[show abstract][hide abstract] ABSTRACT: Trichalcogenasumanenes were synthesized on a multigram scale through a two-step approach that takes advantage of non-pyrolytic cyclization and solventless ring contraction. Solid-state structure and photophysical investigations demonstrate that these compounds are promising candidates for electronic materials.
Angewandte Chemie International Edition 01/2014; 53(2):535-8. · 13.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: The well-known 8-aminoquinoline framework offers an ideal model for the development of fluorescence-enhanced chemosensors through simple and convenient syntheses. Herein, a novel and simple molecule chemosensor, 5-diethylamino-2-(quinolin-8-yliminomethyl)-phenol (), has been designed by combining an 8-aminoquinoline moiety and a 4-(diethylamino)salicylaldehyde in a single molecule to prove the selectivity and sensitivity for Mg(2+), Zn(2+), and Co(2+) in a dual-channel mode (fluorescence emission and UV/Vis). When binding Mg(2+), not only showed an obvious fluorescence enhancement but also enabled the Mg(2+) detection range over 1.68 ppb. Meanwhile, in mixed solvent media, displayed selectivity for Zn(2+) over other cations by the emission spectrum. It was worth noting that could be a colorimetric sensor for Co(2+) in a semi-aqueous solution by monitoring the absorption spectral behavior and be a colorimetric reagent for sensing and staining of Co(2+) in the cells. The results indicate that can be applied in multianalyte detection.
[show abstract][hide abstract] ABSTRACT: Five new polyketides, plakortoxides A (1) and B (2), simplextones C (3) and D (4), and plakorsin D (5), together with six known analogues (6-11) were isolated from the South China Sea sponge Plakortis simplex. Their structures were identified by spectroscopic and chemical methods, including NMR, MS, and IR. Experimental and calculated ECD spectra and the modified Mosher's method were used to determine the absolute configurations. Structurally, both plakortoxides A and B feature a butenolide coupled to an epoxide moiety, while simplextones C and D consist of γ-butyrolactone and cyclopentane moieties, and plakorsin D is a furan acetic acid polyketide. The cytotoxic activities of the isolates were tested, and compounds 8, 10, and 11 showed potent cytotoxicity against both K562 and HeLa tumor cell lines with IC50 values ranging from 0.8 to 5.3 μM. Compound 3 showed significant inhibitory activity against c-Met kinase.
Journal of Natural Products 04/2013; 76(4):600-606. · 3.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent advances in nanotechnologies have led to wide use of nanomaterials in biomedical field. However, nanoparticles are found to interfere with protein misfolding and aggregation associated with many human diseases. It is still a controversial issue whether nanoparticles inhibit or promote protein aggregation. In this study, we used molecular dynamics simulations to explore the effects of three kinds of carbon nanomaterials including graphene, carbon nanotube and C60 on the aggregation behavior of islet amyloid polypeptide fragment 22-28 (IAPP22-28). The diverse behaviors of IAPP22-28 peptides on the surfaces of carbon nanomaterials were studied. The results suggest these nanomaterials can prevent β-sheet formation in differing degrees and further affect the aggregation of IAPP22-28. The π-π stacking and hydrophobic interactions are different in the interactions between peptides and different nanoparticles. The subtle differences in the interaction are due to the difference in surface curvature and area. The results demonstrate the adsorption interaction has competitive advantages over the interactions between peptides. Therefore, the fibrillation of IAPP22-28 may be inhibited at its early stage by graphene or SWCNT. Our study can not only enhance the understanding about potential effects of nanomaterials to amyloid formation, but also provide valuable information to develop potential β-sheet formation inhibitors against type II diabetes.
