyl group, the prenylation grade of the core, and the relative configuration at C-7 within the core. About 10% of the reported structures, however, possess an additional chiral center at C-6. Herein we describe a straightforward access to guttiferone A and epi-guttiferone A, in which full control of stereoselectivity is achieved via conformational control, and a strict separation of framework decorating from framework constructing operations sets the stage for a short 13-step synthesis. [ABSTRACT FROM AUTHOR]

Humanneutrophil elastase (HNE) is an attractive target for treating chronicand acute inflammatory lung diseases. An optimization campaign ofthe kojic acid scaffold to develop new potent HNE inhibitors is reported. O3-Pivaloyl derivatives were shown to be themost potent inhibitors with IC5ovalues down to 80 nM.These compounds presented excellent selectivity and cytotoxicity profileswith suitable ligand efficiency. [ABSTRACT FROM AUTHOR]

The efficacy of DNA-damaging anticancerdrugs is highly influencedby cellular DNA repair capacity, and by inhibiting the relevant DNArepair pathway, efficacy of alkylating agents may be increased. Therefore,combining DNA repair inhibitors with anticancer agents that selectivelytarget tumor tissue should improve cancer treatment. The objectiveof this study was to test the hypothesis that cotreatment of cancercells with acylfulvene (AF, alkylating agent) and UCN-01 (DNA repairinhibitor) would improve drug efficacy and promote the persistenceof DNA adducts. Previous data regarding the relative susceptibilityof repair proficient versus deficient cells toward an AF analoguesuggests that corresponding adducts are repaired by nuclear excisionrepair (NER), a cellular process that has been shown to be preventedwith UCN-01. In this study, cells were cotreated with nontoxic levelsof UCN-01 together with increasing doses of AF. The efficacy of AFwas assessed by measuring cytotoxicity and DNA adducts. In addition,cells were cotreated with nontoxic levels of methoxyamine, a knownbase excision repair (BER) inhibitor, to determine if inhibiting BERalso promotes cytotoxicity of AF. DNA-adducts were measured in a sensitiveand precise manner by using stable isotope-labeled mass spectrometryanalysis. The data obtained in this study demonstrate for the firsttime that pharmacological inhibition of the NER pathway of DNA repairleads to the persistence of AF-specific adducts and promotes AF cytotoxicity. [ABSTRACT FROM AUTHOR]

An efficient and scalable transformation of 3-halo-N-acyl anilines to the corresponding benzoxazoles within a continuous flow reactor is reported. This transformation proceeds viabase-mediated deprotonation, ortho-lithiation, and intramolecular cyclization to provide unstable lithiated benzoxazole moieties. The subsequent in-line electrophilic quench results in the formation of substituted benzoxazoles in high yield and quality. Continuous flow technology allowed for accurate temperature control and immediate in-line quench while minimizing the hold-up time for the unstable lithiated intermediates thereby minimizing associated byproduct formation. [ABSTRACT FROM AUTHOR]

Bacteria that cause most of the hospital-acquired infections make use of class C β-lactamase (CBL) among other enzymes to resist a wide spectrum of modern antibiotics and pose a major public health concern. Other than the general features, details of the defensive mechanism by CBL, leading to the hydrolysis of drug molecules, remain a matter of debate, in particular the identification of the general base and role of the active site residues and substrate. In an attempt to unravel the detailed molecular mechanism, we carried out extensive hybrid quantum mechanical/molecular mechanical Car−Parrinello molecular dynamics simulation of the reaction with the aid of the metadynamics technique. On this basis, we report here the mechanism of the formation of the acyl−enzyme complex from the Henry−Michaelis complex formed by β-lactam antibiotics and CBL. We considered two β-lactam antibiotics, namely, cephalothin and aztreonam, belonging to two different subfamilies. A general mechanism for the formation of a β-lactam antibiotic−CBL acyl−enzyme complex is elicited, and the individual roles of the active site residues and substrate are probed. The general base in the acylation step has been identified as Lys67, while Tyr150 aids the protonation of the β-lactam nitrogen through either the substrate carboxylate group or a water molecule. [ABSTRACT FROM AUTHOR]

