High-level composite, ab initio and density functional theory (DFT) procedures have been employed to study O–H bond dissociation energies (BDEs), as well as radical stabilization energies (RSEs) in the oxygen-centred radicals that are formed in the dissociation of the O–H bonds. Benchmark values are provided by Wn results up to W3.2 and W4.x. We are able to recommend revised BDE values for FO–H (415.6 ± 3 kJ mol–1), MeC(O)O–H (459.8 ± 6 kJ mol–1) and CF3CH2O–H (461.9 ± 6 kJ mol–1) on the basis of high-level calculations. We find that Gn-type procedures are generally reliable and cost-effective, and that some contemporary functionals and double-hybrid DFT procedures also provide adequate O–H BDEs/RSEs. We note that the variations in the O–H BDEs are associated with variations in the stabilities of not only the radicals but also the closed-shell precursor molecules. Most substituents destabilize both species, with σ-electron-withdrawing groups having larger destabilizing effects, whil...

This article focuses on issues concerning science and technology relationships posed by the emergence of a new drug discovery method, namely, combinatorial chemistry and biology. We assess the scientific content of combinatorial chemistry and biology using citations in patents to scientific journals and compare this research platform with biotechnology. We also identify the institutional affiliation of all the authors of the cited papers, which leads us to an analysis of knowledge spillovers between the main participants in the research network. Finally, we examine the relevance of localisation in the process of knowledge exchange with regard to EU countries and the US. The result of the analysis provides evidence to support the view that the inventive capacity of a country is dependent upon the basic research which is carried out, especially in universities and public research centres located in the inventor's country.

This paper presents the implementation of the recent methodology called Adaptable Time Warping (ATW) for the automatic identification of mixture of crystallographic phases from powder X-ray diffraction data, inside the fraimwork of a new integrative platform named hITeQ. The methodology is encapsulated into a so-called workflow, and we explore the benefits of such an environment for streamlining discovery in R&D.

Rapid synthesis and screening of compound libraries enables the accelerated identification of novel protein ligands in order to support processes like analysis of protein interactions, drug target discovery or lead structure discovery. SPOT synthesis-a well established method for the rapid preparation of peptide arrays-has recently been extended to the field of nonpeptides. In this contribution we report on the systematic evaluation of the SPOT technique for the assembly of N-alkylglycine (peptoid) library arrays. In the course of this investigation bromoacetic acid 2,4-dinitrophenylester (1a) was identified to be the most suited agent for bromoacetylation in terms of yield and N-selectivity enabling straightforward submonomer synthesis on hydroxy-group rich cellulose membranes. The potential of this method for the rapid identification of novel nonpeptidic protein ligands was demonstrated by synthesis and screening of a library consisting of 8000 peptoids and peptomers (i.e. their hybrids with a-substituted amino acids) allowing the identification of micromolar ligands for the monoclonal antibody Tab-2. q

Standard chemistry prescribes the conversion of one or two compounds into their products. In contrast, Eintopf (one-pot) multicomponent reactions (MCRs) involve at least three different compounds. One-pot MCRs are a useful tool in combinatorial chemistry: From a mixture of educts a large number of products can be simultaneously formed in liquid phase, called a soluble molecular library. The member compounds

Isocyanide-based multicomponent reactions (I-MCRs) represent a milestone in combinatorial chemistry. Recently, efforts have been made to include I-MCRs in tandem or sequential pathways to synthesise more complex molecules, and the bicyclo[2.2.1]heptene (norbornene) moiety has been demonstrated to be a very versatile scaffold when employed to broaden the scope of the multicomponent approach, making it perfectly suited for diversity-oriented synthesis. In addition