PLoS ONE 01/2013; 8(6):e65579. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: A new selective fluorescent sensor for Cu2+ and S2−, 2-hydroxy-N′-((quinolin-2-yl)methylene)benzohydrazide (HL), based on 2-methylquinoline derivative has been designed, synthesized and evaluated. The fluorescence of the sensor HL was quenched by Cu2+ with a 1:1 binding ratio, behaving as an “on–off” type sensor even in the presence of a wide range of biological cations. Once binding with Cu2+, it can display high selectivity for S2−. Among the various anions, only sulfide anion induces the revival of fluorescence of HL, resulting in “off–on” type sensing of sulfide anion. The signal transduction occurs via reversible formation–separation of complex L–Cu and CuS. With the addition of Cu2+, sensor HL give rise to a colorless to yellow color change. The resulting yellow solution switches to colorless immediately upon the addition of S2−; however, no changes were observed in the presence of other anions, including CN−, NO3−, P2O74−, various forms of sulfate, and some other reactive sulfur species (RSS) including SCN−, l-methionine (l-Me) and l-cysteine (l-Cys). Notably, the color change is so distinct that the recycling process can be seen clearly by the naked eye.
Sensors and Actuators B Chemical 01/2013; 185:125–131. · 3.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: The rapid emergence of cross-resistance to the integrase strand transfer inhibitors (INSTIs) has become a serious problem in the therapy of human immunodeficiency virus type 1 (HIV-1) infection. Understanding the detailed molecular mechanism of INSTIs cross-resistance is therefore critical for the development of new effective therapy against cross-resistance. On the basis of the homology modeling constructed structure of tetrameric HIV-1 intasome, the detailed molecular mechanism of the cross-resistance mutation E138K/Q148K to three important INSTIs (Raltegravir (RAL, FDA approved in 2007), Elvitegravir (EVG, FDA approved in 2012), Dolutegravir (DTG, Phase III clinical trials)) was investigated by using molecular dynamics (MD) simulation and residue interaction network (RIN) analysis. The results from conformation analysis and binding free energy calculation can provide some useful information about the detailed binding mode and cross-resistance mechanism for the three INSTIs to HIV-1 intasome. Binding free energy decomposition analysis revealed that Pro145 residue in the 140s 1oop (Gly140 to Gly149) of the HIV-1 intasome had strong hydrophobic interactions with INSTIs and played an important role in the binding of INSTIs to HIV-1 intasome active site. A systematic comparison and analysis of the RIN proves that the communications between the residues in the resistance mutant is increased when compared with that of the wild-type HIV-1 intasome. Further analysis indicates that residue Pro145 may play an important role and is relevant to the structure rearrangement in HIV-1 intasome active site. In addition, the chelating ability of the oxygen atoms in INSTIs (e.g., RAL and EVG) to Mg2+ in the active site of the mutated intasome was reduced due to this conformational change and is also responsible for the cross-resistance mechanism. Notably, the cross-resistance mechanism we proposed could give some important information for the future rational design of novel INSTIs overcoming cross-resistance. Furthermore, the combination use of molecular dynamics simulation and residue interaction network analysis can be generally applicable to investigate drug resistance mechanism for other biomolecular systems.
