The use of molecular graphics and quantum mechanically derived electrostatic potentials to visualize Brönsted acid site strength in zeolites

The use of the quantum mechanically derived electrostatic potential is introduced to visualize the variation in acidity across a series of cluster molecules corresponding to models of terminal and bridged hydroxyl groups in zeolites. The electrostatic potential is color coded onto the electron density surfaces of the molecules involved, and the variation in acid strength can be followed from the color scheme used. This simple visualization scheme is shown to mirror the experimentally observed acidity variation of terminal hydroxyls, bridged gallium hydroxyls, and bridged aluminium hydroxyls found for zeolites.From the value of the electrostatic potential near the acidic hydrogen we estimate that the acidity of terminal hydroxyls is similar to acetic acid while the bridged aluminium form is the same as sulphuric acid.     

Design and synthesis of simplified taxol analogs based on the T-Taxol bioactive conformation

A series of compounds designed to adopt a conformation similar to the tubulin-binding T-Taxol conformation of the anticancer drug paclitaxel has been synthesized. Both the internally bridged analogs 37-39, 41 and the open-chain analogs 27-29 and 43 were prepared. The bridged analogs 37-39 and 41 were synthesized by Grubbs' metatheses of compounds 30-32 and 33, which, in turn, were prepared by coupling β-lactams 24-26 with alcohols 22 and 23. Both the bridged and the open-chain analogs showed moderate to good cytotoxicity.     

Synthesis and properties of 2'-O,4'-C-methyleneoxymethylene bridged nucleic acid

A novel bridged nucleic acid (BNA) analogue, 2'-O,4'-C-methyleneoxymethylene bridged nucleic acid (2',4'-BNA(COC)), was synthesized and incorporated into oligonucleotides. The 2',4'-BNA(COC) modified oligonucleotides showed high binding affinity with an RNA complement and significant enzymatic stability against snake venom phosphodiesterase.     

Structural conformation of ciliary dynein arms and the generation of sliding forces in Tetrahymena cilia

The sliding tubule model of ciliary motion requires that active sliding of microtubules occur by cyclic cross-bridging of the dynein arms. When isolated, demembranated Tetrahymena cilia are allowed to spontaneously disintegrate in the presence of ATP, the structural conformation of the dynein arms can be clearly resolved by negative contrast electron microscopy. The arms consist of three structural subunits that occur in two basic conformations with respect to the adjacent B subfiber. The inactive conformation occurs in the absence of ATP and is characterized by a uniform, 32 degrees base-directed polarity of the arms. Inactive arms are not attached to the B subfiber of adjacent doublets. The bridged conformation occurs strictly in the presence of ATP and is characterized by arms having the same polarity as inactive arms, but the terminal subunit of the arms has become attached to the B subfiber. In most instances the bridged conformation is accompanied by substantial tip-directed sliding displacement of the bridged doublets. Because the base-directed polarity of the bridged arms is opposite to the direction required for force generation in these cilia and because the bridges occur in the presence of ATP, it is suggested that the bridged conformation may represent the initial attachment phase of the dynein cross-bridge cycle. The force-generating phase of the cycle would then require a tip-directed deflection of the arm subunit attached to the B subfiber.     

A microfluidic device to establish concentration gradients using reagent density differences

Microfabrication has become widely utilized to generate controlled microenvironments that establish chemical concentration gradients for a variety of engineering and life science applications. To establish microfluidic flow, the majority of existing devices rely upon additional facilities, equipment, and excessive reagent supplies, which together limit device portability as well as constrain device usage to individuals trained in technological disciplines. The current work presents our laboratory-developed bridged μLane system, which is a stand-alone device that runs via conventional pipette loading and can operate for several days without need of external machinery or additional reagent volumes. The bridged μLane is a two-layer polydimethylsiloxane microfluidic device that is able to establish controlled chemical concentration gradients over time by relying solely upon differences in reagent densities. Fluorescently labeled Dextran was used to validate the design and operation of the bridged μLane by evaluating experimentally measured transport properties within the microsystem in conjunction with numerical simulations and established mathematical transport models. Results demonstrate how the bridged μLane system was used to generate spatial concentration gradients that resulted in an experimentally measured Dextran diffusivity of (0.82 ± 0.01) × 10(-6) cm(2)/s.     

