Volume 79, Issue 12

It was a great honor and personal privilege for us to organize the 9th Eurasia Conference on Chemical Sciences (EuAs C 2 S-9) in Antalya, Turkey, 9-13 September 2006. The choice of Turkey as a venue was especially appropriate in view of its special location and character as a bridge between Europe and Asia. Turkey's rich history and diversified cultural heritage provided an extra dimension to the atmosphere of the conference. The aim of the Eurasia Conferences is to support the scientific research of chemists in the Eurasia continent by inviting the participation of leading scientists from around the world. The Eurasia region has increased its profile in chemistry, particularly in chemical biology, over the last 20 years. The growing role of chemistry and the contributions of the chemical and pharmaceutical industries to science are significant. The next century will witness more momentous achievements in chemistry as well as its application in different fields for the benefit of mankind in terms of healthy, productive, long, and comfortable life. We particularly thank the participants who contributed scientific studies as oral and poster presentations at this conference. With the participation of the world's leading scientists from 39 countries, the conference was a good opportunity for all researchers to access recent information on achievements in the chemical sciences as well as to share and exchange their experiences during the conference. The scientific program consisted of 10 plenary lectures, 35 invited lectures, 12 session lectures, 24 oral presentations, and 128 poster presentations. The topics covered included biodiversity and natural product chemistry, biomolecular chemistry, catalysis and nanotechnology, computational chemistry, coordination chemistry (organized as a mini-symposium through the efforts of Prof. Dr. Susumu Kitagawa), environmental and analytical chemistry, and materials science and solution chemistry. The IUPAC-sponsored conference was attended by 268 participants from 39 countries. The participation of a large group of active young Turkish chemists was made possible by the financial support of the TUBITAK. In addition, a half-day excursion was organized for participants to Aspendos, Perge, and Side. The lecturers included: Prof. Dr. Robert Huber, Nobel laureate, from Germany and keynote speaker; HRH Princess Prof. Dr. Chulabhorn Mahidol from Thailand; Prof. Dr. U. K. Pandit; Prof. Dr. B. M. Rode; Prof. Dr. T. Norin; Prof. Dr. M. Isobe; Prof. Dr. S. Kitagawa; and Prof. Dr. H. Ohtaki. Six plenary lectures are published in this issue of Pure and Applied Chemistry along with the manuscripts from the project "Chemistry for Biology". The conference proceedings are being published by Springer-Verlag as Innovations in Chemical Biology . The news of the sudden and untimely death of Prof. Dr. Hitoshi Ohtaki on 5 November 2006 was received after the conference. He enthusiastically promoted international cooperation and took it upon himself to publicize Japanese science to the wider world. His plenary lecture will serve as a memorable contribution to that goal. He also prepared a separate chapter, including tributes, in the proceedings. Prof. Dr. Ohtaki will be missed by all of us. The next Eurasia conference, the 10th Eurasia Conference on Chemical Sciences (EuAs C 2 S-10), will be held in Manila, Philippines in 2008. Prof. Dr. Bilge Sener Chair, National Organizing Committee

Numerous hypotheses about how life on earth could have started can be found in the literature. In this article, we give an overview about the most widespread ones and try to point out which of them might have occurred on the primordial earth with highest probability from a chemical point of view. The idea that a very early stage of life was the "RNA world" encounters crucial problems concerning the formation of its building blocks and their stability in a prebiotic environment. Instead, it seems much more likely that a "peptide world" originated first and that RNA and DNA took up their part at a much later stage. It is shown that amino acids and peptides can be easily formed in a realistic primordial scenario and that these biomolecules can start chemical evolution without the help of RNA. The origin of biohomochirality seems strongly related to the most probable formation of the first peptides via the salt-induced peptide formation (SIPF) reaction.

The approach to drug design on the basis of molecular-level information on biological processes is being driven by the expanding knowledge of the details of molecular events in biological systems. We have directed attention to the design of potentially active compounds based on the aforementioned "biomolecular" concepts. Selected examples from our studies are discussed. This paper presents three case studies of approaches to the development of potential medicinal agents whose design has evolved from considerations of molecular mechanisms of processes in selected biological systems.

