Structure and Function of a “Head‐to‐Middle” Prenyltransferase: Lavandulyl Diphosphate Synthase

We report the first X‐ray structure of the unique “head‐to‐middle” monoterpene synthase, lavandulyl diphosphate synthase (LPPS). LPPS catalyzes the condensation of two molecules of dimethylallyl diphosphate (DMAPP) to form lavandulyl diphosphate, a precursor to the fragrance lavandulol. The structure is similar to that of the bacterial cis‐prenyl synthase, undecaprenyl diphosphate synthase (UPPS), and contains an allylic site (S1) in which DMAPP ionizes and a second site (S2) which houses the DMAPP nucleophile. Both S‐thiolo‐dimethylallyl diphosphate and S‐thiolo‐isopentenyl diphosphate bind intact to S2, but are cleaved to (thio)diphosphate, in S1. His78 (Asn in UPPS) is essential for catalysis and is proposed to facilitate diphosphate release in S1, while the P1 phosphate in S2 abstracts a proton from the lavandulyl carbocation to form the LPP product. The results are of interest since they provide the first structure and structure‐based mechanism of this unusual prenyl synthase.     

One‐Pot Enzymatic Synthesis of Merochlorin A and B

The polycycles merochlorin A and B are complex halogenated meroterpenoid natural products with significant antibacterial activities and are produced by the marine bacterium Streptomyces sp. strain CNH‐189. Heterologously produced enzymes and chemical synthesis are employed herein to fully reconstitute the merochlorin biosynthesis in vitro. The interplay of a dedicated type III polyketide synthase, a prenyl diphosphate synthase, and an aromatic prenyltransferase allow formation of a highly unusual aromatic polyketide‐terpene hybrid intermediate which features an unprecedented branched sesquiterpene moiety from isosesquilavandulyl diphosphate. As supported by in vivo experiments, this precursor is furthermore chlorinated and cyclized to merochlorin A and isomeric merochlorin B by a single vanadium‐dependent haloperoxidase, thus completing the remarkably efficient pathway.     

Octadecanuclear Gear Wheels by Self‐Assembly of Self‐Assembled “Double Saddle”‐Type Coordination Entities: Molecular “Rangoli”

A series of self‐assembled “double saddle”‐type trinuclear complexes of [Pd₃L′₃ L ₂] formulation have been synthesized by complexation of a series of cis‐protected palladium(II) components with a slightly divergent “E‐shaped” non‐chelating tridentate ligand, 1,1′‐(pyridine‐3,5‐diyl)bis(3‐(pyridin‐3‐yl)urea ( L ). The cis‐protecting agents L′ employed in the study are ethylenediamine (en), tetramethylethylenediamine (tmeda), 2,2′‐bipyridine (bpy), and 1,10‐phenanthroline (phen), for 1 , 2 , 3 , and 4 , respectively. The crystal structures of [Pd₃(tmeda)₃( L )₂](NO₃)₆ ( 2 ), [Pd₃(bpy)₃( L )₂](NO₃)₆ ( 3 ), and [Pd₃(phen)₃( L )₂](NO₃)₆ ( 4 ) unequivocally support the new architecture. Two of the “double saddle”‐type complexes ( 3 and 4 ) are suitably crafted with π surfaces at the strategically located cis‐protecting sites to facilitate intermolecular π–π interactions in the solid state. As a consequence, six units of the 3 (or 4 ) are assembled, by means of six‐pairs of π–π stacking interactions, in a circular geometry to form an octadecanuclear molecular ring of [(Pd₃L′₃ L ₂)₆] composition. The overall arrangement of the rings in the crystal packing is equated with the traditional Indian art form rangoli.     

Mediating Gel Formation from Structurally Controlled Poly(Electrolytes) Through Multiple “Head‐to‐Body” Electrostatic Interactions

Tuning the chain‐end functionality of a short‐chain cationic homopolymer, owing to the nature of the initiator used in the atom transfer radical polymerization (ATRP) polymerization step, can be used to mediate the formation of a gel of this poly(electrolyte) in water. While a neutral end group gives a solution of low viscosity, a highly homogeneous gel is obtained with a phosphonate anionic moiety, as characterized by rheometry and diffusion nuclear magnetic resonance (NMR). This novel type of supramolecular control over poly(electrolytic) gel formation could find potential use in a variety of applications in the field of electro‐active materials.

