Syntheses of dendritic branches based on L-lysine: is the stereochemistry preserved throughout the synthesis?

This paper reports the syntheses of individual dendritic branches based on L-lysine and functionalised with either Boc or Bz surface groups. Convergent and divergent synthetic approaches were employed and the preservation of stereochemistry during the syntheses was monitored using polarmetry, NMR and HPLC. In addition, racemic dendritic branches based on D,L-lysine were synthesised for comparative purposes. It was observed that the preservation of stereochemistry in the dendritic peptide was dependent on the method of synthesis, with divergent methodology being preferred. The results are discussed in terms of the known stereochemical outcomes of traditional peptide coupling processes, and are generalised to the synthesis of other dendritic peptides. Such observations about the chirality of dendritic peptides are of relevance to chemists developing dendritic systems for applications where single enantiomer dendrimers would clearly be preferred, such as enantioselective catalysis or pharmaceutical chemistry.     

Attenuation of airway inflammation by simvastatin and the implications for asthma treatment: is the jury still out?

Although some studies have explained the immunomodulatory effects of statins, the exact mechanisms and the therapeutic significance of these molecules remain to be elucidated. This study not only evaluated the therapeutic potential and inhibitory mechanism of simvastatin in an ovalbumin (OVA)-specific asthma model in mice but also sought to clarify the future directions indicated by previous studies through a thorough review of the literature. BALB/c mice were sensitized to OVA and then administered three OVA challenges. On each challenge day, 40 mg kg⁻¹ simvastatin was injected before the challenge. The airway responsiveness, inflammatory cell composition, and cytokine levels in bronchoalveolar lavage (BAL) fluid were assessed after the final challenge, and the T cell composition and adhesion molecule expression in lung homogenates were determined. The administration of simvastatin decreased the airway responsiveness, the number of airway inflammatory cells, and the interleukin (IL)-4, IL-5 and IL-13 concentrations in BAL fluid compared with vehicle-treated mice (P<0.05). Histologically, the number of inflammatory cells and mucus-containing goblet cells in lung tissues also decreased in the simvastatin-treated mice. Flow cytometry showed that simvastatin treatment significantly reduced the percentage of pulmonary CD4⁺ cells and the CD4⁺/CD8⁺ T-cell ratio (P<0.05). Simvastatin treatment also decreased the expression of the vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 proteins, as measured in homogenized lung tissues (P<0.05) and human epithelial cells. The reduction in the T cell influx as a result of the decreased expression of cell adhesion molecules is one of the mechanisms by which simvastatin attenuates airway responsiveness and allergic inflammation. Rigorous review of the literature together with our findings suggested that simvastatin should be further developed as a potential therapeutic strategy for allergic asthma.     

Natural and biotech-derived therapeutic proteins: what is the future?

A myriad of novel proteins and ligands of unknown function will be generated by the Human Genomic Project. Due to differences in post-translational processing, proteins produced by recombinant DNA technology may not possess proper biological activity. One way to find their function is to search for their natural counterparts. Proteins are produced in the tissues, and many of them are secreted into plasma and excreted into urine. There is a virtually "unlimited" array of human proteins in our plasma and urine, many of them in a fully active form. They include small molecules like steroids, peptides, and large glycoproteins like human menopausal gonadotropin. A library of plasma and urinary proteins could be developed to serve as a reference for the novel proteins generated by the functional genomic projects.     

Why is chemical synthesis and property optimization easier than expected?

Identifying optimal conditions for chemical and material synthesis as well as optimizing the properties of the products is often much easier than simple reasoning would predict. The potential search space is infinite in principle and enormous in practice, yet optimal molecules, materials, and synthesis conditions for many objectives can often be found by performing a reasonable number of distinct experiments. Considering the goal of chemical synthesis or property identification as optimal control problems provides insight into this good fortune. Both of these goals may be described by a fitness function J that depends on a suitable set of variables (e.g., reactant concentrations, components of a material, processing conditions, etc.). The relationship between J and the variables specifies the fitness landscape for the target objective. Upon making simple physical assumptions, this work demonstrates that the fitness landscape for chemical optimization contains no local sub-optimal maxima that may hinder attainment of the absolute best value of J. This feature provides a basis to explain the many reported efficient optimizations of synthesis conditions and molecular or material properties. We refer to this development as OptiChem theory. The predicted characteristics of chemical fitness landscapes are assessed through a broad examination of the recent literature, which shows ample evidence of trap-free landscapes for many objectives. The fundamental and practical implications of OptiChem theory for chemistry are discussed.     