Cleavage of RNA in hybrid duplexes by E. coli ribonuclease H. II. Substrate properties of nucleotides containing non-nucleotide linkers]

The 20-mer bridged oligodeoxynucleotides containing short oligomers joined by the hexamethylenediol and hexaethylene glycol linkers were shown to form complementary DNA/DNA and RNA/DNA complexes whose thermostability depends on the length and number of the nonnucleotide linkers. Hybrid complexes of the bridged oligonucleotides proved to be substrates for the E. coli ribonuclease H. The presence of one-three nonnucleotide linkers in a 20-mer decreased the hydrolysis efficacy only 1.2-1.4-fold. It is the composition of the RNA cleavage products that was influenced the most significantly by the nonnucleotide linkers. RNase H simultaneously hydrolyzed the RNA 3'-ends of each hybrid duplex involving a bridged oligonucleotide. The presence of an inverted 3'-3'-phosphodiester bond at the 3'-end of the oligodeoxyribonucleotide only slightly affected the RNase H activity.     

Design, synthesis and biological evaluation of a new bridged immunosuppressor

A bridged peptide with the sequence: H-Thr-Pro-Gln-Arg-Gly-Asp-Val-gamma-Abu-Asn-Asp-Gln-Glu-Glu-Thr-Thr-Gly-Val-Val-Ser-Thr-Pro-Leu-Ile-Arg-Asn-Gly-OH was designed to mimic the discontinuous epitope of the HLA-DQ molecule that might interact with CD4. The bridged peptide revealed distinct suppressory effect in the humoral immune response. This result supports our suggestion that the 164-172 region of the HLA-DQ molecule may enhance its interactions with coreceptors, possibly with CD4.     

A New sp2‐sp2 Dialkylethylene‐Bridged Heptacyclic Ladder‐Type Arene for High Efficiency Polymer Solar Cells

A new dithienobenzo‐carbazole (DTBC) heptacyclic arene using sp²‐sp² dialkylethylene moiety as the bridge was successfully synthesized by Suzuki‐Miyaura cross‐coupling reaction. This facile benzoannulation planarizes the conjugated framework with the concomitant introduction of four octyl substituents, making the newly designed copolymer PDTBCDTBT exhibit solution processability, superior absorption ability, lower‐lying HOMO energy level, and crystalline nature. The solar cell using PDTBCDTBT has produced a high efficiency of 6.2%, which outperforms the corresponding sp³‐hybridized C‐bridged, Si‐bridged and N‐bridged analogous polymers.     

Synthesis and biological evaluation of 2',4'- and 3',4'-bridged nucleoside analogues

Most nucleosides in solution typically exist in equilibrium between two major sugar pucker forms, N-type and S-type, but bridged nucleosides can be locked into one of these conformations depending on their specific structure. While many groups have researched these bridged nucleosides for the purpose of determining their binding affinity for antisense applications, we opted to look into the potential for biological activity within these conformationally-locked structures. A small library of 2',4'- and 3',4'-bridged nucleoside analogues was synthesized, including a novel 3',4'-carbocyclic bridged system. The synthesized compounds were tested for antibacterial, antitumor, and antiviral activities, leading to the identification of nucleosides possessing such biological activities. To the best of our knowledge, these biologically active compounds represent the first example of 2',4'-bridged nucleosides to demonstrate such properties. The most potent compound, nucleoside 33, exhibited significant antiviral activity against pseudoviruses SF162 (IC(50)=7.0 μM) and HxB2 (IC(50)=2.4 μM). These findings render bridged nucleosides as credible leads for drug discovery in the anti-HIV area of research.     

An efficient route into synthetically challenging bridged achiral 1,2,4,5-tetraoxanes with antimalarial activity

Here we present an efficient route into synthetically challenging bridged 1,2,4,5-tetraoxanes. The key to the success of this route is the use of H(2)O(2) and catalytic I(2) to form the gem-dihydroperoxide followed by a Ag(2)O mediated alkylation using 1,3-diiodopropane. Using this methodology a range of bridged tetraoxanes which display good in vitro antimalarial activity were synthesized.     