     

Synthesis and phase behavior of a polynorbornene‐based molecular brush with dual “jacketing” effects

In this study, a series of well‐defined liquid crystalline molecular brushes with dual “jacketing” effects, polynorbornene‐g‐poly{2,5‐bis[(4‐methoxyhenyl)oxycarbonyl] styrene} (PNb‐g‐PMPCS), were synthesized by the “grafting through” method from ring opening metathesis polymerization of α‐norbornenyl‐terminated PMPCS. The rigid PMPCS side chain was synthesized by Cu(I)‐catalyzed atom transfer radical polymerization initiated by N‐[(2‐bromo‐2‐methylpropanoyl)ethyl]‐cis‐5‐norbornene‐exo‐2,3‐dicarboximide. The chemical structures of the molecular brushes were confirmed by ¹H NMR and gel permeation chromatography (GPC), and the thermal properties were studied by thermogravimetric analysis (TGA). GPC results reveal that the molecular brushes have relatively narrow polydispersities. TGA results show that the molecular brushes have excellent thermal stabilities. The PMPCS side chains in all the molecular brushes form the columnar nematic liquid crystalline phase, which is a little different from the behavior of linear PMPCS possibly due to the confinement or other effects of the brush architecture which leads to decreased order. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2116–2123     

Exploiting Aromatic Interactions for β‐Peptide Foldamer Helix Stabilization: A Significant Design Element

Tetrameric H10/12 helix stabilization was achieved by the application of aromatic side‐chains in β‐peptide oligomers by intramolecular backbone–side chain CH–π interactions. Because of the enlarged hydrophobic surface of the oligomers, a further aim was the investigation of the self‐assembly in a polar medium for the β‐peptide H10/12 helices. NMR, ECD, and molecular modeling results indicated that the oligomers formed by cis‐[1S,2S]‐ or cis‐[1R,2R]‐1‐amino‐1,2,3,4‐tetrahydronaphthalene‐2‐carboxylic acid (ATENAC) and cis‐[1R,2S]‐ or cis‐[1S,2R]‐2‐aminocyclohex‐3‐enecarboxylic acid (ACHEC) residues promote stable H10/12 helix formation with an alternating backbone configuration even at the tetrameric chain length. These results support the view that aromatic side‐chains can be applied for helical structure stabilization. Importantly, this is the first observation of a stable H10/12 helix with tetrameric chain‐length. The hydrophobically driven self‐assembly was achieved for the helix‐forming oligomers, seen as vesicles in transmission electron microscopy images. The self‐association phenomenon, which supports the helical secondary structure of these oligomers, depends on the hydrophobic surface area, because a higher number of aromatic side‐chains yielded larger vesicles. These results serve as an essential element for the design of helices relating to the H10/12 helix. Moreover, they open up a novel area for bioactive foldamer construction, while the hydrophobic area gained through the aromatic side‐chains may yield important receptor–ligand interaction surfaces, which can provide amplified binding strength.     

Macromolecular brushes synthesized by “grafting from” approach based on “click chemistry” and RAFT polymerization

Well‐defined macromolecular brushes with poly(N‐isopropyl acrylamide) (PNIPAM) side chains on random copolymer backbones were synthesized by “grafting from” approach based on click chemistry and reversible addition‐fragmentation chain transfer (RAFT) polymerization. To prepare macromolecular brushes, two linear random copolymers of 2‐(trimethylsilyloxy)ethyl methacrylate (HEMA‐TMS) and methyl methacrylate (MMA) (poly(MMA‐co‐HEMA‐TMS)) were synthesized by atom transfer radical polymerization and were subsequently derivated to azide‐containing polymers. Novel alkyne‐terminated RAFT chain transfer agent (CTA) was grafted to polymer backbones by copper‐catalyzed 1,3‐dipolar cycloaddition (azide‐alkyne click chemistry), and macro‐RAFT CTAs were obtained. PNIPAM side chains were prepared by RAFT polymerization. The macromolecular brushes have well‐defined structures, controlled molecular weights, and molecular weight distributions (M_w/M_n ≦ 1.23). The RAFT polymerization of NIPAM exhibited pseudo‐first‐order kinetics and a linear molecular weight dependence on monomer conversion, and no detectable termination was observed in the polymerization. The macromolecular brushes can self‐assemble into micelles in aqueous solution. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 443–453, 2010     

Building the “Phosphoindigo” Backbone by Oxidative Coupling of Phosphindolin‐3‐ones with Selenium Dioxide

Oxidative coupling of racemic 1‐ethoxy‐1‐oxophosphindolin‐3‐one ( 1 ) and its 5‐CF₃‐derivative 6 with SeO₂ furnishes 1,1′‐diphosphaindigo derivatives 5 and 7 as bis‐phosphinic esters, i. e. as P^V‐compounds. Like indigo and thioindigo, 5 and 7 exist in the E‐configuration; the crude products of 5 and 7 are mixtures of isomers that are trans‐ and cis‐configurated with respect to the relative orientation of the ester groups oat phosphorus. The structure of the centrosymmetric E‐P(R)P′(S) isomer [(E)‐trans‐isomer] of 5 was determined by X‐ray crystallography. Ester cleavage of 5 , followed by addition of triethylamine to bis‐phosphinic acid 9 (the 1,1,1′,1′‐tetroxide of “phosphoindigo”), furnishes the related bis‐triethylammonium salt 10 as a crystalline hydrate that exhibits an extended hydrogen bonding network.     