Maleimide cycloadditions by sulfinyldienes: is the sulfur configuration the only controller of the diastereofacial selectivity?

Cyclohexylsulfinyl-3-methyl-1,3-butadienes 5, 6, and 1-[1-(cyclohexylsulfinyl)ethenyl]cyclohexene (7), easily prepared from cyclohexanethiol (1) via transient cyclohexanesulfenic acid (4), were reacted with N-phenylmaleimide under different conditions, at normal and high pressure. The stereochemical outcome of these cycloadditions contributes a better understanding of the relationships among different factors controlling facial diastereoselection.     

Clinical pharmacokinetic data of racemic drugs obtained by the indirect method following precolumn diastereomer formation: is the influence of racemization during chiral derivatization significant?

This report reviews the stereoselective data of a number of racemic drugs (n = 17) obtained from indirect chiral method (via diastereomer formation) in comparison to similar data generated by the application of a direct chiral method. While it was noted that the indirect method still continued to be used to characterize the stereoselective disposition of racemic drugs, the present review critically evaluates the issue of racemization that has the potential to skew the stereoselective data obtained from the indirect method. The review describes various remedies to counter and/or minimize the impact of racemization on the final outcome of the stereoselective analysis by the indirect method. On the basis of this review it could be concluded that the indirect method is a viable and important tool for gathering stereoselective data of racemic drugs used in medical practice as well for those racemic drugs still in discovery and developmental stages.     

Clean photochemical synthesis mediated by radical-radical reactions: radical buffer or the persistent free radical effect?

[reaction: see text] A new synthetic methodology is reported that takes advantage of the persistent free radical effect (PFRE), where clean products can be obtained in good yields from radical cross-combination reactions, despite their reputation for being of little synthetic value and for resulting in complex mixtures; these problems can be avoided when the PFRE is used as a synthetic tool.     

Expanding the synthesis of Stöber spheres: towards the synthesis of nano-magnesium oxide and nano-zinc oxide

In order to synthesise Stöber spheres of different diameters, fixed amounts of ethanol, ammonia and water were used with varying amounts of tetraethyl orthosilicate. This simple method was further applied to the synthesis of nano-ZnO and nano-MgO from their respective precursors, zinc methoxide and magnesium ethoxide. The spherical nano-SiO₂, nano-ZnO and nano-MgO synthesised in this way were characterised by X-ray diffraction, Fourier-transform infrared spectroscopy, scanning electron microscopy and transmission electron microscopy. Preliminary investigations found that nano-ZnO and nano-MgO showed good catalytic activity in the trans-esterification reaction that converts vegetable oil to biodiesel.     

A systematic study of the synthesis of silver nanoplates: is citrate a "magic" reagent?

In this work we have carried out systematic studies and identified the critical role of hydrogen peroxide instead of the generally believed citrate in the well-known chemical reduction route to silver nanoplates. This improved understanding allows us to develop consistently reproducible processes for the synthesis of nanoplates with high efficiency and yields. By harnessing the oxidative power of H(2)O(2), various silver sources including silver salts and metallic silver can be directly converted to nanoplates with the assistance of an appropriate capping ligand, thus significantly enhancing the reproducibility of the synthesis. Contrary to the previous conclusion that citrate is the key component, we have determined that the group of ligands with selective adhesion to Ag (111) facets can be expanded to many di- and tricarboxylate compounds whose two nearest carboxylate groups are separated by two or three carbon atoms. We have also found that the widely used secondary ligand polyvinylpyrrolidone can be replaced by many hydroxyl group-containing compounds or even removed entirely while still producing nanoplates of excellent uniformity and stability. In addition to the general understanding of NaBH(4) as a reducing agent, it has also been found to act as a capping agent to stabilize the silver nanoparticles, prolong the initiation time required for nanoplate nucleation, and contribute to the control of the thickness as well as the aspect ratio of silver nanoplates. The improved insight into the specific roles of the reaction components and significantly enhanced reproducibility are expected to help elucidate the formation mechanism of this interesting nanostructure.     

