A carbon–carbon hybrid – immobilizing carbon nanodots onto carbon nanotubes

The thrust of this work is to integrate small and uniformly sized carbon nanodots (CNDs) with single-walled carbon nanotubes (SWCNT) of different diameters as electron donors and electron acceptors, respectively, and to test their synergetic interactions in terms of optoelectronic devices. CNDs (denoted pCNDs, where p indicates pressure) were prepared by pressure-controlled microwave decomposition of citric acid and urea. pCNDs were immobilized on single-walled carbon nanotubes by wrapping the latter with poly(4-vinylbenzyl trimethylamine) (PVBTA), which features positively charged ammonium groups in the backbone. Negatively charged surface groups on the CNDs lead to attractive electrostatic interactions. Ground state interactions between the CNDs and SWCNTs were confirmed by a full-fledged photophysical investigation based on steady-state and time-resolved techniques. As a complement, charge injection into the SWCNTs upon photoexcitation was investigated by ultra-short time-resolved spectroscopy.     

A catalytic asymmetric total synthesis of (–)-perophoramidine

We report a catalytic asymmetric total synthesis of the ascidian natural product perophoramidine. The synthesis employs a molybdenum-catalyzed asymmetric allylic alkylation of an oxindole nucleophile and a monosubstituted allylic electrophile as a key asymmetric step. The enantioenriched oxindole product from this transformation contains vicinal quaternary and tertiary stereocenters, and is obtained in high yield along with high levels of regio-, diastereo-, and enantioselectivity. To install the second quaternary stereocenter in the target, the route utilizes a novel regio- and diastereoselective allylation of a cyclic imino ether to deliver an allylated imino ether product in near quantitative yield and with complete regio- and diastereocontrol. Oxidative cleavage and reductive amination are used as final steps to access the natural product.     

Catalytic arylsulfonyl radical-triggered 1,5-enyne-bicyclizations and hydrosulfonylation of α,β-conjugates

A catalytic bicyclization reaction of 1,5-enynes anchored by α,β-conjugates with arylsulfonyl radicals generated in situ from sulfonyl hydrazides has been established using TBAI (20 mol%) and Cu(OAc)₂ (5 mol%) as co-catalysts under convenient conditions. In addition, the use of benzoyl peroxide (BPO) as the oxidant and pivalic acid (PivOH) as an additive was proven to be necessary for this reaction. The reactions occurred through 5-exo-dig/6-endo-trig bicyclizations and homolytic aromatic substitution (HAS) cascade mechanisms to give benzo[b]fluorens regioselectively. A similar catalytic process was developed for the synthesis of γ-ketosulfones. These reactions feature readily accessible starting materials and simple one-pot operation.     

Remote stereoselective deconjugation of α,β-unsaturated esters by simple amidation reactions

The thermodynamically disfavored isomerization of α,β-unsaturated esters to deconjugated β,γ-unsaturated analogues occurs readily when coupled to an amidation. Within the framework of macrocyclic derivatives, it is shown that 15, 16, and 18 membered macrocycles react with tBuOK and anilines to generate, in one-pot, β,γ-unsaturated amides (yields up to 88%). Importantly, single (chiral) diastereomers are isolated (d.r. > 49 : 1, ¹H NMR) irrespective of the size and nature of the rings, showing an effective transmission of remote stereochemistry during the isomerization process. CSP-chromatographic resolution and absolute configuration determination by VCD are achieved.     

Effect of amyloid beta peptides Aβ<Subscript>1–28</Subscript> and Aβ<Subscript>25–40</Subscript> on model lipid membranes

To investigate the molecular interaction of amyloid beta peptides Aβ_1–28 or Aβ_25–40 with model lipid membranes differential scanning calorimetry (DSC) and DPH and TMA DPH fluorescence anisotropy approaches were used. The main transition temperature (T _m) and enthalpy change (ΔH) of model lipid membranes composed of DMPC/DPPG on addition of Aβ_25–40 or Aβ_25–40 at 10:1 (w/w) phospholipid/peptide ratio either non-aggregated or previously aggregated were examined. The effect of Aβ_1–28 and Aβ_25–40 on the membrane fluidity of liposomes made of DMPC/DPPG (98:2 w/w) was determined by fluorescence anisotropy of incorporated DPH and TMA DPH. The results of this study provide information that Aβ_1–28 preferentially interacts with the hydrophilic part of the model membranes, while Aβ_25–40 rather locates itself in the hydrophobic core of the bilayer where it reduces the order of the phospholipids packing.     

