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Embedding both boron and nitrogen into the backbone of acenes to generate their isoelectronic structures has significantly enriched the acene chemistry to offer appealing properties. However, only small BN‐heteroacenes have been extensively investigated, with BN‐heptacenes as the hitherto longest homologue. Herein, we report the synthesis of three new nonacene BN‐isosteres via incorporating a pair of antiaromatic B2C4 and N2C4 heterocycles, representing a new length record for BN‐heteroacenes. The distance between the B2C4 and N2C4 rings affects the contribution of the charge‐separated resonance forms, leading to tunable antiaromaticity of the two heterocycles. The adjusted local antiaromaticity manifests substantial influence on the molecular orbital arrangement, and consequently, the radiative transition rate of BN‐3 is greatly enhanced compared with BN‐1 and BN‐2, realizing a high fluorescence quantum yield of 92 %. This work provides a novel design concept of large acene BN‐isosteres and reveals the importance of BN/CC isosterism on their luminescent properties. [ABSTRACT FROM AUTHOR]

Embedding both boron and nitrogen into the backbone of acenes to generate their isoelectronic structures has significantly enriched the acene chemistry to offer appealing properties. However, only small BN‐heteroacenes have been extensively investigated, with BN‐heptacenes as the hitherto longest homologue. Herein, we report the synthesis of three new nonacene BN‐isosteres via incorporating a pair of antiaromatic B2C4 and N2C4 heterocycles, representing a new length record for BN‐heteroacenes. The distance between the B2C4 and N2C4 rings affects the contribution of the charge‐separated resonance forms, leading to tunable antiaromaticity of the two heterocycles. The adjusted local antiaromaticity manifests substantial influence on the molecular orbital arrangement, and consequently, the radiative transition rate of BN‐3 is greatly enhanced compared with BN‐1 and BN‐2, realizing a high fluorescence quantum yield of 92 %. This work provides a novel design concept of large acene BN‐isosteres and reveals the importance of BN/CC isosterism on their luminescent properties. [ABSTRACT FROM AUTHOR]

The replication of human immunodeficiency virus type I (HIV-l) can be profoundly inhibited by the natural ligands of two major HIV-1 coreceptors, CXCR4 and CCRS. Stromal cell-derived factor-lα (SDF-lα) is a natural ligand of CXCR4. We have recently developed a synthetic biology approach of using synthetically and modularly modified (SMM)-chemokines to dissect various aspects of the structure-function relationship of chemokines and their receptors. Here we used this approach to design novel SMM-SDF-lα analogues containing unnatural N-methylated residues in the amino terminus to investigate whether the polypeptide main chain amide bonds in the N-terminus of SOF-lα play a role in SDF-lα signaling via CXCR4 and/or receptor internalization. The results show that SDF-lα analogues with a modiged N-methylated main chain at position 2, 3, or 5 retain significant CXCR4 binding and yet completely lose signaling activities. Furthermore, a representative N-methylated analogue has been shown to be incapable of causing CXCR4 internalization, These results suggest that the ability of SDF-lα to activate CXCR4 signaling and internalization is dependent upon the main chain amide bonds in the N-terminus of SDF-lα. This study demonstrates the feasibility and value of applying a synthetic biology approach to chemically engineer natural proteins and peptide ligands as probes of important biological functions that are not addressed by other biological techniques. [ABSTRACT FROM AUTHOR]

The recovery of solvent dissolved in wastewater from the extraction of penicillin in fermentation broth is explored using a simulating wastewater. Results show that butyl acetate can be separated partially, no matter what type of surfactant is used. The butyl acetate is evaporated from the wastewater into the gas phase, as it is highly volatile. With the concentration of surfactant at a suitable low level, the maximum separation of butyl acetate is obtained. The amount of butyl acetate volatilized to the gas phase will increase with the increase in surfactant until it reaches the maximum. The residual ratio of butyl acetate with sodium dodecyl sulfate as surfactant is higher than that with dodecylsulfonate as surfactant. Both the butyl acetate residual ratio and the enrichment concentration decrease with the increase in initial butyl acetate concentration when Tween80 is used as surfactant. [ABSTRACT FROM AUTHOR]