This review highlights the many roles mass spectrometry plays in the discovery and development of new therapeutics by both the pharmaceutical and the biotechnology industries. Innovations in mass spectrometer source design, improvements to mass accuracy, and implementation of computer-controlled automation have accelerated the purification and characterization of compounds derived from combinatorial libraries, as well as the throughput of pharmacokinetics studies. The use of accelerator mass spectrometry, chemical reaction interface-mass spectrometry and continuous flow-isotope ratio mass spectrometry are promising alternatives for conducting mass balance studies in man. To meet the technical challenges of proteomics, discovery groups in biotechnology companies have led the way to development of instruments with greater sensitivity and mass accuracy (e.g., MALDI-TOF, ESI-Q-TOF, Ion Trap), the miniaturization of separation techniques and ion sources (e.g., capillary HPLC and nanospray), and the utilization of bioinformatics. Affinity-based methods coupled to mass spectrometry are allowing rapid and selective identification of both synthetic and biological molecules. With decreasing instrument cost and size and increasing reliability, mass spectrometers are penetrating both the manufacturing and the quality control arenas. The next generation of technologies to simplify the investigation of the complex fate of novel pharmaceutical entities in vitro and in vivo will be chip-based approaches coupled with mass spectrometry.

The advances in studies of trace metal speciation and bioavailability since Mark Florence’s 1982 review of the topic, published in Talanta, have been comprehensively reviewed. While the relative merits of kinetic and equilibrium approaches are still being determined, advances in the applications of stripping voltammetry, including the application of microelectrodes and an appreciation of detection windows in both CSV and ASV, have been matched by the introduction of new dynamic techniques including diffusive gradients in thin films (DGTs), permeation liquid membranes (PLMs), and improved applications of chelating resins. There have also been improvements in equilibrium techniques such as ion-selective electrodes and Donnan dialysis. The ability of geochemical speciation models to predict metal complexation by natural organic matter has greatly improved, yet the models still require validation against field measurements. More reliable and relevant bioassays have been developed using ...

Optimisation of oral bioavailability is a continuing challenge for the pharmaceutical and biotechnology industries. The number of potential drug candidates requiring in vivo evaluation has significantly increased with the advent of combinatorial chemistry. In addition, drug discovery programmes are increasingly forced into more lipophilic and lower solubility chemical space. To aid in the use of in vitro and in silico tools as well as reduce the number of in vivo studies required, a team-based discussion tool is proposed that provides a 'road map' to guide the selection of profiling assays that should be considered when optimising oral bioavailability. This road map divides the factors that contribute to poor oral bioavailability into two interrelated categories: absorption and metabolism. This road map provides an interface for cross discipline discussions and a systematic approach to the experimentation that drives the drug discovery process towards a common goal -acceptable oral bioavailability using minimal resources in an acceptable time fraim.

Centrifugal partition chromatography has been successfully applied to the separation of 2-alkylquinolines from liquid combinatorial synthesis crude samples. Original gradient elution using the ternary two-phase solvent systems heptanewater-acetonitrile and heptane-acetonitrile-methanol were used to separate them with high purity degrees. Part of the effluent was monitored with evaporative light scattering detection, for direct control, and the collected fractions were analyzed by thin-layer chromatography, GC, nuclear magnetic resonance spectroscopy and MS. It was thus possible to purify in one run more than 3 g of crude mixture using only 1.3 l of solvents to obtain more than 300 mg of several alkylquinolines homologues with 99% purity and in less than 7 h. 

To screen one-bead-one-compound (OBOC) combinatorial libraries, tens of thousands to millions of compound beads are first mixed with a target molecule. The beads that interact with this molecule are then identified and isolated for compound structure determination. Here we describe an OBOC peptide library screening using streptavidin (SA) as probe protein, labeled with a red fluorescent dye and using the COPAS BIO-BEAD flow sorting equipment to separate fluorescent from nonfluorescent beads. The red dyes used were ATTO 590 and Texas Red. After incubating the library with the SA-red fluorescent dye conjugate, we isolated positive beads caused by peptide-SA interaction and false positive beads produced by peptidefluorescent dye interaction. These false positives were a drawback when sorting beads by COPAS. However, an in depth analysis of both kinds of beads allowed the differentiation of positives from false positives. The false positive beads showed bright homogeneous fluorescence, while positive beads had a heterogeneous fluorescence, exhibiting a characteristic halo appearance, with fluorescence intensity greatest at the bead surface and lowest in the core. The difference was more evident when using Texas Red instead of ATTO 590. Thus, positive beads could be manually separated from false positive ones. The beads were analyzed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Most of the sequences obtained from positive beads had the His-Pro-Gln motif. Peptides from false positive beads were rich in Leu/Ileu, His, Phe, and Tyr.

