A Chemical Approach to Protein Design—Template-Assembled Synthetic Proteins (TASP)

Advances in methodology in both chemistry and molecular biology allow us to take a fresh look at protein science. Chemical synthesis of peptides and site-directed mutagenesis are now standard research tools, paving the way for the construction of new proteins with tailor-made structural and functional properties. The decisive hurdle on the way lies not in the synthesis of the molecules proper but rather in a better understanding of the complex folding pathways of polypeptide chains into spatially well-defined structures. Can the chemist use his synthetic tools to bypass the notorious “folding problem?” In this article, we present a new approach developed in our laboratory, which opens a chemical route to artificial proteins with predetermined three-dimensional structures, allowing a first step towards the synthesis of new proteins with functional properties.     

Trinuclear Gold Clusters Supported by Cyclic (alkyl)(amino)carbene Ligands: Mimics for Gold Heterogeneous Catalysts

The synthesis of air‐ and moisture‐stable trinuclear mixed‐valence gold(I)/gold(0) clusters is described. They promote the catalytic carbonylation of amines under relatively mild conditions. The synthetic route leading to the trinuclear clusters involves a simple ligand exchange from the readily available μ³‐oxo‐[(Ph₃PAu)₃O]⁺ complex. This synthetic method paves the way for the preparation of a variety of mixed‐valence gold(I)/gold(0) polynuclear clusters. Moreover, the well‐defined nature of the complexes demonstrates that the catalytic process involves a rare example of a definite change of oxidation state of gold from Au⁰₂Au^I to Au^I₃.     

New Reductive Transformations of Unsaturated Cyclic Hydrocarbons [New Synthetic Methods (66)]

The successive reduction of fully conjugated cyclic hydrocarbons leads to singly and multiply charged ions with unusual bonding. The charge distribution in these ions can be determined spectroscopically, and the information so obtained is then used in kinetically controlled trapping reactions for the regioselective introduction of electrophilic groups. When non-benzenoid substrates are used, syntheses become possible which can either not be carried out or can only be carried out with great difficulty in other ways. Examples of new preparative applications are cycloannelation and bridging reactions as well as polymerization reactions. The ion pair structure of the intermediate and the type of electrophile used are of paramount importance in controlling the mechanism of these reductive transformations.     

Cyclic Adenosine 5′‐Diphosphoribose (cADPR) Mimics Used as Molecular Probes in Cell Signaling

Cyclic adenosine 5′‐diphosphate ribose (cADPR) is a second messenger in the Ca²⁺ signaling pathway. To elucidate its molecular mechanism in calcium release, a series of cADPR analogues with modification on ribose, nucleobase, and pyrophosphate have been investigated. Among them, the analogue with the modification of the northern ribose by ether linkage substitution (cIDPRE) exhibits membrane‐permeate Ca²⁺ agonistic activity in intact HeLa cells, human T cells, mouse cardiac myocytes and neurosecretory PC12 cell lines; thus, cIDPRE and coumarin‐caged cIDPRE are valuable probes to investigate the cADPR‐mediated Ca²⁺ signal pathway.     

Long-Term Antibacterial Film Nanocomposite Incorporated with Patchouli Essential Oil Prepared by Supercritical CO2 Cyclic Impregnation for Wound Dressing

Biocompatible skin wound dressing materials with long-term therapeutic windows and anti-infection properties have attracted great attention all over the world. The cooperation between essential oil and non-toxic or bio-based polymers was a promising strategy. However, the inherent volatility and chemical instability of most ingredients in essential oils make the sustained pharmacological activity of essential oil-based biomaterials a challenge. In this study, a kind of film nanocomposite loaded with patchouli essential oil (PEO-FNC) was fabricated. PEO-loaded mesoporous silica nanoparticles (PEO-MSNs) with drug load higher than 40 wt% were firstly prepared using supercritical CO₂ cyclic impregnation (SCCI), and then combined with the film matrix consisting of polyvinyl alcohol and chitosan. The morphology of PEO-MSNs and PEO-FNC was observed by transmission and scanning electron microscope. The mechanical properties, including hygroscopicity, tensile strength and elongation at break (%), were tested. The release behavior of PEO from the film nanocomposite showed that PEO could keep releasing for more than five days. PEO-FNC exhibited good long-term (>48 h) antibacterial effect on Staphylococcus aureus and non-toxicity on mouse fibroblast (L929 cells), making it a promising wound dressing material.     