The effects of ionizing radiation, used in post-harvest treatment of fruit and vegetables, were investigated on cultured apple cells (Pyrus malus L. cv. Royal Red) on a short-term period. Irradiation (2 kGy) induced an increase of passive ion effluxes from cells and a decrease of cell capacity to regulate external pH. These alterations are likely due to effects on plasma membrane structure and function and were further investigated by studying the effects of irradiation on plasma membrane H+-ATPase activity. Plasma membrane-enriched vesicles were prepared and the H+-ATPase activity was characterized. Irradiation of the vesicles induced a dose dependent inhibition of H+-ATPase activity. The loss of enzyme activity was immediate, even at low doses (0.5 kGy), and was not reversed by the addition of 2 mM dithiothreitol. This inhibition may be the result of an irreversible oxidation of enzyme sulfhydryl moieties and/or the result of changes induced within the lipid bilayer affecting the membrane-enzyme interactions. Further analysis of the H+-ATPase activity was carried out on vesicles obtained from irradiated cells confirming the previous results. In vivo recovery of activity was not observed within 5 h following the treatment, thus explaining the decrease of cell capacity to regulate external pH. This rapid irreversible inhibition of the plasma membrane H+-ATPase must be considered as one of the most important primary biochemical events occurring in irradiated plant material. [ABSTRACT FROM AUTHOR]

Group IIA secreted/synovial phospholipase A2 (GIIAPLA2) is an enzyme involved in the synthesis of eicosanoids such as prostaglandin E2 (PGE2), the main eicosanoid contributing to pain and inflammation in rheumatic diseases. We designed, by molecular modeling, 7 novel analogs of 3-{4-[5(indol-1-yl)pentoxy]benzyl}-4H-1,2,4-oxadiazol-5-one, denoted C1, an inhibitor of the GIIAPLA2 enzyme. We report the results of molecular dynamics studies of the complexes between these derivatives and GIIAPLA2, along with their chemical synthesis and results from PLA2 inhibition tests. Modeling predicted some derivatives to display greater GIIAPLA2 affinities than did C1, and such predictions were confirmed by in vitro PLA2 enzymatic tests. Compound C8, endowed with the most favorable energy balance, was shown experimentally to be the strongest GIIAPLA2 inhibitor. Moreover, it displayed an anti-inflammatory activity on rabbit articular chondrocytes, as shown by its capacity to inhibit IL-1β-stimulated PGE2 secretion in these cells. Interestingly, it did not modify the COX-1 to COX-2 ratio. C8 is therefore a potential candidate for anti-inflammatory therapy in joints. [ABSTRACT FROM AUTHOR]

The chemokine receptor CXCR4 plays an important role as the receptor fur the normal physiological function of stramal cell-derived factor lα (SDF-1α) and the coreceptor for the entry of human immunodeficiency virus type 1 (HIV-1) into the cell. In a recent work IS. Tian et al., J. Virol. 79:12667-12673, 2005), we found that many residues throughout CXCR4 transmembrane (TM) and extracellular loop 2 domains are specifically involved in interaction with HIV-1 gpl20, as most of these sites did not play a role in either SDF-1α binding or signaling. These results provided direct experimental evidence for the distinct functional sites on CXCR4 for HIV-1 and the normal ligand SDF-1α. To further understand the CXCR4oligand interaction and to develop new CXCR4 inhibitors to block HIV-1 entry., we have recently generated a new family of unnatural chemokines, termed synthetically and modularly modified (SMM) chemokines, derived from the native sequence of SDF-1α or viral macrophage inflammatory protein II (vMIP-II). These SMM chemokines contain various de novo-designed sequence replacements and substitutions by D-amino acids and display more enhanced CXCR4 selectivity, binding affinities, and/or anti-HIV activities than natural chemokines. Using these novel CXCR4-targeting SMM chemokines as receptor probes, we conducted ligand binding site mapping experiments on a panel of site-directed mutants of CXCR4. Here, we provide the first experimental evidence demonstrating that SMM chemokines interact with many residues on CXCR4 TM and extracellular domains that are important for HIV-1 entry, but not SDF-1α binding or signaling. The preferential overlapping in the CXCR4 binding residues of SMM chemokines with HIV-1 over SDF-1α illustrates a mechanism for the potent HIV.1 inhibition by these SMM chemokines. The discovery of distinct functional sites or confurmational states influenced by these receptor sites mediating different functions of the natural ligand versus the viral or synthetic ligands has important implications for drug discovery, since the sites shared by SMM chemokines and HIV-1 but not by SDF.1α can be targeted for the development of selective HIV-1 inhibitors devoid of interference with normal SDF-1α function. [ABSTRACT FROM AUTHOR]