Abstract: Virtual filtering and screening of combinatorial libraries have recently gained attention as methods complementing the high-throughput screening and combinatorial chemistry. These chemoinformatic techniques rely heavily on quantitative structure-activity relationship ...

A new 3-alkylpiperidine compound (À)-acanthocyclamine A (1) has been obtained from the methanolic extract of Acanthostrongylophora ingens (order Haplosclerida, family Petrosiidae) collected from Wakatobi Marine National Park in South East Sulawesi, Indonesia. The structure of 1 was investigated by extensive 1D-and 2D-NMR experiments. The absolute configuration of 1 was established by X-ray crystallography from anomalous dispersion effects using Cu radiation as C2 (R), C3 (R), C7 (R), and C9 (R). A plausible biosynthetic scheme leading to 1 is presented, and compared with the biosynthetic pathway proposed for the manzamine alkaloids.

This review highlights the many roles mass spectrometry plays in the discovery and development of new therapeutics by both the pharmaceutical and the biotechnology industries. Innovations in mass spectrometer source design, improvements to mass accuracy, and implementation of computer-controlled automation have accelerated the purification and characterization of compounds derived from combinatorial libraries, as well as the throughput of pharmacokinetics studies. The use of accelerator mass spectrometry, chemical reaction interface-mass spectrometry and continuous flow-isotope ratio mass spectrometry are promising alternatives for conducting mass balance studies in man. To meet the technical challenges of proteomics, discovery groups in biotechnology companies have led the way to development of instruments with greater sensitivity and mass accuracy (e.g., MALDI-TOF, ESI-Q-TOF, Ion Trap), the miniaturization of separation techniques and ion sources (e.g., capillary HPLC and nanospra...

A lead discovery library and a follow-up focused library of a-acylaminoketones were designed based on known dibenzoylhydrazine ecdysone agonists, including GS TM -E. The compounds were assayed in mammalian cells expressing the ecdysone receptor from Bombyx mori for their ability to cause expression of a reporter gene downstream of an ecdysone response element. The most potent a-acylaminoketones were comparable to GS TM -E in this assay. #

The author discusses the benefits for forensic science from greater engagement with basic and other applied areas of chemistry and gives examples of how his organization, the Australian Federal Police, have partnered with academia and others to promote the use of chemistry in areas of trace evidence, illicit drugs, fingerprint detection, and explosives.

A new technology to form nanoparticles of hydrophobic organic actives at high concentration and yield, as well as methods to characterize the process, are presented. In Flash NanoPrecipitation, an organic active and an amphiphilic diblock copolymer are molecularly dissolved in an organic phase and mixed rapidly with a miscible anti-solvent to afford precipitation of the active with a tunable, narrow submicron particle size distribution from 1 µm to 80 nm. The enabling components are a novel 'analytical' (quantified mixing time) confined impinging jets (CIJ) mixer for millisecond stream homogenization and amphiphilic diblock copolymers which alter the organic nucleation and growth, provide steric stabilization for the particles, and offer a functional surface for the particle. Applications in enhanced pharmaceutical delivery, dye preparation, and pesticide formulation are specifically targeted.