Flash vacuum pyrolysis studies of substituted 6- acetoxy-2,4-cyclohexadienones (3 and 10) from 300 to 500 °C provide strong experimental evidence that direct [3,5]- sigmatropic rearrangements in these molecules are favored over the more familiar [3,3]-sigmatropic rearrangements. The preference holds when the results are extrapolated to 0.0% conversion, indicating that this is a concerted process. Pyrolysis of 6,6-diacetoxy-2-methyl-2,4-cyclohexadienone (9) at 350 °C gives a modest yield of the initial [3,5]-sigmatropic rearrangement product, 2,6-diacetoxy-6-methyl-2,4-cyclohexadienone (11). Qualitative arguments and electronic structure theory calculations are in agreement that the lowest energy pathway for each [3,5]-sigmatropic rearrangement is via an allowed, concerted pseudopericyclic transition state. The crystal structures of compounds 3, 9, and 10 prefigure these transition states. The selectivity for the [3,5] products increases with an increasing temperature. This unexpected selectivity is explained by a concerted, intramolecular, and pseudopericyclic transition state (TS-5) that forms a tetrahedral interemediate (ortho-acid ester 4'), followed by similar ring openings to isomeric phenols, which shifts the equilibrium toward the phenols from the [3,5] (but not the [3,3]) products. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulations oflipid bilayer ribbons have beenperformed to investigate the structures and line tensions associatedwith free bilayer edges. Simulations carried out for dioleoyl phosphatidylcholinewith three different force-field parameter sets yielded edge linetensions of 45 ± 2 pN, over 50% greater than the most recentlyreported experimentally determined value for this lipid. Edge tensionsobtained from simulations of a series of phosphatidylcholine lipidbilayer ribbons with saturated acyl tails of length 12–16 carbonsand with monounsaturated acyl tails of length 14–18 carbonscould be correlated with the excess area associated with forming theedge, through a two-parameter fit. Saturated-tail lipids underwentlocal thickening near the edge, producing denser packing that correlatedwith lower line tensions, while unsaturated-tail lipids showed littleor no local thickening. In a dipalmitoyl phosphatidylcholine ribboninitiated in a tilted gel-phase structure, lipid headgroups tendedto tilt toward the nearer edge producing a herringbone pattern, anaccommodation that may account for the reported edge-induced stabilizationof an ordered structure at temperatures near a lipid gel-fluid phasetransition. [ABSTRACT FROM AUTHOR]

The in vivoand in vitrocharacterization of AntB, a dedicated acyltransferase encoded in the antimycin biosynthetic gene cluster, which catalyzes the C-8 acyloxy formation is reported. It is demonstrated that AntB has broad substrate specificity toward both the acyl substrate and the acyl carrier and produces more antimycin analogues with varying C-8 acyloxy moieties. [ABSTRACT FROM AUTHOR]

Methanolysis of N-acyl-thiazolidin-2-thiones and -oxazolidin-2-thiones in the presence of acyl transfer catalyst benzotetramisole (BTM) proceeds in a highly enantioselective fashion thus enabling kinetic resolution of these substrates. [ABSTRACT FROM AUTHOR]

We disclose the first catalytic activation of carbohydrates as formaldehyde equivalents to generate acyl anions as one-carbon nucleophilic units for a Stetter reaction. The activation involves N-heterocyclic carbene (NHC)-catalyzed C-C bond cleavage of carbohydrates via a retro-benzoin-type process to generate the acyl anion intermediates. This Stetter reaction constitutes the first success in generating formal formaldehyde-derived acyl anions as one-carbon nucleophiles for non-self-benzoin processes. The renewable nature of carbohydrates, accessible from biomass, further highlights the practical potential of this fundamentally interesting catalytic activation. [ABSTRACT FROM AUTHOR]

UsingDFT calculations we identify a low-energy reaction path connectingmethyl acetate and Milstein’s trans-[Ru(H)2(PNN)(CO)] catalyst directly with acetaldehyde and trans-[Ru(H)(OMe)(PNN)(CO)]. The transformation representsa metathesis in which a hydride and an alkoxide are swapped betweena metal center and an acyl group. The reaction leads to a simple mechanismsystematically applicable to the diverse hydrogenation and dehydrogenativecoupling chemistry that can be achieved by the given catalyst. [ABSTRACT FROM AUTHOR]

We report a conceptually new polymerization technique termed migration insertion polymerization (MIP) for main chain metal-containing polymer (MCP) synthesis. Cyclopentadienyldicarbonyldiphenylphosphinopropyliron (FpP) is synthesized and polymerized via MIP, resulting in air stable poly(cyclopentadienylcarbonyldiphenylphosphinobutanoyliron) (PFpP) displaying narrow molecular weight distribution. The backbone of PFpP contains asymmetric iron units connected by both phosphine coordination and Fe-acyl bonds, which is representative of a new type of polymer. Furthermore, PFpP is tested to be soluble in a wide range of organic solvents and shown to possess reactive Fp end groups. PFpP amphiphiles have therefore been prepared via an end group migration insertion reaction in the presence of oligoethylene phosphine. [ABSTRACT FROM AUTHOR]

An efficient palladium-catalyzed synthesis of 3-acylindoles using free (N–H) indoles and nitriles has been developed. The acylation reaction proceeded well under the Pd(OAc)2/2,2′-bipyridine system and with d-(+)-camphorsulfonic acid as the additive. A possible mechanism involving carbopalladation of nitriles and subsequent hydrolysis of ketimines is proposed. [ABSTRACT FROM AUTHOR]