Journal of Chemical Information and Modeling 12/2012; · 4.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hepatitis C virus (HCV) bifunctional NS3/4A is an attractive anti-HCV drug target, as both the protease and helicase functions are required for viral infection and replication. Although the first generation of NS3/4A protease inhibitors (PIs) has focused almost exclusively on the interaction with the protease domain alone, recent studies have shown that PIs also inhibit the full-length NS3/4A protein. However, the detailed molecular mechanism of the interaction between protease inhibitors, as well as the peptide substance with the full-length NS3/4A protein, remains poorly understood. Herein, starting from the recently determined crystal structure of an inhibitor (inhibitor ) bound to the full-length NS3/4A protein, the structures of the full-length NS3/4A complexed with inhibitor ITMN-191 (by InterMune/Roche; Phase II) and substrate 4B5A (the viral cleavage product peptide) were built. Then, residue interaction network (RIN) analysis, molecular dynamics (MD) simulation, binding free energy calculation, decomposition of free energies on per-residue and dynamic substrate recognition pattern analysis were employed to uncover the structural and energetic basis of inhibitor and substrate binding mode in the binding cleft located at the interface of the protease and helicase domains of the full-length NS3/4A. The results from our study reveal that both the protease and helicase residues of the NS3/4A participate in the interactions with the inhibitor , ITMN-191 and 4B5A. Additional analysis of the NS3/4A substrate and inhibitor envelopes reveals the areas where the consensus inhibitor volume extended beyond the substrate envelope. These areas correspond to drug resistance mutations including Arg155, Ala156 and Asp168 at the protease active site as well as the two conserved helicase residues Gln526 and His528 that strongly interact with the inhibitors. Thus, the findings of this study will be very useful for understanding the interaction mechanism between the inhibitor (substrate) and NS3/4A and also for the rational design and development of new potent molecules targeting the full-length NS3/4A.
[show abstract][hide abstract] ABSTRACT: Raltegravir is the first FDA-approved drug targeting the strand transfer step of HIV-1 integration. However, the rapid emergence of viral strains that are highly resistant to raltegravir has become a critical problem. Unfortunately, the detailed molecular mechanism of how HIV-1 integrase (IN) mutations actually confer drug resistance is not well understood. In the present study, starting from our previously constructed complex of HIV-1 IN and viral DNA, we employed molecular dynamics (MD) simulation and molecular mechanics generalized Born surface area (MM-GBSA) calculation, to uncover the molecular mechanism behind the resistant mechanism of HIV-1 IN to raltegravir. The values of the calculated binding free energy follow consistently the experimentally observed ranking of resistance levels. A detailed analysis of the results of MD simulation suggests that the Tyr143 located in the 140s loop (e.g., residues from Gly140 to Gly149) is a key anchoring residue that leads to stable raltegravir binding. The decrease in the interaction at this residue is one of the key reasons responsible for the resistance of HIV-1 IN to raltegravir. Additionally, the calculation results also proved that the 3' adenosine flip in different conformations in the wild-type and mutant HIV-1 IN-viral DNA complexes play an important role in raltegravir binding. Our results could provide a structural and energetic understanding of the raltegravir-resistant mechanism at the atomic level and provide some new clues on how to design new drugs that may circumvent the known resistance mutations.
[show abstract][hide abstract] ABSTRACT: To explore the effect of terminal groups of tripodal ligands on the photoluminescence behaviors of the complexes, lanthanide (Eu(III), Tb(III)) nitrate complexes with two flexible amide-type tripodal ligands, 2,2',2''-nitrilotris-(N-phenylmethyl)-acetamide (L(I)) and 2,2',2''-nitrilotris-(N-naphthalenemethyl)-acetamide (L(II)) were synthesized and characterized. The general formulas of the complexes are [EuL(I)(2)(C(3)H(6)O)]·(NO(3))(3)·(HCCl(3))·(H(2)O)(4) (1), TbL(I)(2)(NO(3))(3)·2H(2)O (2), EuL(II)(NO(3))(3) (3), and TbL(II)(NO(3))(3) (4). Among them, 1, 3, and 4 were characterized by single-crystal X-ray diffraction. Complex 1 demonstrates a 1 : 2 (ML(2)) capsule type stoichiometry, and the complexes 3 and 4 confirm 1 : 1 (ML) type coordination structures. What is more, the triplet energy levels of L(I) and L(II) are 24,331 and 19,802 cm(-1), which were determined from the phosphorescence spectra of the Gd(III) complexes. Ligand modification by changing the terminal groups alters their triplet energy, and results in a different sensitizing ability towards lanthanide ions. The density functional theory (DFT) calculations of energy levels including HOMO, LUMO, singlet, and triplet energies tuned by the different terminal groups are also discussed in detail, and the trends are almost consistent with the experimental conclusions.