The syntheses, structures and photoluminescence properties are reported for two new binuclear cyclometalated iridium(III) complexes, [Ir 2 (ppy) 4 (L)] ( 1 ) and [Ir 2 (F 2 -ppy) 4 (L)] ( 2 ) (ppy=2-phenylpyridine, F 2 -ppy = 2-(2,4-difluorophenyl)pyridine, H 2 L=N,N′-bis(2-hydroxynaphthyl methylidene)-2-hydroxy-1,3-propanediamine. X-ray crystal diffraction shows that L ligands adopt a tetradentate mode to bridge ir(III) ions to form binuclear structures. There are π-π stacking interactions between the binuclear structures, which results in the formation of 3D supramolecular networks. UV–vis absorption spectra and photoluminescence spectra show that the introduction of F − groups in the benzene rings of ppy ligands causes blue shift. [ABSTRACT FROM AUTHOR]

Chemokine receptor CXCR4 is one of two principal coreceptors for the entry of HIV-1 into target cells. CXCR4 is known to form homodimers. We previously demonstrated that the amino terminus of viral macrophage protein II (vM1P-II) is the major determinant for CXCR4 recognition, and that V1 peptide derived from the N-terminus of vMIP-II (1–21 residues) showed significant CXCR4 binding. Interestingly, an all-a-amino acid analogue of V1 peptide, Dv1 peptide, displayed an even higher binding affinity and strong antiviral activity in inhibiting the replication of CXCR4-dependent HIV-1 strains. in this study, we synthetically linked two DV1 peptides with the formation of a disulfide bond between the two cysteine residues present in the peptide sequence to generate a dimeric molecule potentially capable of interacting with two CXCR4 receptors. DV1 dimer exhibited enhanced binding affinity and antiviral activity compared with those of Dv1 monomer. Ligand binding site mapping experiments showed that DV1 dimer overlaps with HIV-1 gp120 on CXCR4 binding sites, including several transmembrane (TM) residues located close to the extracellular side and the N-terminus of CXCR4. This finding was supported by the molecular modeling of CXCR4 dimer–DV1 dimer interaction based on the crystal structure of CXCR4, which showed that DV1 dinier is capable of interacting with the CXCR4 dimeric structure by allowing the N-terminus of each DV1 monomer to reach into the binding pocket of CXCR4 monomer. The development of this bivalent ligand provides a tool for further probing the functions of CXCR4 dimerization and studying CXCR4 heterodimerization with other receptors. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the roles of polyphenolic hydroxyls in certain reported tyrosinase inhibitors. It examines 19 new compounds and 41 known compounds including turmeric, aromatic aldehydes and cyclohexanone. Result suggests that polyphenolic curcumin analogs serve as lead compounds for further design of new tyrosine inhibitors.