A dual catalytic strategy for carbon–phosphorus cross-coupling via gold and photoredox catalysis

A new method for the P-arylation of aryldiazonium salts with H-phosphonates via dual gold and photoredox catalysis is described. The reaction proceeds smoothly at room temperature in the absence of base and/or additives, and offers an efficient approach to arylphosphonates. The reaction is proposed to proceed through a photoredox-promoted generation of an electrophilic arylgold(iii) intermediate that undergoes coupling with the H-phosphonate nucleophile.     

Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo

Following recent work on heterometallic titanocene–gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = S–C₆H₄–COO^–) bound to gold(i)-phosphane fragments through a thiolate group [(η-C₅H₅)₂TiMe(μ-mba)Au(PR₃)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound 5 [(η-C₅H₅)₂TiMe(μ-mba)Au(PPh₃)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1 : 1 ratio) in Caki-1 renal cells was demonstrated for 5 indicating the robustness of the heterometallic compound in vitro. Two compounds were selected for further in vivo studies on mice based on their selectivity in vitro against renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg per kg per every other day) with heterometallic compound 5 as compared with the previously described [(η-C₅H₅)₂Ti{OC(O)-4-C₆H₄-P(Ph₂)AuCl}₂] 3 which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect the in vivo efficacy of this class of compounds.     

Unveiling the nature of supramolecular crown ether–C60 interactions

A series of exTTF-(crown ether)₂ receptors, designed to host C₆₀, has been prepared. The size of the crown ether and the nature of the heteroatoms have been systematically changed to fine tune the association constants. Electrochemical measurements and transient absorption spectroscopy assisted in corroborating charge transfer in the ground state and in the excited state, leading to the formation of radical ion pairs featuring lifetimes in the range from 12 to 21 ps. To rationalize the nature of the exTTF-(crown ether)₂·C₆₀ stabilizing interactions, theoretical calculations have been carried out, suggesting a synergetic interplay of donor–acceptor, π–π, n–π and CH···π interactions, which is the basis for the affinity of our novel receptors towards C₆₀.     

Studying the active-site loop movement of the S?o Paolo metallo-β-lactamase-1

Metallo-β-lactamases (MBLs) catalyse the hydrolysis of almost all β-lactam antibiotics. We report biophysical and kinetic studies on the São Paulo MBL (SPM-1), which reveal its Zn(ii) ion usage and mechanism as characteristic of the clinically important di-Zn(ii) dependent B1 MBL subfamily. Biophysical analyses employing crystallography, dynamic ¹⁹F NMR and ion mobility mass spectrometry, however, reveal that SPM-1 possesses loop and mobile element regions characteristic of the B2 MBLs. These include a mobile α3 region which is important in catalysis and determining inhibitor selectivity. SPM-1 thus appears to be a hybrid B1/B2 MBL. The results have implications for MBL evolution and inhibitor design.     

A simple and effective “capping” approach to readily tune the fluorescence of near-infrared cyanines

Heptamethine cyanines are favorable for fluorescence imaging applications in biological systems owing to their near-infrared (NIR) absorption and emission. However, it is very difficult to quench the fluorescence of NIR dyes by the classic photoinduced electron transfer mechanism due to their relatively high-lying occupied molecular orbital energy levels. Herein, we present a simple and effective “capping” approach to readily tune the fluorescence of NIR cyanines. The resulting new functional NIR CyBX (X = O, N, or S) dyes not only retain the intact tricarbocyanine scaffold, but also have a built-in switch to regulate the fluorescence by spiro-cyclization. When compared to traditional cyanines, novel CyBX dyes have a superior character in that their NIR optical properties can be readily tuned by the intrinsic spiro-cyclization mechanism. We expect that this “capping” strategy can be extended across not only the visual spectrum but also to structurally distinct fluorophores.     