Synthesis of graft copolymers with “V‐shaped” and “Y‐shaped” side chains via controlled radical and anionic polymerizations

A combination of nitroxide‐mediated radical polymerization and living anionic polymerization was used to synthesize a series of well‐defined graft (co)polymers with “V‐shaped” and “Y‐shaped” branches. The polymer main chain is a copolymer of styrene and p‐chloromethylstyrene (PS‐co‐PCMS) prepared via nitroxide‐mediated radical polymerization. The V‐shaped branches were prepared through coupling reaction of polystyrene macromonomer, carrying 1,1‐diphenylethylene terminus, with polystyryllithium or polyisoprenyllithium. The Y‐shaped branches were prepared throughfurther polymerization initiated by the V‐shaped anions. The obtained branches, carrying a living anion at the middle (V‐shaped) or at the end of the third segment (Y‐shaped), were coupled in situ with pendent benzyl chloride of PS‐co‐PCMS to form the target graft (co)polymers. The purified graft (co)polymers were analyzed by size exclusion chromatography equipped with a multiangle light scattering detector and a viscometer. The result shows that the viscosities and radii of gyration of the branched polymers are remarkably smaller than those of linear polystyrene. In addition, V‐shaped product adopts a more compact conformation in dilute solution than the Y‐shaped analogy. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 4013–4025, 2007     

De novo Biosynthesis of “Non‐Natural” Thaxtomin Phytotoxins

Thaxtomins are diketopiperazine phytotoxins produced by Streptomyces scabies and other actinobacterial plant pathogens that inhibit cellulose biosynthesis in plants. Due to their potent bioactivity and novel mode of action there has been considerable interest in developing thaxtomins as herbicides for crop protection. To address the need for more stable derivatives, we have developed a new approach for structural diversification of thaxtomins. Genes encoding the thaxtomin NRPS from S. scabies, along with genes encoding a promiscuous tryptophan synthase (TrpS) from Salmonella typhimurium, were assembled in a heterologous host Streptomyces albus. Upon feeding indole derivatives to the engineered S. albus strain, tryptophan intermediates with alternative substituents are biosynthesized and incorporated by the NRPS to deliver a series of thaxtomins with different functionalities in place of the nitro group. The approach described herein, demonstrates how genes from different pathways and different bacterial origins can be combined in a heterologous host to create a de novo biosynthetic pathway to “non‐natural” product target compounds.     

Photoelectron-spectroscopic Evidence Concerning “Homo-aromaticity”

The first of the two π-bands in the photoelectron spectrum of cis-cis-cis-1, 4, 7-cyclononatriene (I, symmetry C_3v) shows a Jahn-Teller split. This is consistent with the prediction of molecular orbital theory that the top occupied orbitals of I are e (π) and a ₁(π) respectively. From the difference ?( e (π)) - ?( a ₁(π)) = 0.90 to 0.97 eV a value of β_1,3 = ?0.68 eV = 0.27 β (β = -2.5 eV) is obtained for the homoconjugative interaction of two π-orbitals in I. This value represents almost exclusively through-space interaction between the π-orbitals. Through-bond interaction (hyperconjugation) is a minor effect in I. A comparison of the photoelectron data of bicyclo [4.2.1] nonatriene with those of norbornene and cycloheptadiene shows that homoconjugation (homo-aromaticity) can only be detected by photoelectron spectroscopy if the interacting π-bonds (basis orbitals) are symmetry equivalent or have accidentally (almost) degenerate energies.     

Optimal Configurations of “Capped” β‐Cyclodextrin Dimers in Water Maximise Hydrophobic Association

Circular dichroism analysis and proton NMR experiments revealed that solutions of 3‐O‐(2‐methylnaphthyl)‐β‐cyclodextrin form different dimer configurations. The exact nature of the dimer configurations were postulated to be of three types in which these capped cyclodextrins (CDs) are orientated in head‐to‐head and head‐to‐tail arrangements. Here we show from detailed computer simulations and free‐energy calculations on the configurations that the head‐to‐head configuration in which the naphthyl groups are mutually inserted into each other’s CD cavities is the most favoured configuration. This configuration optimises the hydrophobic association of the naphthyl aromatic groups and the ring cavities as well as forming the most inter‐CD hydrogen bonds of the three configurations.     

