Volume 80, Issue 8

In August 2007, IUPAC‚ Organic and Biomolecular Chemistry Division launched a combined Biomolecular-Biotechnology Symposium as a major component of the 41st IUPAC Congress in Turin, Italy. This four-day CHEM-BIO-TECH 2007 Symposium comprised IUPAC‚ 1st Symposium on Biotechnology held jointly with IUPAC‚ 8th Symposium on Bioorganic Chemistry, ISBOC-8. In designing the program, the goal was to focus on work at the interface of biotechnology and biomolecular chemistry from which many key industrial and academic advances have sprung. The program embraced topics ranging from novel drug discovery, biosynthesis, biocatalysis, and organic synthesis through artificial biomolecules and other emerging biotechnological applications. Attention was also devoted to industrial experience in drug research and in biotechnological productions. The special topics discussed during the symposium included: - natural products synthesis, biosynthesis, and isolation - industrial application of bioorganic chemistry and biotechnology - bioorganic and bioinorganic chemistry, biosynthesis, and biocatalysis - analytical methods applied to molecular recognition This issue of Pure and Applied Chemistry comprises a collection of 11 papers based upon the invited lectures delivered at CHEM-BIO-TECH 2007. It offers readers an enduring record of the representative scientific contributions announced during the symposium, in an area of interface between chemistry and biology of great interest and relevant potential applications. Francesco Nicotra and Mary Garson Conference Chair and Co-chair

The 41st IUPAC World Chemistry Congress took place in Turin, Italy on 5-11 August 2007, under the patronage of the President of the Italian Republic. Local organization was carried out through active collaboration between the National Research Council (CNR), the Italian Chemical Society (SCI), the National Institute of Metrological Research (INRIM), the University of Turin (UNITO), the Turin Polytechnic (POLITO), and the University of Eastern Piedmont (UNIPMN). The Lingotto Conference Center in Turin served as the Congress venue. This recently modernized complex formerly housed what was once the largest motor car factory in the world, and is a fitting tribute to an industry that has played a major role in shaping the present-day city as an important industrial and cultural center. The Congress was well attended by more than 2000 delegates from all parts of the world, and they were rewarded with multidisciplinary insights and perspectives that catered for all aspects of the subject. At the same time, it was possible to enjoy the abundant hospitality of the local hosts and, when opportunity permitted, to explore some of the distinctive cultural, historical, and scenic features of Turin and its surroundings. The Congress theme of ‚ÄúChemistry Protecting Health, Natural Environment and Cultural Heritage‚Äù served to highlight topical and challenging issues, and presented a program that celebrated the societal relevance of the chemical sciences in modern times. The tone for the scientific proceedings was set by an outstanding program of plenary presentations that included three Nobel laureates, Profs. R. Hoffmann (Cornell University, USA), R. Hüber (Max-Planck Institute for Biochemistry, Münich, Germany), and K. Wüthrich (ETH, Zürich, Switzerland), along with Profs. V. Balzani (University of Bologna, Italy), A. Fujishima (Kanagawa Academy of Science and Technology, Japan), and Dr. J. Wouters (Royal Institute for Cultural Heritage, Belgium). Major program sessions were devoted to the title themes, exemplifying the positive role that chemistry plays in health, the natural environment, and cultural heritage. Six additional sessions were devoted to subdisciplinary themes and to chemical education. About 45 keynote lectures were delivered during parallel sessions, together with numerous contributed papers and posters. As always, poster sessions proved immensely popular amongst delegates and provided much opportunity for informal interaction, particularly with the large number of younger scientists who featured prominently in this part of the program. Publication of selected works based upon IUPAC Congress proceedings can be traced back to the origins of Pure and Applied Chemistry . It is therefore a pleasure to offer readers a representative glimpse of a diverse scientific program, and to continue a fine publication tradition that promises to enrich the archive. Congress papers are augmented in this issue by co-publication with those arising from the parallel event CHEM-BIO-TECH2007, a joint meeting of the IUPAC 1st Symposium on Chemical Biotechnology (ISCB-1) and the 8th Symposium on Bioorganic Chemistry (ISBOC-8). The organizers are grateful to all who contributed to a successful scientific program, and particularly thank those enthusiastic presenters who consented to contribute to this permanent record of a memorable Congress. James R. Bull IUPAC Scientific Editor Giuseppe Della Gatta Conference Editor