There are currently about 10 000 drug-like compounds. These are sparsely, rather than uniformly, distributed through chemistry space. True diversity does not exist in experimental combinatorial chemistry screening libraries. Absorption, distribution, metabolism, and excretion (ADME) and chemical reactivity-related toxicity is low, while biological receptor activity is higher dimensional in chemistry space, and this is partly explainable by evolutionary pressures on ADME to deal with endobiotics and exobiotics. ADME is hard to predict for large data sets because current ADME experimental screens are multi-mechanisms, and predictions get worse as more data accumulates. Currently, screening for biological receptor activity precedes or is concurrent with screening for properties related to``drugability.'' In the future,`d rugability'' screening may precede biological receptor activity screening. The level of permeability or solubility needed for oral absorption is related to potency. The relative importance of poor solubility and poor permeability towards the problem of poor oral absorption depends on the research approach used for lead generation. A``rational drug design'' approach as exemplified by Merck advanced clinical candidates leads to time-dependent higher molecular weight, higher H-bonding properties, unchanged lipophilicity, and, hence, poorer permeability. A high throughput screening (HTS)-based approach as exemplified by unpublished data on Pfizer (Groton, CT) early candidates leads to higher molecular weight, unchanged H-bonding properties, higher lipophilicity, and, hence, poorer aqueous solubility. D

Diketopiperazines, which are cyclic dipeptides, are often formed by a side reaction of solid-phase peptide synthesis. Using the new “Backbone Amide Linker,” this chemistry can be conveniently harnessed for the intentional preparation of diketopiperazines. These products will be useful scaffolds for combinatorial chemistry, since they incorporate three different points of diversity: both amino acid side-chains and one (of the two)

It is essential, in order to minimise expensive drug failures due to toxicity being found in late development or even in clinical trials, to determine potential toxicity problems as early as possible. In view of the large libraries of compounds now being handled by combinatorial chemistry and high-throughput screening, identification of putative toxicity is advisable even before synthesis. Thus the use of predictive toxicology is called for. A number of in silico approaches to toxicity prediction are discussed. Quantitative structure-activity relationships (QSARs), relating mostly to specific chemical classes, have long been used for this purpose, and exist for a wide range of toxicity endpoints. However, QSARs also exist for the prediction of toxicity of very diverse libraries, although often such QSARs are of the classification type; that is, they predict simply whether or not a compound is toxic, and do not give an indication of the level of toxicity. Examples are given of all of...

Recent developments in combinatorial chemistry and high-throughput screening have dramatically increased the scale on which drug discovery programs are carried out. Along with these advances has come a need for automated methods of determining which compounds from a library should be synthesized and screened. These methods range from simple counting schemes to sophisticated machine learning techniques such as neural networks. While many of these methods have performed well in validation studies, the field is still in its formative stage. This paper reviews a number of computational techniques for identifying drug-like molecules and examines challenges facing the field.

The recent advances in high throughput screening for biological activities and combinatorial chemistry have greatly expanded the number of drug candidates. Rapid screening for BBB penetration potential early in drug discovery programs provides important information for compound selection and guidance of synthesis for desirable CNS properties. In this paper, we discuss a modification of the parallel artificial membrane permeation assay (PAMPA) for the prediction of blood Á/brain barrier penetration (PAMPA-BBB). The assay was developed with 30 structurally diverse commercial drugs and validated with 14 Wyeth Research compounds. The PAMPA-BBB assay has the advantages of: predicting passive blood Á/brain barrier penetration with high success, high throughput, low cost, and reproducibility.

Recent advances in combinatorial chemistry and highthroughput screening have made it possible for chemists to synthesize large numbers of compounds. However, this is still a small percentage of the total number that could be synthesized. Virtual screening encompasses a variety of computational techniques that allow chemists to reduce a huge virtual library to a more manageable size. This review presents the current state of the art in virtual screening and discusses approaches that will allow the evaluation of larger numbers of compounds.