Silica/Poly(1,5‐dioxepan‐2‐one) Hybrid Nanoparticles by “Direct” Surface‐Initiated Polymerization

Summary: Biodegradable poly(1,5‐dioxepan‐2‐one) (PDXO) was grown directly from Si OH groups of a silica nanoparticle by surface‐initiated, ring‐opening polymerization (SI‐ROP) of 1,5‐dioxepan‐2‐one (DXO). The direct SI‐ROP of DXO was achieved by heating a mixture of Sn(Oct)₂, DXO, and the silica nanoparticles (316 nm in diameter) in anhydrous toluene. The resulting silica/PDXO hybrid nanoparticles were characterized by means of ¹H NMR spectroscopy, IR spectroscopy, thermogravimetric analysis, and field‐emission scanning electron microscopy.

The procedure for the surface‐initiated, ring‐opening polymerization of 1,5‐dioxepan‐2‐one on silica nanoparticles reported here.     

“Click”‐Triggered Self‐Healing Graphene Nanocomposites

Strategies to compensate material fatigue are among the most challenging issues, being most prominently addressed by the use of nano‐ and microscaled fillers, or via new chemical concepts such as self‐healing materials. A capsule‐based self‐healing material is reported, where the adverse effect of reduced tensile strength due to the embedded capsules is counterbalanced by a graphene‐based filler, the latter additionally acting as a catalyst for the self‐healing reaction. The concept is based on “click”‐based chemistry, a universal methodology to efficiently link components at ambient reaction conditions, thus generating a “reactive glue” at the cracked site. A capsule‐based healing system via a graphene‐based Cu₂O (TRGO‐Cu₂O‐filler) is used, acting as both the catalytic species for crosslinking and the required reinforcement agent within the material, in turn compensating the reduction in tensile strength exerted by the embedded capsules. Room‐temperature self‐healing within 48 h is achieved, with the investigated specimen containing TRGO‐Cu₂O demonstrating significantly faster self‐healing compared to homogeneous (Cu(PPh₃)₃F, Cu(PPh₃)₃Br), and heterogeneous (Cu/C) copper(I) catalysts.

     

Synthesis of 2‐amino‐4‐oxo‐5‐substitutedbenzylthiopyrrolo[2,3‐d]‐pyrimidines as potential inhibitors of thymidylate synthase

A series of ten novel 2‐amino‐4‐oxo‐5‐[(substitutedbenzyl)thio]pyrrolo[2,3‐d]pyrimidines 2‐11 were synthesized as potential inhibitors of thymidylate synthase and as antitumor agents. The analogues contain various electron withdrawing and electron donating substituents on the benzylsulfanyl ring of the side chains and were synthesized from the key intermediate 2‐amino‐4‐oxo‐6‐methylpyrrolo[2,3‐d]pyrimidine, 14 . Appropriately substituted benzyl mercaptans were appended to the 5‐position of 14 via an oxidative addition reaction using iodine, ethanol and water. The compounds were evaluated against human, Escherichia coli and Toxoplasma gondii thymidylate synthase and against human, Escherichia coli and Toxoplasma gondii dihydrofolate reductase. The most potent inhibitor, ( 6 ) which has a 4′‐methoxy substituent on the side chain, has an IC₅₀=25 μM against human thymidylate synthase. Contrary to analogues of general structure 1 , electron donating or electron withdrawing substituents on the side chain of 2‐11 had little or no influence on the human thymidylate synthase inhibitory activity.     

Acrylic Acid “Reversed” PolyHIPEs

Summary: An oil‐in‐water high internal phase emulsion consisting of acrylic acid, water, and a crosslinker (N,N′‐methylene bisacrylamide) as the water phase, and toluene as the oil phase was successfully stabilised to sustain thermal initiation of radical polymerisation resulting in porous open‐cellular monolithic material. The type of initiator used influenced the average pore size ranging from approx. 708 nm to approx. 1 087 nm, as determined by mercury porosimetry.

Schematic of the preparation of an oil‐in‐water‐type polyHIPE (high internal phase emulsion).     