Methods for crop protection based on semiochemicals show advantages over methods based on conventional insecticides. Applications of semiochemicals for insect pest management have, however, been limited. Some recent studies carried out in an interdisciplinary research program by five research groups in Sweden are presented. In spite of the chemodiversity in nature, it is striking that many simple and common compounds are important as chemical signals. This paper focuses on some examples of such simple signals, which are now used for monitoring and suppression of pest insects.

With 3,3,4,4-tetraethoxy-1-butyne as starting material, we are investigating the preparation of a range of alkylated, partially deoxygenated carbohydrate derivatives. In the lecture, an overview of recent results was given, with particular emphasis on progress in the synthesis of perfluoroalkyl-substituted deoxygenated analogs. Since many of the results discussed in the lecture have recently been or are in the process of being published, this paper focuses on our recent advances in preparing fluorinated analogs.

Bacteria use a number of resistance mechanisms to counter the antibacterial challenge, and one of these is the expression of transmembrane protein-based efflux pumps which can pump out antibacterials from within the cells, thus lowering the antibacterial concentration to nonlethal levels. For example, in S. aureus , the NorA pump can pump out the antibacterial alkaloid berberine and ciprofloxacin. One general strategy to reduce the health threat of resistant bacteria is to block a major bacterial resistance mechanism at the same time as interfering with another bacterial pathway or target site. New developments of this approach in the context of dual-action prodrugs and dual-action (or hybrid) drugs in which one action is targeted at blocking the NorA efflux pump and the second action at an alternative bacterial target site (or sites) for the antibacterial action are discussed. The compounds are based on a combination of 2-aryl-5-nitro-1 H -indole derivatives (as the NorA efflux pump blocking component) and derivatives of berberine. General design principles, syntheses, antibacterial testing, and preliminary work on modes of action studies are discussed.

Remarkable advances in the recent development of porous compounds based upon coordination polymers have paved the way toward functional chemistry having potential applications such as gas storage, separation, and catalysis. From the synthetic point of view, the advantage is a designable framework, which can readily be constructed from building blocks, the so-called bottom-up assembly. Compared with conventional porous materials such as zeolites and activated carbons, porous inorganic-organic hybrid frameworks have higher potential for adsorption of small molecules because of their designability with respect to the coordination geometry around the central metal ion as well as size and probable multifunctionality of bridging organic ligands. Although rigidity and robustness of porous framework with different degree of adsorption are the most studied properties of metal-organic coordination frameworks, there are few studies on dynamic porous frameworks, which could open up a new dimension in materials chemistry.