Mutual stabilisation between MII 4L6 tetrahedra and MIIX4 2– metallate guests

A complex host–guest equilibrium employing metal ions incorporated into both the host and guest is discussed. M^IIX₄ ^2– metallate guests are shown to provide a good size and shape match for encapsulation within the M₄L₆ tetrahedral capsules, facilitating the generation of previously unreported Zn₄L₆ complexes. Displacement of the initial, primary template anion (ZnBr₄ ^2–) by a secondary template anion (ClO₄ ^–) is shown to result in the formation of a pentagonal-prismatic Zn₁₀L₁₅ structure that incorporates both Br^– and ClO₄ ^–. Furthermore, the formation of heterometallic complexes provides direct evidence for metal exchange between the guest and host complex.     

In vitro reconstitution of α-pyrone ring formation in myxopyronin biosynthesis

Myxopyronins are α-pyrone antibiotics produced by the terrestrial bacterium Myxococcus fulvus Mx f50 and possess antibacterial activity against Gram-positive and Gram-negative pathogens. They target the bacterial RNA polymerase (RNAP) “switch region” as non-competitive inhibitors and display no cross-resistance to the established RNAP inhibitor rifampicin. Recent analysis of the myxopyronin biosynthetic pathway led to the hypothesis that this secondary metabolite is produced from two separate polyketide parts, which are condensed by the stand-alone ketosynthase MxnB. Using in vitro assays we show that MxnB catalyzes a unique condensation reaction forming the α-pyrone ring of myxopyronins from two activated acyl chains in form of their β-keto intermediates. MxnB is able to accept thioester substrates coupled to either N-acetylcysteamine (NAC) or a specific carrier protein (CP). The turnover rate of MxnB for substrates bound to CP was 12-fold higher than for NAC substrates, demonstrating the importance of protein–protein interactions in polyketide synthase (PKS) systems. The crystal structure of MxnB reveals the enzyme to be an unusual member of the ketosynthase group capable of binding and condensing two long alkyl chains bound to carrier proteins. The geometry of the two binding tunnels supports the biochemical data and allows us to propose an order of reaction, which is supported by the identification of novel myxopyronin congeners in the extract of the producer strain. Insights into the mechanism of this unique condensation reaction do not only expand our knowledge regarding the thiolase enzyme family but also opens up opportunities for PKS bioengineering to achieve directed structural modifications.     

β,β′-Linked cofacial bis-porphyrins

The copper(II) porphyrin 1, bearing a fused methylenepropano ring, undergoes an unusual self-sensitized photo-oxygenation reaction in the presence of DBU to give a high yield of a cofacial bis-porphyrin 7 under very mild conditions. The structures of compounds 1 and 7 were confirmed by X-ray crystallography.     

Copper-catalyzed intermolecular C(sp3)–H bond functionalization towards the synthesis of tertiary carbamates

We describe the development of an intermolecular unactivated C(sp³)–H bond functionalization towards the direct synthesis of tertiary carbamates. The transformation proceeded using a readily available, abundant first-row transition metal catalyst (copper), and isocyanates as the source of the amide moiety. This is a novel strategy for direct transformation of a variety of unactivated hydrocarbon feedstocks to N-alkyl-N-aryl and N,N-dialkyl carbamates without pre-functionalization or installation of a directing group. The reaction had a broad substrate scope with 3° > 2° > 1° site selectivity. The reaction proceeded even on a gram scale, and a corresponding free amine was directly obtained when the reaction was performed at high temperature. Kinetic studies suggested that radical-mediated C(sp³)–H bond cleavage was the rate-determining step.     

Effect of phenolic glycolipids from Mycobacterium kansasii on proinflammatory cytokine release. A structure–activity relationship study

The cell wall of pathogenic mycobacteria is abundant with virulence factors, among which phenolic glycolipids (PGLs) are prominent examples. Mycobacterium kansasii, an important opportunistic pathogen, produces seven PGLs and their effect on the release of important proinflammatory cytokines that mediate disease progression has not been investigated. We previously showed that proinflammatory cytokines are modulated by PGLs from M. tuberculosis, M. leprae and M. bovis. In this paper we describe the synthesis of a series of 17 analogs of M. kansasii PGLs containing a truncated aglycone. Subsequently, the effect of these compounds on the release of proinflammatory cytokines (TNF-α, IL-6, IL-1β, MCP-1) and nitric oxide (NO) was evaluated. These compounds exerted an immunoinhibitory effect on the release of the tested cytokines. The concentration-dependent inhibitory profile of the tested molecules was also found to be dependent on the methylation pattern of the molecule and was mediated via toll-like receptor (TLR)-2. This study led to the discovery of a glycolipid (18) that shows promising potent anti-inflammatory properties making it a potential candidate for further optimization of its anti-inflammatory profile.     