The bottom-up approach to miniaturization, which starts from molecules to build up nanostructures, enables the extension of the macroscopic concepts of a device and a machine to molecular level. Molecular-level devices and machines operate via electronic and/or nuclear rearrangements and, like macroscopic devices and machines, need energy to operate and signals to communicate with the operator. Examples of molecular-level photonic wires, plug/socket systems, light-harvesting antennas, artificial muscles, molecular lifts, and light-powered linear and rotary motors are illustrated. The extension of the concepts of a device and a machine to the molecular level is of interest not only for basic research, but also for the growth of nanoscience and the development of nanotechnology.

Smooth, chemically uniform surfaces are seldom found in nature. Mimicry of natural variegation is a powerful approach for controlling chemical affinity at the nanoscale. Molecular recognition is one of the fundamental concepts underlying the functioning of living cells, and it depends on a particular relationship between the nanoscale, i.e., molecular, variegations of two potentially interacting molecular partners. The primary subject matter of this paper is how to articially generate appropriate nanoscale texture at the surfaces of materials. Excluding "pick and place" chemistry, in which essentially a Maxwellian demon intervenes to place objects with atomic precision, and nowadays achievable through an adaptation of atomic force microscopy, on the grounds that it is too slow to be practicable for fabricating useful quantities of material, three approaches are explored in some detail: (i) "powder", i.e., mixing at least two individually monofunctional (with respect to the ultimate molecular recognition task) precursor components (possibly with secondary functionality enabling them to appropriately self-assemble on a substratum); (ii) mixing polymers with the possibility of phase separation and frustrated phase separation with block copolymers; and (iii) felting. The emphasis is on processes that create more or less irregular structures, rather than regular arrays. The final section deals with the metrology of nanotexture.

Retrometabolic drug design incorporates two major systematic approaches: the design of soft drugs (SDs) and of chemical delivery systems (CDSs). Both aim to design new, safe drugs with an improved therapeutic index by integrating structure-activity and -metabolism relationships; however, they achieve it by different means: whereas SDs are new, active therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their desired therapeutic effect, CDSs are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. General principles and recent developments are briefly reviewed with various illustrative examples from different therapeutic areas with special focus on soft corticosteroids and on brain targeting.

Leucascandrolide A and migrastatin were synthesized efficiently by using chemoselective reactions such as olefin metatheses. The use of an iron-catalyzed cross-coupling reaction overcame difficulties encountered with palladium-catalyzed processes in our synthetic approach toward spirangien A.

The article addresses the design of multitarget drugs, namely, compounds capable of interacting with more than one target simultaneously. These agents could be useful tools in the therapy of complex diseases such as cardiovascular and inflammatory diseases. An interesting case of multitarget compounds are nitric oxide (NO)-donor hybrids, structures which combine the physiological properties of NO with those of a lead drug. In particular, the authors discuss the symbiotic approach used to design NO-donor nonsteroidal anti-inflammatory drugs (NO-NSAIDs) and NO-donor antioxidants. The former could be useful agents in the treatment of anti-inflammatory diseases being devoid of gastro- and cardiotoxicity, the latter could be a valid approach to the treatment of many cardiovascular diseases.

Oxidation is an almost ubiquitous feature of inflammatory reactions. We discuss the development of nanocarriers that respond to the presence of oxidants with profound physical reorganization, which could in perspective allow their use for delivering anti-inflammatory principles in an inflammation-responsive fashion. We also present a study demonstrating that the response of polysulfide nanoparticles has a bulk character, i.e., the odixation reactions happen homogeneously throughout the nanoparticles, and not interfacially.