Secreted phospholipases A2(sPLA2s) have been reported to play an important role in various inflammatory conditions and thus represent an attractive therapeutic target. Previous SAR studies from our laboratory have revealed certain important features of our recently discovered specific hGIIA sPLA2inhibitors, and we report here the synthesis and biological activities of glycerol-containing derivatives of our lead compound III(Figure 1). Efficient and selective synthesis methods have been developed to make glycerol trisubstituted by different groups on desired positions. In terms of biological activities, the best compounds (A3, A6, and A15) are more active than III(Figure 1), as potent as Me-Indoxam, an sPLA2s inhibitor of reference, against hGIIA, hGV, and hGX sPLA2s and at least 10 times less active toward the GIB enzymes in two in vitroassay systems. By synthesis of enantiopure (S)-A6, we demonstrated that no important improvement of the inhibitory potency could be achieved by this approach. Furthermore, the results show that the global lipophilicity is likely responsible for the anti-PLA2activity and two oxadiazolone moieties seem too big to be accommodated by the active site of the hGIIA enzyme. [ABSTRACT FROM AUTHOR]

As the main coreceptors for human immunodeficiency virus type 1 (HIV-1) entry, CXCR4 and CCR5 play important roles in HIV-associated dementia (HAD). HIV-1 glycoprotein gp120 contributes to HAD by causing neuronal damage and death, either directly by triggering apoptotic pathways or indirectly by stimulating glial cells to release neurotoxins. Here, to understand the mechanism of CXCR4 or CCR5 signaling in neuronal apoptosis associated with HAD, we have applied synthetically and modularly modified (SMM)-chemokine analogs derived from natural stromal cell-derived factor-1α or viral macrophage inflammatory protein-II as chemical probes of the mechanism(s) whereby these SMM-chemokines prevent or promote neuronal apoptosis. We show that inherently neurotoxic natural ligands of CXCR4, such as stromal cell-derived factor-1α or viral macrophage inflammatory protein-II, can be modified to protect neurons from apoptosis induced by CXCR4-preferring gp120IIIB, and that the inhibition of CCR5 by antagonist SMM-chemokines, unlike neuroprotective CCR5 natural ligands, leads to neurotoxicity by activating a p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Furthermore, we discover distinct signaling pathways activated by different chemokine ligands that are either natural agonists or synthetic antagonists, thus demonstrating a chemical biology strategy of using chemically engineered inhibitors of chemokine receptors to study the signaling mechanism of neuronal apoptosis and survival. [ABSTRACT FROM AUTHOR]

Chemokines and their receptors play important roles in normal physiological functions and the pathogeneses of a wide range of human diseases, including the entry of human immunodeficiency virus type 1 (HIV-1). However, the use of natural chemokines to probe receptor biology or to develop therapeutic drugs is limited by their lack of selectivity and the poor understanding of mechanisms in ligand-receptor recognition. We addressed these issues by combining chemical and structural biology in research into molecular recognition and inhibitor design. Specifically, the concepts of chemical biology were used to develop synthetically and modularly modified (SMM) chemokines that are unnatural and yet have properties improved over those of natural chemokines in terms of receptor selectivity, affinity, and the ability to explore receptor functions. This was followed by using structural biology to determine the structural basis for synthetically perturbed ligand-receptor selectivity. As a proof-of-principle for this combined chemical and structural-biology approach, we report a novel D-amino acid-containing SMM-chemokine designed based on the natural chemokine called viral macrophage inflammatory protein II (vMIP-II). The incorporation of unnatural D-amino acids enhanced the affinity of this molecule for CXCR4 but significantly diminished that for CCR5 or CCR2, thus yielding much more selective recognition of CXCR4 than wild-type vMIP-II. This D-amino acid-containing chemokine also showed more potent and specific inhibitory activity against HIV-1 entry via CXCR4 than natural chemokines. Furthermore, the high-resolution crystal structure of this D-amino acid-containing chemokine and a molecular-modeling study of its complex with CXCR4 provided the structure-based mechanism for the selective interaction between the ligand and chemokine receptors and the potent anti-HIV activity of D-amino acid-containing chemokines. [ABSTRACT FROM AUTHOR]