The relationship between chemistry and biology is succinctly embodied in the often-cited statement "cells obey the laws of chemistry". In this context, it is also relevant to reflect on the opening lines of the famous paper by Watson and Crick: "We wish to suggest a structure for the salt of deoxyribose nucleic acid [DNA]. This structure has novel features which are of considerable biological interest" [ Nature , April 25, 737 (1953)]. The elucidation of the structure of DNA and the understanding of its implications in the fundamental processes of life have laid the foundation for the transformation of biology into a truly molecular science. An important note of caution on the interaction between chemistry and biology has been wisely expressed by Arthur Kornberg (Nobel laureate in medicine 1959) "...chemistry and biology are two distinctive cultures and the rift between them is serious, generally unappreciated, and counterproductive" [ Biochemistry 26 , 6888 (1987)]. Fortunately, continued developments have resulted in building highly significant bridges between chemistry and biology. Thus, the impact of genomic research has led to further erosion of the boundaries between chemistry and biology. Disciplines in science evolve over time, and new terms emerge which more adequately cover the evolutionary changes that take place in the disciplinary landscape. Today, there is an acknowledged recognition of a multidisciplinary area in which biological phenomena and biological processes are being defined in terms of detailed structural and mechanistic molecular events - this area represents the integration of chemistry and biology. The increasing role of molecular-level chemistry in biology has led to definitions such as biological chemistry or biomolecular chemistry. IUPAC is alert to new developments in all areas in which the role of chemistry is implicated. In an earlier initiative, the scope of activities of two of the IUPAC Divisions of basic chemistry (viz. organic and physical chemistry) was expanded to include the activities directed at understanding the chemical basis of biological phenomena. Furthermore, an interdivisional committee on biomolecular chemistry was established. Deliberations within this committee have resulted in the development of the IUPAC project 2005-042-1-300 on "Chemistry for Biology". The focus of this project was to organize a Symposium-in-Print that would illustrate the fundamental role of chemistry in a wide variety of biological topics. The project has been initiated by the Division of Organic and Biomolecular Chemistry and is actively supported by a number of IUPAC Divisions and standing committees. These groups have assigned representatives to the task group of the project in order to have an input into the project from their specific chemical background. Some of the task group members have contributed papers to the present Symposium-in-Print. It should be pointed out that the present Symposium-in-Print complements the contributions from several recent IUPAC-sponsored conferences such as the combined International Conference on Biodiversity (ICOB-5) and International Symposium on the Chemistry of Natural Products (ISCNP-25) in Kyoto, Japan, 2006, and the 9th Eurasia Conference on Chemical Sciences, Antalya, Turkey, 2006. Proceedings of these symposia are published in Pure and Applied Chemistry ( PAC ). Taken together, these contributions constitute a broad spectrum of illustrations demonstrating the role and the fundamental implications of chemistry for biology. It is a sad duty to report that Prof. Alastair I. Scott, one of the contributors to the Symposium-in-Print, passed away on 18 April 2007. Prof. Scott was Distinguished Professor of Chemistry and Biochemistry and Director, Center of Biological NMR, Texas A and M University. He was internationally held in high esteem as a scientist who built bridges between chemistry and biology with his work. Within IUPAC's Division of Organic and Biomolecular Chemistry, he played an active role in enthusiastically promoting the awareness of the relevance of chemistry for biology. Ian, as he was known to many of us, will be missed by all those who knew him. This issue of PAC is dedicated to his memory. Torbjörn Norin Task Group Chairman Upendra Pandit Task Group Member

The genetic engineering of Escherichia coli for the over-expression of enzymes of the aerobic and anaerobic pathways to cobalamin has resulted in the in vivo and in vitro biosynthesis of new intermediates and other products that were isolated and characterized using a combination of bioorganic chemistry and high-resolution NMR. Analyses of these products were used to deduct the functions of the enzymes that catalyze their synthesis. CobZ, another enzyme for the synthesis of precorrin-3B of the aerobic pathway, has recently been described, as has been BluB, the enzyme responsible for the oxygen-dependent biosynthesis of dimethylbenzimidazole. In the anaerobic pathway, functions have recently been experimentally confirmed for or assigned to the CbiMNOQ cobalt transport complex, CbiA ( a,c side chain amidation), CbiD (C-1 methylation), CbiF (C-11 methylation), CbiG (lactone opening, deacylation), CbiP ( b,d,e,g side chain amidation), and CbiT (C-15 methylation, C-12 side chain decarboxylation). The dephosphorylation of adenosylcobalamin-phosphate, catalyzed by CobC, has been proposed as the final step in the biosynthesis of adenosylcobalamin.

This account traces the development of our synthetic glycopeptide- and glycoprotein-based research program over the past decade. We recount the syntheses of a number of biologically relevant, natural product-inspired glycopeptide constructs, including those associated with prostate specific antigen (PSA) and with the gp120 surface envelope protein of HIV. We also describe our progress toward the synthesis of the multiply glycosylated protein, erythropoietin (EPO). Particular emphasis is placed on the development of enabling methodologies which allow for the ligation of complex glycopeptide fragments, thus rendering it possible to access, through purely synthetic means, homogeneous, multidomainal glycopeptide and glycoprotein constructs.

In this review, a short account of H- phosphonate chemistry and its application to the synthesis of biologically important phosphates and their analogs is given.

The structural diversity as well as the biological significance of N -acetylglucosamine-containing glycans are exemplified. The problem of forming the respective glycosidic bonds of synthetic targets is addressed. Special emphasis has been given to human milk oligosaccharides (HMOs), in view of their biological relevance, and synthetic approaches of selected examples are reported.

