It was a privilege for me to have served as conference editor for this issue of Pure and Applied Chemistry . The nine papers in this volume constitute selected contributions from four symposia that took place at the 43rd IUPAC Congress, which was held in the Puerto Rico Convention Center, San Juan, Puerto Rico between 30 July and 7 August 2011. The theme of the congress, with more than 1300 scientific presentations, was "Chemistry Bridging Innovation Among the Americas and the World". The papers in this issue arise from four symposia that were part of one of the central themes of the congress, the "Chemistry of Life". Four of the contributions [by Profs. Vanderlan Bolzani (Brazil), Abimael D. Rodriguez (Puerto Rico), Adriano D. Andricopulo (Brazil), and Néstor M. Carballeira (Puerto Rico)] arise from the symposium "Modern Medicinal Chemistry: Natural Products and Synthetic Molecules as Valuable Tools", while one contribution [by Prof. George Kokotos (Greece)] was presented at the symposium "From Protein Structure to Cell Regulation". Three other contributions [by Profs. Ken Kitajima (Japan), Dipak. K. Banerjee (Puerto Rico), and Adriana Pietropaolo (Italy)] are from the symposium "Balancing Life with Bioconjugates", and the last contribution [by Prof. Julian Echave (Argentina)] is from the symposium "Structure Dynamics of Chemical and Biological Systems". We certainly acknowledge the great contribution made to this congress by the congress chair, Prof. Gabriel A. Infante, and the local organizing and scientific committees. We also acknowledge the different organizers and session chairs for the symposia from which these contributions were possible, in particular: V. Bolzani, A. Palermo, S. Campbell, and J. Colón for the medicinal chemistry symposium; D. K. Banerjee for the glycoconjugates symposium; A. Azzi, J. Pande, and M. Walsh for the protein- cell symposium; and M. Chergui and J. López Garriga for the structure dynamics symposium. I would also like to thank the many scientific contributors to this conference, in particular, those who took the time to write a more thorough account of their science and were able to transform it into valuable papers for all of us to share and enjoy. We also thank the editorial staff for their valuable help and guidance. Néstor M. Carballeira Conference Editor

Natural products are the inspiration for many valuable therapeutic agents and attest to biodiversity being a rich source of new molecular structures. Their value as templates for medicinal chemistry remains undisputed, even after the growth of the combinatorial chemistry era. Tropical environments, such as Brazilian biomes, offer a particularly rich potential for biologically active compounds with unique structures and continue to contribute toward modern drug discovery. Our bioprospecting of plant species of the Cerrado and Atlantic Forest biomes has yielded promising bioactive secondary metabolites, and we describe some of these molecules and semisynthetic derivatives as potential acetylcholinesterase (AChE) inhibitors.

Two new diterpenes having the rare cubitane skeleton were isolated from a southwestern Caribbean gorgonian coral of the genus Eunicea . The structures of the new metabolites, as well as those of three known cubitanes were elucidated by extensive spectroscopic analysis. One compound showed significant in vitro cytotoxic activity against a National Cancer Institute (NCI) panel of cancer cell lines, whereas the remaining metabolites were shown to exert mild antitubercular and antimalarial activities against the pathogenic microbes Mycobacterium tuberculosis and Plasmodium falciparum .

Drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein–ligand interactions. Structure- (SBDD) and ligand-based drug design (LBDD) approaches bring together the most powerful concepts in modern chemistry and biology, linking medicinal chemistry with structural biology. The definition and assessment of both chemical and biological space have revitalized the importance of exploring the intrinsic complementary nature of experimental and computational methods in drug design. Major challenges in this field include the identification of promising hits and the development of high-quality leads for further development into clinical candidates. It becomes particularly important in the case of neglected tropical diseases (NTDs) that affect disproportionately poor people living in rural and remote regions worldwide, and for which there is an insufficient number of new chemical entities being evaluated owing to the lack of innovation and R&D investment by the pharmaceutical industry. This perspective paper outlines the utility and applications of SBDD and LBDD approaches for the identification and design of new small-molecule agents for NTDs.

The fatty acids (±)-2-methoxy-6 Z -heptadecenoic acid, (±)-2-methoxy-6-hepta-decynoic acid, and (±)-2-methoxyheptadecanoic acid were synthesized and their inhibitory activity against the Leishmania DNA topoisomerase IB enzyme ( Ld TopIB) determined. Both 2-OMe-17:1 fatty acids were synthesized from 4-bromo-1-pentanol, the olefinic fatty acid in 10 steps and in 7 % overall yield, while the acetylenic fatty acid in 7 steps and in 14 % overall yield. The 2-OMe-17:0 acid was prepared in 6 steps and in 42 % yield from 1-hexa-decanol. The 2-OMe-17:1 acids inhibited Ld TopIB, with the acetylenic acid displaying an EC 50 = 16.6 ± 1.1 μM, but the 2-OMe-17:0 acid did not inhibit Ld TopIB. The (±)-2-methoxy-6 Z -heptadecenoic acid preferentially inhibited Ld TopIB over the human TopIB enzyme. Unsaturation seems to be a prerequisite for effective inhibition, rationalized in terms of weak intermolecular interactions between the active site of Ld TopIB and either the double or triple bonds of the fatty acids. Toxicity toward Leishmania donovani promastigotes was also investigated, resulting in the order acetylenic > olefinic > saturated with the (±)-2-methoxy-6-heptadecynoic acid displaying an EC 50 = 74.0 ± 17.1 μM. Our results indicate that α-methoxylation decreases the toxicity of C 17:1 fatty acids toward L. donovani promastigotes, but improves their selectivity index.