Rh-catalyzed desymmetrization of α-quaternary centers by isomerization-hydroacylation

We describe a Rh-catalyzed desymmetrization of all-carbon quaternary centers from α,α-bis(allyl)aldehydes by a cascade featuring isomerization and hydroacylation. This desymmetrization competes with two other novel olefin functionalizations that are triggered by C–H bond activation, including carboacylation and bisacylation. A BIPHEP ligand promotes enantioselective formation of α-vinylcyclopentanones. Mechanistic studies support irreversible and enantioselective olefin-isomerization followed by olefin-hydroacylation.     

Aβ28-Induced Specific and Effective Serum Antibodies Against Aβ42

Though phase I clinical trial of immunotherapy for Alzheimer's disease(AD) with inoculated Aβ42 in humans had been proven to be effective,phase II immunotherapy trial was discontinued in 2002 because a few patients developed significant inflammatory reactions caused by C-terminal domain of Aβ42.The aim of the study was to investigate the levels and the abilities of antibodies induced by C-terminal truncated Aβ species to inhibit Aβ42 aggregation and cytotoxity in vitro.46-week-old male BALB/c mice,Aβ42 and Aβ28/Aβ35/Aβ42 with a C-terminal eight-histidine tag(Aβ28H8,Aβ35H8,and Aβ42H8) were applied in the present study.The mice were randomly divided into 5 groups(n=8),control mice immunized with the normal saline,Aβ42-immunized mice and Aβ42H-/Aβ35H-/Aβ28H-immunized mice.All the serum antibodies were evaluated by measuring their abilities to inhibit Aβ42 aggregation and cytotoxity in vitro.Each mouse was vaccinated with purified Aβ peptide emulsified with Freund's adjuvant(volume ratio 1:1).Titers,concentrations and isotypes of serum antibodies against Aβ42 were measured by indirect ELISA.Effects of serum antibodies on Aβ42 aggregation and disassembly of Aβ42 fibrils in vitro were observed by electron microscopy.Effects of serum antibodies on Aβ42 cytotoxicity were determined by MTT assay.Aβ42 or Aβ28 could induce higher anti-Aβ42 antibody titer(1:6400) than Aβ35(1:3200).Significantly,Aβ28 induced more IgG1 and IgG2b isotype antibodies and less IgG2b isotype antibody than other Aβ species though all the induced serum antibodies could inhibit Aβ42 aggregation or fibrillogenesis,could induce the disassembly of Aβ42 aggregates,and neutralized or inhibited the cytotoxicity of Aβ42 in vitro.C-Terminal truncated Aβ28 could induce the same effective but safer serum antibodies against Aβ42 than full length Aβ42 by eliciting more Th2-type immune responses.     

Non-equilibrium cobalt(iii) “click” capsules

Cobalt(iii) tetrahedral capsules have been prepared using an assembly-followed-by-oxidation protocol from a cobalt(ii) precursor and a readily derivatizable pyridyl-triazole ligand system. Experiments designed to probe the constitutional dynamics show that these architectures are in a non-equilibrium state. A preliminary investigation into the host–guest chemistry of a water-soluble derivative shows it can bind and differentiate a range of different neutral organic molecules. The stability of this ensemble also permits the study of guest-binding at high salt concentrations.     

Synthesis and properties of 10-hydroxy-10-oxo-10<Emphasis Type="Italic">H</Emphasis>-10λ<Superscript>5</Superscript>-phenoxaphosphine-2,8-dicarboxylic acid and related polybenzoimidazoles

Oxidation of 10-hydroxy-2,8-dimethyl-10H-10⁵-phenoxaphosphine 10-oxide (1) with potassium permanganate in an alkaline medium afforded 10-hydroxy-10-oxo-10H-10⁵-phenoxaphosphine-2,8-dicarboxylic acid (2). The latter exists as a stable crystal hydrate containing two water molecules. With the aim of examining the possibility of performing the synthesis of polybenzoazoles based on acid 2, the model reaction of the latter with o-phenylenediamine in polyphosphoric acid (PPA) was studied. New high-molecular-weight phosphorus-containing polybenzoimidazoles were prepared by the reaction of 2 with various aromatic tetraamines in PPA and Eatons reagent.