Proper handling and communication of data on chemical systems require knowledge about the mathematical characteristics of different types of property and the unambiguous representation of singular properties. Using the terminology of the International Organization for Standardization (ISO), the concept "property" is generically divided according to various statistical characteristics of property values. The formatting of representation of dedicated kinds-of-property as elaborated by clinical chemists in the International Union of Pure and Applied Chemistry (IUPAC) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) should ensure correct data transmission between laboratory dialects in any chemical discipline.

A series of metal-catalyzed processes are presented, in which carboxylic acids act as sources of either carbon nucleophiles or electrophiles, depending on the catalyst employed, the mode of activation, and the reaction conditions. A first reaction mode is the addition of carboxylic acids or amides over C-C multiple bonds, giving rise to enol esters or enamides, respectively. The challenge here is to control both the regio- and stereoselectivity of these reactions by the choice of the catalyst system. Alternatively, carboxylic acids can efficiently be decarboxylated using new Cu catalysts to give aryl-metal intermediates. Under protic conditions, these carbon nucleophiles give the corresponding arenes. If carboxylate salts are employed instead of the free acids, the aryl-metal species resulting from the catalytic decarboxylation can be utilized for the synthesis of biaryls in a novel cross-coupling reaction with aryl halides, thus replacing stoichiometric organometallic reagents. An activation with coupling reagents or simple conversion to esters allows the oxidative addition of carboxylic acids to transition-metal catalysts under formation of acyl-metal species, which can either be reduced to aldehydes, or coupled with nucleophiles. At elevated temperatures, such acyl-metal species decarbonylate, so that carboxylic acids become synthetic equivalents for aryl or alkyl halides, e.g., in Heck reactions.

The review addresses features of special interest concerning two classes of functionalized semiconducting polymers: poly(aryleneethynylene)s (PAEs) bearing biomolecules as chiral nonracemic pendant groups and poly(phenylenevinylene)s (PPVs), which are fluorinated in various positions of the repeating units. Molecular design and choice of specific substituents, synthetic protocols, and the effect of functionalization on properties of the polymers both in solution and in the solid state are discussed.

The synthesis and characterization of polyolefins continues to be one of the most important areas for academic and industrial polymer research. One consequence of the development of new "tailor-made" polyolefins is the need for new and improved analytical techniques for the analysis of polyolefins with respect to molar mass and chemical composition distribution. The present article briefly reviews different new and relevant techniques for polyolefin analysis. Crystallization analysis fractionation is a powerful new technique for the analysis of short-chain branching in linear low-density polyethylene (LLDPE) and the analysis of polyolefin blends and copolymers regarding chemical composition. For the fast analysis of the chemical composition distribution, a new high-temperature gradient high-performance liquid chromatography (HPLC) system has been developed. The efficiency of this system for the separation of various olefin copolymers is demonstrated. The correlation between molar mass and chemical composition can be accessed by on-line coupling of high-temperature size exclusion chromatography (HT-SEC) and 1 H NMR spectroscopy. It is shown that the on-line NMR analysis of chromatographic fractions yields information on microstructure and tacticity in addition to molar mass and copolymer composition.

In April 1997, the Chemical Weapons Convention (CWC) entered into force, banning chemical weapons (CW) worldwide and requiring their destruction under international verification by 2007, a date that has since been extended to 2012. At the same time, the CWC aims to prevent the recurrence of CW, including their possible use by non-State actors such as terrorists. The CWC is an agreement between governments, but it also sets norms that apply, through national laws and ethical principles, to the individual scientist and engineer. Many chemists, however, have had little or no exposure during their training and professional life to the ethical norms and regulatory requirements of the CWC. At the same time, advances in the life sciences are creating enormous opportunities - with the potential of being quite beneficial to humankind but also prone to abuse. Education and awareness-raising about the norms and principles enshrined in the CWC are therefore becoming increasingly important. Through its activities in the field of chemistry education as well as its links to the chemical industry, IUPAC has responsibility, as well as capacity, to promote professional conduct that is in full compliance with the norms of the CWC.