The DEBS1-TE fusion protein is comprised of the loading module, the first two extension modules, and the terminal TE domain of the Saccharopolyspora erythraea 6-deoxyerythronolide B synthase. DEBS1-TE produces triketide lactones that differ on the basis of the starter unit selected by the loading module. Typical fermentations with plasmid-based expression of DEBS1-TE produce a 6:1 ratio of propionate to isobutyrate-derived triketide lactones. Functional dissection of the loading module from the remainder of DEBS1-TE results in 50% lower titers of triketide lactone and a dramatic shift in the production to a 1:4 ratio of propionate to isobutyrate-derived products. A series of radiolabeling studies of the loading module has shown that transfer from the AT to the ACP occurs much faster for propionate than for isobutyrate. However, the equilibrium occupancy of the AT favors isobutyrate such that propionate is outcompeted for ACP occupancy. Thus, propionyl-ACP is the kinetic product, while isobutyryl-ACP is the thermodynamic product. A slowed transfer from the loading domain ACP to first-extension module KS due to functional dissection of DEBS1-TE allows this isobutyryl-ACP-favored equilibrium to be realized and likely accounts for the observed shift in triketide lactone products. [ABSTRACT FROM AUTHOR]

We report a tin-free one-pot radical approach to the synthesis of N-acyl isothioureas and acylguanidines from N-acyl cyanamides. Photoactivated reduction of aromatic disulfides in the presence of Hünig’s base results in hydrothiolation of the cyanamide moiety, followed by spontaneous 1,3-migration of the acyl group. Onward reaction of the isothioureas obtained with amines led to the corresponding N-acylguanidines, where the acyl group is attached to the nitrogen atom formerly at the cyano-end of the starting material. [ABSTRACT FROM AUTHOR]

A simple catalytic system that uses commercially available cobalt(II) perchlorate as the catalyst and 3-chloroperoxybenzoic acid as the oxidant was found to be very effective in the epoxidation of a variety of olefins with high product selectivity under mild experimental conditions. More challenging targets such as terminal aliphatic olefins were also efficiently and selectively oxidized to the corresponding epoxides. This catalytic system features a nearly nonradical-type and highly stereospecific epoxidation of aliphatic olefin, fast conversion, and high yields. Olefin epoxidation by this catalytic system is proposed to involve a new reactive CoII-OOC(O)R species, based on evidence from H218O-exchange experiments, the use of peroxyphenylacetic acid as a mechanistic probe, reactivity and Hammett studies, EPR, and ESI-mass spectrometric investigation. However, the O-O bond of a CoII-acylperoxo intermediate (CoII-OOC(O)R) was found to be cleaved both heterolytically and homolytically if there is no substrate. [ABSTRACT FROM AUTHOR]

Mediated by sodium persulfate (Na2S2O8), a series of polysubstituted 4-pyridones were synthesized via self-condensation of N-aryl acetoacetamides, during which a novel N to C 1,3-acyl migration should be involved. The structure of 4-pyridone was unequivocally confirmed by X-ray diffraction analysis. However, the self-condensation of N-benzyl acetoacetamides under the same condition gave polysubstituted 2-pyridones instead of 4-pyridones. [ABSTRACT FROM AUTHOR]

α,β-Unsaturated imides, formylated at the nitrogen atom, comprise a new and valuable family of dienophiles for servicing DielsAlder reactions. These systems are assembled through extension of recently discovered isonitrile chemistry to the domain of α,β-unsaturated acids. Cycloadditions are facilitated by Et2A1CI, presumably via chelation between the two carbonyl groups of the N-formyl aniide. Applications ot the isonitrile/Diels-Alder logic to the IMDA reaction, as well as methodologies to modify the N-formyl amide of the resultant cycloaddition product, are described. It is expected that this easily executed chemistry will provide a significant enhancement for application of Diels-Alder reactions to many synthetic targets. [ABSTRACT FROM AUTHOR]

Relative reactivity evaluations showed the graded arming of toluenyl thioglucosides by variously positioned silyl groups but not by their acyl counterparts. These findings were applied in reactivity-based one-pot assembly of linker-attached Lc4 and IV2Fuc-Lc4, which are components of human embryonic stem cell surface. The sugar-galectin-1 binding was also examined. [ABSTRACT FROM AUTHOR]

Tetrabutylammonium fluoride has been found to catalyzethe deacylationof cellulose esters. More surprisingly, the deacylation is highlyregioselective. Even more remarkably, in contrast with the C-6 regioselectivityof other reactions of cellulose and its derivatives, this deacylationshows substantial selectivity for the removal of the acyl groups fromthe esters of the secondary alcohols at C-2 and C-3, affording cellulose-6-O-esterswith high regioselectivity by a simple one-step process employingno protective groups. [ABSTRACT FROM AUTHOR]