Polymer Brushes by the “Grafting to” Method

This paper focuses on the attachment of densely grafted polymer layers (polymer brushes) to various inorganic and polymeric substrates by the “grafting to” method. A brief overview of synthesis of polymer brushes by the method is first provided, with emphasis on chemical approaches to polymer attachment. The second part of the paper covers the synthesis of polymer layers via a recently developed macromolecular anchoring layer approach. Several examples of application of the grafting technique are presented for generation of hydrophobic, hydrophilic, gradient, and switchable surfaces.

     

Synthesis and clustering of supramolecular “graft” polymers

The synthesis and melt rheology of supramolecular poly(isobutylene) polymers bearing statistically distributed hydrogen‐bonding moieties is reported, aiming at understanding the formation of the underlying supramolecular networks for self‐healing polymers. Two different hydrogen bonds were incorporated into a poly(isobutylene) (PIB) copolymer, one based on a (weak) pyridinium/pyridine interaction, the other based on a (stronger) 2,6‐diaminotriazine/thymine interaction. A direct copolymerization based on living cationic polymerization of isobutene and the comonomers 1 , 2 , and 4 in amounts of 1 mol % lead to the copolymers PIB‐ 1 , PIB‐ 2 , and PIB‐ 4 with a content of ～1 mol % of comonomer and molecular weights ranging from ～2000 to 19,000 g mol^?1 (M_w/M_n ～ 1.2–1.5). Subsequent azide/alkyne “click” chemistry enabled the attachment of 2,6‐diaminotriazine‐ and thymine‐moieties to yield the copolymers PIB‐ 5 , PIB‐ 6 , and PIB‐ 7 . Proof of the statistical incorporation of ～1 mol % of hydrogen‐bonding moieties was achieved by ¹H NMR spectroscopy and matrix‐assisted laser desorption ionization measurements. The true presence of a supramolecular network in PIB‐ 1 (pyridinium/pyridine interaction) as well as with 1/1 blends of PIBs interacting via the 2,6‐diaminotriazine/thymine interaction (PIB‐ 5 /PIB‐ 6 ) was proven via the increasing plateau modulus with increasing molecular weights (5.5k, 9.9k, 12.4k, 16k, and 19k). Dynamics of the hydrogen bonds in the melt state was investigated by determining the effective cluster lifetime ( τ ) observing a clear difference in the (weaker) pyridinium/pyridine interaction ( τ ～ 1 s) to the 2,6‐ (stronger) diamintriazine/thymine interaction ( τ ～ 100 s). The so‐generated materials will be useful as a basis for self‐healing polymers, as dynamics plays a major role in such polymers. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Synthesis and postfunctionalization of well‐defined star polymers via “double” click chemistry

In this article, the synthesis and the functionalization of well‐defined, narrow polydispersity (polydispersity index < 1.2) star polymers via reversible addition‐fragmentation chain transfer polymerization is detailed. In this arm first approach, the initial synthesis of a poly(pentafluorophenyl acrylate) polymer, and subsequent, cross‐linking using bis‐acrylamide to prepare star polymers, has been achieved by reversible addition fragmentation chain transfer polymerization. These star polymers were functionalized using a variety of amino functional groups via nucleophilic substitution of pentafluorophenyl activated ester to yield star polymers with predesigned chemical functionality. This approach has allowed the synthesis of star glycopolymer using a very simple approach. Finally, the core of the stars was modified via thiol‐ene click chemistry reaction using fluorescein‐o‐acrylate and DyLigh 633 Maleimide. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

“Bottom‐Up” Fabrication of BODIPY‐Functionalized Fluorescent Hyperbranched Glycopolymers for Hepatoma‐Targeted Imaging

A novel type of multivalent and highly specific fluorescent hyperbranched glycopolymers h‐P(GalEA‐co‐VBPT‐co‐BYMA) (hPGVB) is designed and prepared successfully via a facile “bottom‐up” strategy. The acetylated hPGVB is prepared by one‐pot reversible addition‐fragmentation chain transfer (RAFT) copolymerization of acrylate‐type galactose monomers AcGalEA and methacrylate‐type fluorescent monomers BYMA in presence of an inimer‐type RAFT chain transfer agent. After deacetylation, the resulting amphiphilic hPGVB can self‐assemble into stable nanoparticles in aqueous media, showing strong green fluorescence with relative high quantum yields and good photostability. The cell viability study indicates the excellent biocompatibility of the hPGVB fluorescent nanoparticles (FNPs) against HepG2 and NIH3T3 cells. More importantly, comparing with the galactose‐free fluorescent hyperbranched polymers h‐P(OEGMA‐co‐VBPT‐co‐BYMA), hPEVB FNPs can be selectively internalized by asialoglycoprotein (ASGP) receptor‐rich HepG2 cells, indicating their potential application in the bioimaging fields.