Synthetic studies pertaining to a novel class of structurally related glycosidic 14-membered macrolides of marine origin are reported. The evolution of a versatile aldol-based strategy that culminated in the total syntheses of callipeltoside A and aurisides A and B is detailed. Using a combination of biogenetic considerations and conformational analysis, a revised stereochemical assignment for the related polyketide dolastatin 19 was proposed and validated by total synthesis.

Antileishmanial activity of several classes of natural compounds was evaluated by using an in vitro parasitic assay model. This has led to the discovery of new antileishmanial agents with potential to be useful in the treatment of visceral and cutaneous leishmaniasis.

Terpene synthases catalyze the conversion of linear prenyl-diphosphates to a multitude of hydrocarbon skeletons with often high regio- and stereoselectivity. These remarkable enzymes all rely on a shared fold for activity, namely, the class I terpene cyclase fold. Recent work has illuminated the catalytic strategy used by these enzymes to catalyze the arguably most complex chemical reactions found in Nature. Terpene synthases catalyze the formation of a reactive carbocation and provide a template for the cyclization reactions while at the same time providing the necessary stability of the carbocationic reaction intermediates as well as strictly controlling water access.

Drug discovery remains a top priority in medical science. The phenomenon of drug resistance has heightened the need for both new classes of pharmaceutical, as well as novel modes of action. A new paradigm for drug activity is presented, which includes both recognition and subsequent irreversible inactivation of therapeutic targets. Application to both RNA and enzyme therapeutic targets has been demonstrated, while incorporation of both binding and catalytic centers provides a double-filter mechanism for improved target selectivity and lower dosing. In contrast to RNA targets that are subject to strand scission chemistry mediated by ribose H-atom abstraction, proteins appear to be inactivated through oxidative damage to amino acid side chains around the enzyme active site. Methods to monitor both intracellular delivery and activity against RNA targets have been developed based on plasmid expression of the green fluorescent protein (GFP). Herein, the activity of representative metallodrugs is described in the context of both in vitro and cellular assays, and the mechanism of action is discussed. Studies with scavengers of reactive oxygen species (ROS) confirmed hydrogen peroxide to be an obligatory diffusible intermediate, prior to formation of a Cu-bound hydroxyl radical species generated from Fenton-type chemistry.

The development of new drugs today is a hugely expensive process, with estimated costs of up to $1 billion to take a drug through to market. However, despite this seemingly massive expenditure, statistics show that the great majority of prescription drugs on the market today are only effective for around 40 % of the patients to whom they are administered. Worse still, recently there have been a series of high-profile instances where potentially block-busting FDA-approved drugs have subsequently been withdrawn due to unanticipated side effects that were only revealed when the drug entered use in the general population. A variety of factors are at play in underpinning such statistics, but at the heart of the problem is the fact that, despite the extensive knowledge being generated in the postgenomic era about the genetic differences between individuals, Western medicine still today largely ignores such differences. The hope therefore is that by gaining a greater understanding of the individual nature of disease progression and of drug response, we might move toward a new era of personalized medicine in which the right drug is prescribed at the right dose to treat the precise disease afflicting the specific patient. As a step along this road, this review will discuss new approaches in the pharmacogenomics field to understanding in a quantitative manner the molecular consequence of polymorphic variation and mutation, both on encoded protein function and on protein-drug interactions.

A series of cyclic ADP-ribose (cADPR) analogs, in which modifications mainly focused on riboses, was synthesized in order to explore the molecular mechanism of calcium release regulated by cADPR. Biological activities investigated in intact T-lymphocytes showed that the structurally simplified analogs, N1-ethoxymethyl-substituted cyclic inosine diphosphoribose (cIDPRE), N1,N9-diethoxymethyl-substituted cyclic inosine diphosphoribose (cIDPDE), and N1-ethoxymethyl-substituted cyclic adenosine diphosphoribose (cADPRE) in which the northern ribose or both northern and southern riboses were replaced by ether linkages are membrane-permeant and induce calcium release from intracellular stores. This research has provided novel molecules to probe cADPR-mediated calcium signaling and enlarges our knowledge of the structure-activity relationships of cADPR analogs.