Cyclic imides. XII(i). Absorption and fluorescence spectra of 3-benzamidophthalimides

The ultraviolet absorption, fluorescence, and infrared absorption spectra of fifteen 3-benz-amidophthalimides are described. In general, the nature or position of the substituents on the benzamide moiety has little effect on the ultraviolet absorption and fluorescence spectra of these, compounds. The absorption baud at 271 nm is more sensitive to substituent variations than the other two bands (at 227 nm and 341 nm), indicating this band is a composite of bands observed in the spectra of 3-aminophthalimide and the substituted benzamide. The fluorescence of 3-amino-phthalirnide and the 3-benzamidophthalimides is due to the same transitions. The infrared absorption wavenumbers for the amide and imide vibrations of the 3-benzamidophthalimides are characterized.     

Expanding Catch and Release DNA Decoy (CRDD) Technology with Pyrimidine Mimics

Catch and release DNA decoys (CRDDs) utilize photochemically responsive nucleoside analogues that generate abasic sites upon exposure to light. Herein, we describe the synthesis and evaluation of four candidate CRDD monomers containing nucleobases that mimic endogenous pyrimidines: 2-nitroimidazole ( 2-NI ), 2-nitrobenzene ( 2-NB ), 2-nitropyrrole ( 2-NP ) and 3-nitropyrrole ( 3-NP ). Our studies reveal that 2-NI and 2-NP can function as CRDDs, whereas 3-NP and 2-NB undergo decomposition and transformation to a higher-ordered structure upon photolysis, respectively. When incorporated into DNA, 2-NP undergoes rapid photochemical cleavage of the anomeric bond (1.8 min half-life) to yield an abasic site. Finally, we find that all four pyrimidine mimics show significantly greater stability when base-paired against the previously reported 7-nitroindole CRDD monomer. Our work marks the expansion of CRDD technology to both purine and pyrimidine scaffolds.     

Copper(II) and nickel(II) complexes of mono-oxocyclam(5-oxo-1,4,8,11-tetraazacyclotetradecane). Synthetic and potentiometric studies

Summary The macrocyclic mono-oxotetraamine, 5-oxo-1,4,8,11-tetraazacyclotetradecane (mono-oxocyclam=LH) has been prepared by reaction of methyl acrylate with 2,3,2-tetra(1,9-diamino-3,7-diazanonane). The protonation constants of the ligand are log K₁=9.40, log K₂=6.65 and log K₃=2.87 at 25 °C (I=0.1 mol dm^–3 NaClO₄). Detailed potentiometric studies of the interaction of the base with copper(II) and nickel(II) have been carried out. In the pH range 2.5–7.0 two complexes, [CuLH]²⁺ and [CuL]⁺, form; the deprotonated complex being 100% abundant at pH 7. For nickel(II), only [NiL]⁺ forms (log _11–1 = 3.90), the yellow low spin nickel complex reaching its maximum concentration above pH 6. The [CuL][ClO₄] · H₂O and [NiL][ClO₄] 0.5 H₂O complexes have been characterised in the solid state. The nickel(II) complex is square planar with a d-d band at 22625 cm^–1.     

Interactions of hydrogen with CeO(2).

The interactions of hydrogen with ceria have been the subject of several experimental studies, but whether hydrogen atoms enter the bulk or are merely chemisorbed on the surfaces is disputed. We combine first-principles calculations with thermodynamic arguments and conclude that the uptake of small amounts of hydrogen by ceria is spontaneous below 665 K. The calculations also predict that hydrogen atoms within the bulk form hydroxyl groups and slightly expand the lattice. The predicted hydrogen content, OH vibrational frequency, and ceria lattice expansion upon hydrogen uptake are consistent with available data.     

Bringing the Science of Proteins into the Realm of Organic Chemistry: Total Chemical Synthesis of SEP (Synthetic Erythropoiesis Protein)

Erythropoietin, commonly known as EPO, is a glycoprotein hormone that stimulates the production of red blood cells. Recombinant EPO has been described as “arguably the most successful drug spawned by the revolution in recombinant DNA technology”. Recently, the EPO glycoprotein molecule has re‐emerged as a major target of synthetic organic chemistry. In this article I will give an account of an important body of earlier work on the chemical synthesis of a designed EPO analogue that had full biological activity and improved pharmacokinetic properties. The design and synthesis of this “synthetic erythropoiesis protein” was ahead of its time, but has gained new relevance in recent months. Here I will document the story of one of the major accomplishments of synthetic chemistry in a more complete way than is possible in the primary literature, and put the work in its contemporaneous context.