Nuclease resistance and RNase H sensitivity of oligonucleotides bridged by oligomethylenediol and oligoethylene glycol linkers

The properties of new chimeric oligodeoxynucleotides made of short sequences (tetramers, pentamers, octamers, and decamers) bridged by hexamethylenediol and hexaethylene glycol linkers have been investigated. These chimeric oligonucleotides showed an improved resistance toward snake venom 3'-phosphodiesterase, with an increased stability when a terminal 3'-3'-internucleotide phosphodiester bond is present. It also has been demonstrated that the hybrid complexes formed by bridged oligonucleotides and a complementary 20-mer RNA are able to elicit the activity of ribonuclease H (RNase H) from Escherichia coli. The substrate properties of chimeric oligonucleotides depend on the length of the oligonucleotide fragments bridged by linkers. Introduction of a nonnucleotide spacer into the native oligonucleotide only slightly hampers the extent of the RNA hydrolysis in the hybrid complexes, whereas a modification of the site of reaction is observed as a possible consequence of the steric disturbance due to the aliphatic linkers. Hence, these new chimeric oligonucleotides, namely, short oligonucleotide fragments bridged by nonnucleotide linkers, demonstrate a favorable combination of exonuclease resistance and high substrate activity toward RNase H. As a consequence, these chimeric oligonucleotides could be proposed as new, promising analogs to be used in the antisense strategy.     

Preparation and electrochemical properties of novel cyclic dinuclear acetylacetonato ruthenium complexes doubly bridged with sulfur and/or disulfur

A novel cyclic dinuclear acetylacetonato ruthenium complex doubly bridged with sulfur and/or disulfur at the γ-position of acetylacetonato ligand has been obtained by two different synthetic methods. The molecular structure of the dinuclear complex has been determined by single crystal X-ray diffraction study. Other two cyclic dinuclear β-diketonato ruthenium complexes were also prepared in good yields by the reaction of single bridged dinuclear complexes as starting materials with disulfur dichloride. The cyclic voltammograms of all the dinuclear complexes exhibit two one-electron reduction and oxidation waves in acetonitrile (AN) and dichloromethane (DM). The comproportionation constants (K_c) for mixed-valence state of both Ru^II/Ru^III and Ru^III/Ru^IV were evaluated in both solvents at 25 or −30 °C. The values of both K_c (Ru^II/Ru^III) and log₁₀ K_c (Ru^III/Ru^IV) for double bridged complex are large compared to those of corresponding single bridged complexes. This fact was rationally explained by the double bridging effect caused by the spread of electronic communication and also demonstrated the usefulness of the double bridged dinuclear complexes.     

Detour-free synthesis of platinum-bis-NHC chloride complexes, their structure and catalytic activity in the CH activation of methane

Chelating biscarbene ligands are one way to extend the stability of catalysts in homogenous catalysis. Methylene bridged palladium and platinum biscarbene complexes with various counterions have been published, but until now the corresponding chloride complexes were only available by time consuming anion exchange procedures. Here, we present a new direct synthesis for methylene bridged bisimidazolium chloride salts and their platinum biscarbene complexes using dichloromethane as a reagent. Solid state structures of the imidazolium salts and the platinum complexes are reported. The new complexes were successfully tested in the catalytic CH activation of methane.     

Cleavage of RNA in hybrid duplexes by theE. coli ribonuclease H: II. Substrate properties of oligonucleotides containing nonnucleotide linkers

The 20-mer bridged oligodeoxynucleotides containing short oligomers joined by the hexamethylenediol and hexaethylene glycol linkers were shown to form complementary DNA/DNA and RNA/DNA complexes whose thermostability depends on the length and number of the nonnucleotide linkers. Hybrid complexes of the bridged oligonucleotides proved to be substrates for theE. coli ribonuclease H. The presence of one-three nonnucleotide linkers in a 20-mer decreased the hydrolysis efficacy only 1.2–1.4-fold. It is the composition of the RNA cleavage products that was influenced the most significantly by the nonnucleotide linkers. RNase H simultaneously hydrolyzed the RNA 3′-ends of each hybrid duplex involving a bridged oligonucleotide. The presence of an inverted 3′-3′-phosphodiester bond at the 3′-end of the oligodeoxyribonucleotide only slightly affected the RNase H activity. For the previous report, see [1].     

New steroid haptens for radioimmunoassay: synthesis of steroids substituted with thioether or ester linkages at the 2 alpha-position

Haptens with bridge at the 2-position have not yet been explored. Radioimmunoassays with antibodies directed against 2 alpha-alkyl bridged steroid haptens are expected to be highly specific due to greater topographical exposure and similarity in conformation to the native steroid. The 2 alpha-alkyl bridged haptens were synthesized by first adding a cyclopropane ring to 2-methylene-4-en-3-one. Selective opening of the three-membered ring with trimethyl silyl iodide and transformation of the iodo group gave a carbocyclic acid, the desired analog for conjugation with protein.     