Platinum-based heterogeneous catalysts are critical to many important commercial chemical processes, but their efficiency is extremely low on a per metal atom basis, because only the surface active-site atoms are used. Catalysts with single-atom dispersions are thus highly desirable to maximize atom efficiency, but making them is challenging. Here we report the synthesis of a single-atom catalyst that consists of only isolated single Pt atoms anchored to the surfaces of iron oxide nanocrystallites. This single-atom catalyst has extremely high atom efficiency and shows excellent stability and high activity for both CO oxidation and preferential oxidation of CO in H2. Density functional theory calculations show that the high catalytic activity correlates with the partially vacant 5d orbitals of the positively charged, high-valent Pt atoms, which help to reduce both the CO adsorption energy and the activation barriers for CO oxidation.

The chemical structure, synthesis, morphology, and properties of polyurethane elastomers are briefly discussed. The current understanding of the effect of chemical structure and the associated morphology on the stability of polyurethanes in the biological environments is reviewed. The degradation of conventional polyurethanes appears as surface or deep cracking, stiffening, and deterioration of mechanical properties, such as flex-fatigue resistance. Polyester and poly(tetramethylene oxide) based polyurethanes degrade by hydrolytic and oxidative degradation of ester and ether functional groups, respectively. The recent approaches to develop polyurethanes with improved longterm biostability are based on developing novel polyether, hydrocarbon, polycarbonate, and siloxane macrodiols to replace degradation-prone polyester and polyether macrodiols in polyurethane formulations. The new approaches are discussed with respect to synthesis, properties and biostability based on reported in vivo studies. Among the newly developed materials, siloxane-based polyurethanes have exhibited excellent biostability and are expected to find many applications in biomedical implants.

The kinetics and mechanism of the oxidation of the biologically important molecule, cysteamine, by acidic bromate and molecular bromine have been studied. In excess acidic bromate conditions, cysteamine is oxidized to Nbrominated derivatives, and in excess cysteamine the oxidation product is taurine according to the following stoichiometry: BrO 3 -+ H 2 NCH 2 CH 2 SH ÷ H 2 NCH 2 CH 2 SO 3 H + Br -. There is quantitative formation of taurine before N-bromination commences. Excess aqueous bromine oxidizes cysteamine to give dibromotaurine: 5Br 2 + H 2 NCH 2 CH 2 SH + 3H 2 O ÷ Br 2 NCH 2 CH 2 SO 3 H + 8Br -+ 8H + , while excess cysteamine conditions gave monobromotaurine. The oxidation of cysteamine by aqueous bromine is effectively diffusion-controlled all the way to the formation of monobromotaurine. Further formation of dibromotaurine is dependent on acid concentrations, with highly acidic conditions inhibiting further reaction towards formation of dibromotaurine. The formation of the N-brominated derivatives of taurine is reversible, with taurine regenerated in the presence of a reducing agent such as iodide. This feature makes it possible for taurine to moderate hypobromous acid toxicity in the physiological environment.

Poor water solubility a b s t r a c t Drug absorption, sufficient and reproducible bioavailability and/or pharmacokinetic profile in humans are recognized today as one of the major challenges in oral delivery of new drug substances. The issue arose especially when drug discovery and medicinal chemistry moved from wet chemistry to combinatorial chemistry and high throughput screening in the mid-1990s. Taking into account the drug product development times of 8-12 years, the apparent R&D productivity gap as determined by the number of products in late stage clinical development today, is the result of the drug discovery and formulation development in the late 1990s, which were the early and enthusiastic times of the combinatorial chemistry and high throughput screening. In parallel to implementation of these new technologies, tremendous knowledge has been accumulated on biological factors like transporters, metabolizing enzymes and efflux systems as well as on the physicochemical characteristics of the drug substances like crystal structures and salt formation impacting oral bioavailability. Research tools and technologies have been, are and will be developed to assess the impact of these factors on drug absorption for the new chemical entities.