This revision describes an up-to-date review of our efforts to investigate the interaction of carbohydrates with aromatic moieties at different levels of complexity. Protein-sugar interactions have been studied using NMR experiments on a variety of hevein/chitooligosaccharide systems. In addition, NMR and computational methods have also been used to evaluate the interaction of simple aromatic entities with simple monosaccharides. In between, the stacking features of aromatic-containing glycomolecules have also been described by using an analogous experimental-theoretical approach.

In animals, cellular and physiological responses to oxygen level variations are regulated via the post-translational modification of the heterodimeric hypoxia-inducible transcription factor (HIF). Hydroxylation of the HIF-α subunit at either of two conserved prolyl residues enables binding to the von Hippel-Lindau protein (pVHL) elongin C/B complex (VCB) which targets HIF-α for degradation via the ubiquitin proteasome pathway. Hydroxylation of an asparaginyl residue in the C-terminal transcriptional activation domain of HIF-α reduces its interaction with the transcriptional coactivator p300. Thus, post-translational hydroxylation is used both to "make" (HIF-VCB) and "break" (HIF-p300) protein-protein interactions in the hypoxic response. The requirement for oxygen of the HIF prolyl and asparaginyl hydroxylases in catalysis links changes in oxygen concentration and transcription of the gene array that enables cells to adapt to hypoxia. All four identified human HIF hydroxylases are members of the Fe(II) and 2-oxoglutarate (2OG)-dependent family of oxygenases. Inhibition of HIF hydroxylases mimics the hypoxic response resulting in the upregulation of erythropoietin (EPO), vascular endothelial growth factor (VEGF), and other proteins of biomedicinal importance. We briefly review biochemical analyses on the HIF hydroxylases and discuss how their structural and mechanistic characteristics may make them suited to their oxygen-sensing role.

The intrinsic ability of all antibodies to generate hydrogen peroxide (H 2 O 2 ) from singlet dioxygen ( 1 O 2 *) via the antibody-catalyzed water-oxidation pathway (ACWOP) has triggered a rethink of the potential role of antibodies both in immune defense, inflammation, and disease. It has been shown that photochemical activation of this pathway is highly bactericidal. More recently, cholesterol oxidation by-products that may arise from the ACWOP have been discovered in vivo and are receiving a great deal of attention as possible key players in atherosclerosis and diseases of protein misfolding, such as Alzheimer's disease and Parkinson's disease.

Among the various classes of modified nucleotides and oligonucleotides, phosphorothioate analogs, in which the sugar-phosphate backbone is modified by the substitution of a sulfur atom for one of the nonbridging oxygen atoms, have been most extensively studied in both in vitro and in vivo experiments. However, this substitution induces P-chirality of the dinucleoside phosphorothioate moiety. Consequently, even short phosphorothioate oligonucleotides synthesized using standard chemical methods exist as mixtures of many diastereoisomers. In our laboratory, the oxathiaphospholane (OTP) method has been developed for a stereocontrolled synthesis of oligo(deoxyribonucleoside phosphorothioate)s. Recently, this approach has been extended to ribonucleoside derivatives, and stereodefined phosphorothioate diribonucleotides were incorporated into oligomers suitable for mechanistic studies on deoxyribozymes. Next, it was found that the OTP ring can be opened with nucleophiles as weak as the phosphate or pyrophosphate anion, giving rise to nucleoside α-thiopolyphosphates. Surprisingly, the reaction between nucleoside OTP and O , O -dialkyl H-phosphonate or O , O -dialkyl H-phosphonothioate led to nucleoside 5'- O -(α-thio-β- O , O -dialkyl-hypophosphate) or 5'- O -(α,β-dithio-β- O , O -dialkyl-hypophosphate), respectively, i.e., derivatives containing a direct P-P bond.

The objective with synthetic multifunctional nanoarchitecture is to create large suprastructures with interesting functions. For this purpose, lipid bilayer membranes or conducting surfaces have been used as platforms and rigid-rod molecules as shape-persistent scaffolds. Examples for functions obtained by this approach include pores that can act as multicomponent sensors in complex matrices or rigid-rod π-stack architecture for artificial photosynthesis and photovoltaics.