Phospholipases A 2 (PLA 2 s) are enzymes that are capable of catalyzing the hydrolysis of the sn -2 ester bond of glycerophospholipids, releasing free fatty acids, including arachidonic acid (AA), and lysophospholipids. Both products are precursor signaling molecules involved in inflammation. Among the various PLA 2 s, cytosolic GIVA cPLA 2 is considered a major target for inflammatory diseases, while secreted GIIA sPLA 2 is involved in cardiovascular diseases. We have developed lipophilic 2-oxoamides based on ( S )-γ- or δ-amino acids as potent and selective inhibitors of GIVA cPLA 2 , which present interesting in vivo anti-inflammatory activity. 2-Oxoamides based on natural α-amino acids are selective inhibitors of GIIA sPLA 2 . The mode of binding of 2-oxoamides with either GIVA cPLA 2 or GIIA sPLA 2 has been studied by various techniques.

Polysialic acid (polySia) is a homopolymer of sialic acid with a degree of polymerization (DP) of 8–400. When present on neural cell adhesion molecule (NCAM), polySia has anti-adhesive effects on cell–cell interactions owing to its bulky polyanionic nature, and is involved in the regulation of neurogenesis and neuronal functions. Recently, we demonstrated that polySia functions not only as an anti-cell adhesion molecule, but also as a reservoir scaffold for brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF2), which are biologically active molecules in neurogenesis. To understand the significance of polySia structure in the reservoir function, we focused on polySia-NCAM biosynthesized by mutated polysialyltransferase (ST8SiaII or STX) that was reported in a schizophrenia patient. The polySia-NCAM biosynthesized by mutant ST8SiaII/STX contained less polySia with shorter chain length and exhibited impaired reservoir function for BDNF and FGF2 as compared with that synthesized by wild-type (wt) ST8SiaII/STX. Our findings suggest that the quantity and quality of polySia on NCAM are important for normal neuronal functioning.

Asparagine-linked protein glycosylation is a hallmark for glycoprotein structure and function. Its impairment by tunicamycin [a competitive inhibitor of N -acetylglucos-aminyl 1-phosphate transferase (GPT)] has been known to inhibit neo-vascularization (i.e., angiogenesis) in humanized breast tumor due to an induction of endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR). The studies presented here demonstrate that (i) tunicamycin inhibits capillary endothelial cell proliferation in a dose-dependent manner; (ii) treated cells are incapable of forming colonies upon its withdrawal; and (iii) tunicamycin treatment causes nuclear fragmentation. Tunicamycin-induced ER stress-mediated UPR event in these cells was studied with the aid of Raman spectroscopy, in particular, the interpretation of bands at 1672, 1684, and 1694 cm –1 , which are characteristics of proteins and originate from C=O stretching vibrations of mono-substituted amides. In tunicamycin-treated cells, these bands decreased in area as follows: at 1672 cm –1 by 41.85 % at 3 h and 55.39 % at 12 h; at 1684 cm –1 by 20.63 % at 3 h and 40.08 % at 12 h; and also at 1994 cm –1 by 33.33 % at 3 h and 32.92 % at 12 h, respectively. Thus, in the presence of tunicamycin, newly synthesized protein chains fail to arrange properly into their final secondary and/or tertiary structures, and the random coils they form had undergone further degradation.

A formalism to quantify the chemical stereoselectivity, based on free energy of binding calculations, is here discussed. It is used to explain the stereoselectivity of two diastereoisomeric frameworks, comprising the dimer of a copper(II)-peptide core of L- and D-carnosine, respectively, each bound to two chains of D-trehalose, in which copper(II) adopts a type-II coordination geometry. The stereocenter of carnosine is varied both L and D, giving rise to two diastereoisomers. A thermodynamic cycle crossing the formation of the two enantiomeric copper(II) peptide cores was devised. A harmonic restraining potential that depends only on the bond distance was added to ensure reversibility in bond formation and dissociation, for an accurate estimate of the free energy. The calculation of the free energy of binding between D-trehalose and the two enantiomeric copper(II) peptide cores reproduces the free-energy quantities observed from stability constants and isothermal titration calorimetry (ITC) measurements. This is an example of chirality selection based on free-energy difference.

Proteins fluctuate, and such fluctuations are functionally important. As with any functionally relevant trait, it is interesting to study how fluctuations change during evolution. In contrast with sequence and structure, the study of the evolution of protein motions is much more recent. Yet, it has been shown that the overall fluctuation pattern is evolutionarily conserved. Moreover, the lowest-energy normal modes have been found to be the most conserved. The reasons behind such a differential conservation have not been explicitly studied. There are two limiting explanations. A “biological” explanation is that because such modes are functional, there is natural selection pressure against their variation. An alternative “physical” explanation is that the lowest-energy normal modes may be more conserved because they are just more robust with respect to random mutations. To investigate this issue, I studied a set of globin-like proteins using a perturbed elastic network model (ENM) of the effect of random mutations on normal modes. I show that the conservation predicted by the model is in excellent agreement with observations. These results support the physical explanation: the lowest normal modes are more conserved because they are more robust.

A metrological background for investigating out-of-specification (OOS) test results of chemical composition is discussed. When an OOS test result is identified, it is important to determine its root causes and to avoid reoccurrence of such results. An investigation of the causes based on metrological concepts is proposed. It includes assessment of validation data of the measurement process and its metrological traceability chains, evaluation of measurement uncertainty, and related producer’s and consumer’s risks. This approach allows distinguishing between OOS test results that indicate an actual change in chemical composition of an analyzed object, and OOS test results that are metrologically related with a certain confidence probability, i.e., caused by measurement problems, while the analyzed object still meets the specification requirements at the time of testing. Practical examples illustrating applications of the described approach in environ-mental and food analysis, as well in drug analysis and stability study of drug products, are described. Acceptance limits, warning and action lines for the test results, and corresponding producer’s and consumer’s risks are discussed.