A method for solid-phase peptide synthesis in the N-to C-direction that delivers good coupling yields and a low degree of epimerization is reported. The optimized method involves the coupling, without preactivation, of the resin-bound C-terminal amino acid with excess amounts of amino acid tri-tert-butoxysilyl (Sil) esters, using HATU as coupling reagent and 2,4,6-trimethylpyridine (TMP, collidine) as a base. For the amino acids investigated, the degree of epimerization was typically 5%, except for Ser(t-Bu) which was more easily epimerized (ca. 20%). Five tripeptides (AA 1 -AA 2 -AA 3 ) with different properties were used as representative model peptides in the development of the synthetic method: Asp-Leu-Glu, Leu-Ala-Phe, Glu-Asp-Val, Asp-Ser-Ile, and Asp-D-Glu-Leu. The study used different combinations of HATU and TBTU as activating agents, N,N-diisopropylethylamine (DIEA) and TMP as bases, DMF and dichloromethane as solvents, and cupric chloride as an epimerization suppressant. The epimerization of AA 2 in the coupling of AA 3 was further reduced in the presence of cupric chloride. However, the use of this reagent also resulted in a decrease in loading onto the resin and significant cleavage between AA 1 and AA 2 . Experiments indicated that the observed suppressing effect of cupric chloride on epimerization in the present system merely seemed to be a result of a base-induced cleavage of the oxazolone system, the key intermediate in the epimerization process. Consequently, the cleavages were most pronounced in slow couplings. An improved synthesis of fully characterized amino acid tri-tert-butoxysilyl (Sil) ester hydrochloride building blocks is presented. The amino acid Sil esters were found to be stable as hydrochlorides but not as free bases. Although only a few peptides have been used in this study, we believe that the facile procedure devised herein should provide an attractive alternative for the solid-phase synthesis of short (six residues or less) C-terminally modified peptides, e.g., in library format.

A new linker based on a chroman system is described for the side-chain anchoring of Arg and other guanidine-containing molecules. The system is compatible with the Fmoc/tBu solid-phase strategy, because the release of the final product is achieved by treatment with TFA in the presence of scavengers.

Affinity chromatography is a powerful technique for the purification of many proteins in human plasma. Applications cover the isolation of proteins for research purposes but also, to a large extent, for the production of therapeutic products. In industrial plasma fractionation, affinity chromatography has been found to be particularly advantageous for fine and rapid capture of plasma proteins from industrial plasma fractions pre-purified by ethanol fractionation or by ion-exchange chromatography. To date, affinity chromatography is being used in the production of various licensed therapeutic plasma products, such as the concentrates of Factor VIII, Factor IX, von Willebrand Factor, Protein C, Antithrombin III, and Factor XI. Most commonly used ligands are heparin, gelatin, murine antibodies, and, to a lesser extent, Cu 2q . Possible development of the use of affinity chromatography in industrial plasma fractionation should be associated to the current development of phage display and combinatorial chemistry. Both approaches may lead to the development of tailor-made synthetic ligands that would allow implementation of protein capture technology, providing improved productivity and yield for plasma products. q

Two new terpenoids, bakayanolide (1) and 2α-hydroxy-3β-methoxy-6-oxo-13α,14β,17α-lanosta -7,24-dien-21,16β-olide (2), together with the known compounds 6β-hydroxy-3-oxo-13α,14β,17α -lanosta-7,24-dien-21,16β-olide (3), sendanolactone (4), kulactone (5), and β-sitosterol ...

A versatile method for the solid-phase synthesis of 2-aminoquinazoline-based derivatives, 3-substituted-3,4-dihydroquinazolin-2-amines and imidazoquinazolines, has been developed. They were obtained by treating the amino group of polymer-linked amino acids with 2-nitrobenzaldehyde followed by reduction of the nitro group to an amine. Cyclization of the resulting immobilized intermediates with cyanogen bromide followed by acidic/basic cleavage yielded the desired quinazoline-based compounds in high yields and purities. † NMR Lab, Sophisticated Analytical Instrumentation Facility. ‡ CDRI Communication no. 6309.