Identification of a novel series of potent HCV NS5B Site I inhibitors

Efforts investigating spatially comparative alternates of the ethylene-bridged piperazine in BMS-791325 that would offer a maintained or improved virologic and pharmacokinetic profile have been multifaceted. One foray involved the utilization of various octahydropyrrolo[3,4-c]pyrrole propellanes. Many of the propellane analogs described in this work exhibited better than targeted potency (less than 20 nM). Additionally, improved exposure in rats was achieved through the employment of two newly invented and now readily accessible carbon bridged propellanes as compared to their heteroatom bridged analogs.     

Mn K-edge XANES spectroscopy of a photosynthetic O2-evolving complex. High-quality pre-edge features and distinct fine structures in the S1- and S2-states

High-resolution XANES (X-ray Absorption Near Edge Structure) spectroscopy for Mn in the S1 and S2 states of the spinach photosynthetic O2-evolving complex revealed distinct features in K-edge spectra, when a high signal-to-noise (S/N) ratio of ca. 80 with a low and constant background-to-signal (B/S) ratio of 0.15 to 0.18 was attained. Six features resolved in each S-state spectrum involve a pre-edge feature due to 1s----3d transitions, a main-edge feature possibly due to 1s----4s transitions and four fine structures superimposed on the principal absorption bands due to 1s----4p* transitions. The high-quality pre-edge features were analyzed according to a parametric ligand-field theory in comparison with those of some typical authentic Mn complexes. It was deduced that i) all of the four Mn ions in the S1-state are octahedrally coordinated and two of them constitute a di-mu-oxo bridged Mn(III, III) dimeric subunit; ii) the bridged Mn(III) ions are further bridged by a deprotonated water dimer, (HOHOH)-, and coordinated by imidazole-N and carboxylate-O- on the opposite side of the Mn atom from the di-mu-oxo bridge; iii) the other two Mn ions exist in the form of Mn(III) monomeric subunits; and iv) upon the S1----S2 transition, only the bridged Mn(III,III) is oxidized to Mn(III,IV). The distinct change in the principal absorption band shape upon the S1----S2 transition is briefly discussed to obtain the XANES evidence for a tetrameric Mn-cluster.     

Bridging of anions by hydrogen bonds in nest motifs and its significance for Schellman loops and other larger motifs within proteins

The nest is a protein motif of three consecutive amino acid residues with dihedral angles 1,2‐α_Rα_L (RL nests) or 1,2‐α_Lα_R (LR nests). Many nests form a depression in which an anion or δ‐negative acceptor atom is bound by hydrogen bonds from the main chain NH groups. We have determined the extent and nature of this bridging in a database of protein structures using a computer program written for the purpose. Acceptor anions are bound by a pair of bridging hydrogen bonds in 40% of RL nests and 20% of LR nests. Two thirds of the bridges are between the NH groups at Positions 1 and 3 of the motif (N1N3‐bridging)—which confers a concavity to the nest; one third are of the N2N3 type—which does not. In bridged LR nests N2N3‐bridging predominates (14% N1N3: 75% N2N3), whereas in bridged RL nests the reverse is true (69% N1N3: 25% N2N3). Most bridged nests occur within larger motifs: 45% in (hexapeptide) Schellman loops with an additional 4 → 0 hydrogen bond (N1N3), 11% in Schellman loops with an additional 5 → 1 hydrogen bond (N2N3), 12% in a composite structure including a type 1β‐bulge loop and an asx‐ or ST‐ motif (N1N3)—remarkably homologous to the N1N3‐bridged Schellman loop—and 3% in a composite structure including a type 2β‐bulge loop and an asx‐motif (N2N3). A third hydrogen bond is a previously unrecognized feature of Schellman loops as those lacking bridged nests have an additional 4 → 0 hydrogen bond. Proteins 2014; 82:3023–3031. © 2014 Wiley Periodicals, Inc.     

Tetrahydrofluorenones with conformationally restricted side chains as selective estrogen receptor beta ligands

A series of 2-9a bridged tetrahydrofluorenone derivatives were prepared which exhibited significant binding affinity for ERbeta and were highly selective.     

the synthesis of diporphyrin systems on the basis of tetraphenylporphyrin derivatives bridged with peptide spacers

Diporphyrin systems based on tetraphenylporphyrin derivatives bridged with dipeptide or tripeptide spacers containing Gly and Phe residues were synthesized, and their physicochemical properties were studied.