The field of metal-based anticancer drugs was initiated by cisplatin, one of the leading agents in clinical use. Cisplatin acts by binding to DNA and forming 1,2 intrastrand cross-links. Its importance is reflected by the fact that it is estimated that 50-70 % of cancer patients are treated with a platinum drug [7]. For some time, molecular designs in the metallo-drug field remained obdurately anchored in cis -diamine platinum(II) chemistry, but now the field is evolving rapidly with a variety of alternate and very diverse designs being explored. These designs give rise to new spectra of activity and potency and can circumvent cisplatin resistance. This critical review considers the existing clinical platinum drugs, and those currently in commercial development, alongside the new designs including ruthenium anticancer and antimetastatic drugs in clinical trials, polynuclear drugs, organometallic drugs, titanium and gallium drugs, and emerging supramolecular metallo-drugs that act on DNA by noncovalent interactions. The rapid evolution of the field is being informed by post-genomic knowledge and approaches, and further dramatic step-change breakthroughs can be expected as a result; harnessing this knowledge and responding to and taking advantage of this new environment requires integration of chemistry and biology research.

Diseases are manifestations of complex biological processes in living systems. Through the applications of molecular biology and genetics, many diseases are now understood at the molecular level. This has provided researchers opportunities to develop lead molecules with the capacity of blocking a particular disease mechanism. Diabetes is a complex metabolic disorder, characterized by hyperglycemia. The first objective of antidiabetic chemotherapy is to achieve normal glycemic index. Recently, major discoveries have been made to understand how the disease progresses and manifests its complications. We have used this growing understanding to work toward discovery of effective α-glucosidase inhibitors and antiglycation agents of natural and synthetic origins. Reliable bench-top biochemical assays were employed, and several new molecular entities were studied with reference to their structure-activity relationships.

Naturally occurring enzyme inhibitors play an important role in a drug discovery program. Glutathione S -transferases (GSTs) play a significant role in the detoxification and metabolism of many xenobiotic and endobiotic compounds. GSTs are considered to be responsible for decreasing the effectiveness of anticancer/antiparasitic agents used for the treatment of cancer and parasitic diseases. The effectiveness of these biomedical agents may be improved by using GST inhibitors as an adjuvant during chemotherapy. Acetylcholinesterase (AChE) inhibitors have potential applications in curing cardiac problems and Alzheimer's disease. This article describes the identification of natural products exhibiting GST and AChE inhibitory activities, from medicinally important plants. Results obtained from the structure-activity relationship (SAR) studies of some of these newly discovered enzyme inhibitors are also discussed.

The enzyme tyrosinase is known to be a multifunctional copper-containing enzyme from the oxidase superfamily, which is the key protein involved in the biosynthesis of the large biological pigment, melanin. The enzyme catalyzes two distinct reactions of melanin biosynthesis, the hydroxylation of a monophenol and the conversion of an o -diphenol to the corresponding o -quinone. Inhibitors of this protein have a huge impact on industry and economy. So a number of research groups around the world are engaged and are expending much effort in the discovery of these inhibitors. In this report, we review the importance and applications of the recently designed synthetic tyrosinase inhibitors from our and other leading laboratories of the world, which have been published in recent years. In our continuing search for tyrosinase inhibitors from natural resources to semi- and full synthetic approaches, until now we discovered and reported a large number of mild to potent inhibitors of several classes, such as phenolics, terpenes, steroids, chalcones, flavonoids, alkaloids, long-chain fatty acids, coumarins, sildenafil analogs, bipiperidines, biscoumarins, oxadiazole, tetraketones, etc. The structure-activity relationships (SARs) of different classes of synthetic tyrosinase inhibitors have been discussed in this review.