Computational and spectroscopic studies of organic mixed-valence compounds: where is the charge?

This article discusses recent progress by a combination of spectroscopy and quantum-chemical calculations in classifying and characterizing organic mixed-valence systems in terms of their localized vs. delocalized character. A recently developed quantum-chemical protocol based on non-standard hybrid functionals and continuum solvent models is evaluated for an extended set of mixed-valence bis-triarylamine radical cations, augmented by unsymmetrical neutral triarylamine-perchlorotriphenylmethyl radicals. It turns out that the protocol is able to provide a successful assignment to class II or class III Robin-Day behavior and gives quite accurate ground- and excited-state properties for the radical cations. The limits of the protocol are probed by the anthracene-bridged system 8, where it is suspected that specific solute-solvent interactions are important and not covered by the continuum solvent model. Intervalence charge-transfer excitation energies for the neutral unsymmetrical radicals are systematically overestimated, but dipole moments and a number of other properties are obtained accurately by the protocol.     

α-Trifluoromethyl-β-aryl enamines in the synthesis of trifluoromethylated heterocycles by the Fischer and the Pictet-Spengler reactions

α-Trifluoromethyl-β-aryl enamines were successfully used as synthetic equivalents of benzyltrifluoromethyl ketones in both the Fischer indole synthesis and the Pictet-Spengler reaction. Accordingly, 2-trifluoromethyl indoles and a variety of trifluoromethylated 4,5,6,7-terahydro-1H-pyridines including carbolines were synthesized in moderate to good yields.     

Chalcogen-nitrogen ��-heterocyclic radical anion salts: the synthesis and properties

The review concerns methods of synthesis, as well as the molecular, electronic, and crystal structures and the magnetic properties of a novel class of paramagnetic compounds, namely, chalcogen-nitrogen ??-heterocyclic radical anion salts derived from 1,2,5-chalcogenadiazole.     

Supramolecular chemistry: What is the commercialisation plan?

Opportunities for commercialisation along with personal views are provided in this essay.     

Extended Dötz-like cyclization reactions towards the synthesis of eight-membered ring-containing polycycles: scope and theoretical studies

The reaction between cyclobutene-containing dienyl Fischer carbene complexes (FCCs) and alkynes has been studied from both an experimental and a theoretical point of view. We have found that the reaction follows different pathways depending on the nature of the terminal double bond of the carbene complex. Thus, eight-membered carbocycles have been obtained from an extended D?tz-like reaction of dienyl FCCs and indolyl- or benzofuryl-substituted alkenyl FCCs. On the other hand, phenyl- and naphthyl-substituted alkenyl FCCs follow a typical benzannulation pathway giving rise to cyclohexadienones. DFT calculations have allowed us to formulate detailed mechanistic proposals and to provide an explanation for the formation of either the benzannulation products or the eight-membered carbocycles.     

Stabilities and Biological Activities of Vanadium Drugs: What is the Nature of the Active Species?

Diverse biological activities of vanadium(V) drugs mainly arise from their abilities to inhibit phosphatase enzymes and to alter cell signaling. Initial interest focused on anti‐diabetic activities but has shifted to anti‐cancer and anti‐parasitic drugs. V‐based anti‐diabetics are pro‐drugs that release active components (e.g., H₂VO₄⁻) in biological media. By contrast, V anti‐cancer drugs are generally assumed to enter cells intact; however, speciation studies indicate that nearly all drugs are likely to react in cell culture media during in vitro assays and the same would apply in vivo. The biological activities are due to V^V and/or V^IV reaction products with cell culture media, or the release of ligands (e.g., aromatic diimines, 8‐hydroxyquinolines or thiosemicarbazones) that bind to essential metal ions in the media. Careful consideration of the stability and speciation of V complexes in cell culture media and in biological fluids is essential to design targeted V‐based anti‐cancer therapies.     

Progress toward the synthesis of piperazimycin A: exploration of the synthesis of γ-hydroxy and γ-chloropiperazic acids

Employing Hamada’s chemistry with MAOS optimization of several steps, an expedient route to key (3S,5S)- and (3R,5R)-γ-hydroxy and (3R,5S)-γ-chloropiperazic acids, was developed en route to a total synthesis of piperazimycin A.