The hexane extracts of eight Cephalaria (Dipsacaceae) species, which were collected from southwestern Anatolia, were obtained by Soxhlet apparatus. The fatty acids were derived to methyl esters and determined by gas chromatography/flame ionization detector (GC/FID) and gas chromatography/mass spectrometry (GC/MS) systems. The dominant fatty acid components and maximum percentages were detected as myristic [in C. joppica (17.48 %)], palmitic [in C. cilicica , C. elmaliensis , C. isaurica , C. scoparia (19.51 %), and C. gazipashaensis ], linoleic [in C. joppica (33.02 %), C. elmaliensis , C. dipsacoides , and C. gazipashaensis ], α-linolenic (ALA) [in C. cilicica , C. elmaliensis , C. isaurica , C. scoparia , C. lycica , and C. gazipashaensis (47.95 %)] and oleic [in C. isaurica and C. dipsacoides (40.66 %)] acids. The antioxidant activity of all hexane extracts was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH), ferric thiocyanate (FTC), and thiobarbituric acid (TBA) methods. The results indicate that hexane extracts of Cephalaria species possess considerable antioxidant activity. The highest radical scavenging activity was detected in C. isaurica (IC 50 = 741 μg/mL). The most effective species on lipid peroxidation are C. lycica and C. gazipashaensis in FTC and TBA assays, respectively. This study reveals that Cephalaria species are attractive sources of fatty acid components, especially the essential ones, as well as of effective natural antioxidants.

Chemical ecology (CE) is an active, interdisciplinary field between chemistry and biology, which, stimulated by natural curiosity and possible applied aspects, has grown to its present position during the last 40-odd years. This area has now achieved a degree of maturity with its own journals, its own international society with annual meetings, and many enthusiastic scientists in laboratories around the world. The focus is on chemical communication and other chemical interactions between organisms, including volatile chemical signals, which guide behaviors linked to various vital needs. It reflects both biodiversity and chemodiversity. All living organisms have these important signal systems, which go back to the origins of life. Successful work in this area has called for close collaboration between chemists and biologists of different descriptions. It is thus a good example of chemistry for biology. The aim of the article is to give a short introduction to the field, with an emphasis on the role of chemistry in a biological context by: giving an overview of the development of the area; showing some examples of studies of chemical communication in insects and plants, basically from our own work; and describing some current trends and tendencies and possible future developments.

Various aspects of the participation of Fenton chemistry in biology and medicine are reviewed. Accumulated evidence shows that both hydroxyl radical and ferryl [Fe(IV)=O] 2+ can be formed under a variety of Fenton and Fenton-like reactions. Some examples of metal-independent hydroxyl radical production are included. Extracellular Fenton reaction is illustrated by the white rot and brown rot wood-decaying fungi. The natural and practical utilization of catechol-driven Fenton reaction is also presented.

An electrospray ionization/mass spectrometry (ESI/MS)-based assay for the determination of acetylcholinesterase (AChE)-inhibiting activity in snake venom was developed. It allows the direct monitoring of the natural AChE substrate acetylcholine (AC) and the respective product choline. The assay scheme was employed in the screening for neurotoxic activity in fractions of the venom of Bothrops moojeni . AChE inhibition was assessed in two fractions. As a positive control, the established AChE inhibitor 1,5-bis(4-allyl-dimethylammoniumphenyl)pentan-3-one dibromide (BW284c51) was used, a dose-response curve for this compound was generated and the IC 50 value for the inhibitor was determined to be 1.60 ± 0.09 × 10 -9 mol L -1 . The dose-response curve was used as "calibration function" for the venom inhibition activity, resulting in BW284c51-equivalent concentrations of 1.76 × 10 -9 mol L -1 and 1.07 × 10 -9 mol L -1 for the two fractions containing activity. The ESI/MS-based assay scheme was validated using the established Ellman reaction. The data obtained using both methods were found to be in good agreement. The ESI/MS-based assay scheme is therefore an attractive alternative to the standard colorimetric assay.

Metals have complex environmental chemistry. When metals are present at elevated levels, they cause toxicity. Some metals are essential for living organisms, and those metals occur naturally in the environment. The latter aspect has allowed biological species to adapt to long- and short-term variations in metal levels. Chemical speciation, bioavailability, bioaccumulation, toxicity, and mixture effects are key issues in assessing the hazards of metals. In the present contribution, a global overview is given of the interactions between the chemistry and biology of metals, mostly at the interface of biological and environmental matrices. The environmental chemistry of metals and resulting methods for assessing metal availability are assumed as tokens, and the emphasis is thus on biological processes affecting the fate and effects of metals following interaction of the organism with the bioavailable metal fraction. The overview culminates in linking metal compartmentalization in organisms to bioaccumulation and toxicity.