Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion

Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge. To demonstrate the effective nature of such libraries within fragment-based drug discovery, we herein describe the screening of a 40-member DOS library against three functionally distinct biological targets using X-Ray crystallography. Firstly, we demonstrate the importance for diversity in aiding hit identification with four fragment binders resulting from these efforts. Moreover, we also exemplify the ability to readily access a library of analogues from cheap commercially available materials, which ultimately enabled the exploration of a minimum of four synthetic vectors from each molecule. In total, 10–14 analogues of each hit were rapidly accessed in three to six synthetic steps. Thus, we showcase how DOS-derived fragment libraries enable efficient hit derivatisation and can be utilised to remove the synthetic limitations encountered in early stage fragment-based drug discovery.

Fragment-based screening of a shape-diverse collection yielded four hits against three proteins. Up to 14 analogues of each hit were rapidly generated, enabling four fragment growth vectors to be explored using inexpensive materials and reliable synthetic transformations.     

Synthesis of symmetrically modified α-cyclodextrins: an efficient and easy method

Efficient and simple synthetic methods of designed specific synthons of cyclodextrins are fundamental for the further development of more sophisticated supramolecular devices. Here, a new two step synthesis was proposed for the obtention of the 6^A,6^C,6^E-triazido-6^A,6^C,6^E-trideoxy-6^B,6^D,6^F-tri-O-methylhexakis-(2,3-di-O-methyl)cyclomaltohexaose on a large scale.     

Formation of Langmuir layers and surface modification using new upper-rim fully tethered bipyridinyl or bithiazolyl cyclodextrins and their fluorescent metal complexes

Seven new amphiphilic cyclodextrins bearing bipyridyl or bithiazolyl moieties at the narrow rim and free hydroxyl or methoxyl groups at the wide rim of the cyclooctaamylose crown were synthesized using a one step "phosphine imide" approach. These ligands form metal complexes that have fluorescence properties with potentials for optical applications. Here, the cyclodextrin derivatives were used as probes for evaluating the role of different moieties in the self-assembly process, providing crucial information in creating functional devices. The behavior of these molecules and of complexes with EuIII in some cases was studied in Langmuir films using surface pressure (pi) and surface potential (deltaV) measurements performed as a function of film compression (compression isotherms). For chosen cyclodextrins, Brewster angle microscopy (BAM) in monolayers was performed. Films formed with derivatives 1, 3, 7, and 2compl were transferred on mica using the Langmuir-Blodgett technique. The properties of the films deposited on mica were analyzed with fluorimetry and, in the case of derivative 7, using fringe of equal chromatic order technique (FECO). The monolayer structure and the fluorescence properties of the Langmuir-Blodgett films indicate that the derivatives studied can be used for preparing cyclodextrin-based optical devices.     

Homogeneous and heterogeneous catalysis: bridging the gap through surface organometallic chemistry

Surface organometallic chemistry is an area of heterogeneous catalysis which has recently emerged as a result of a comparative analysis of homogeneous and heterogeneous catalysis. The chemical industry has often favored heterogeneous catalysis, but the development of better catalysts has been hindered by the presence of numerous kinds of active sites and also by the low concentration of active sites. These factors have precluded a rational improvement of these systems, hence the empirical nature of heterogeneous catalysis. Catalysis is primarily a molecular phenomenon, and it must involve well-defined surface organometallic intermediates and/or transition states. Thus, one must be able to construct a well-defined active site, test its catalytic performance, and assess a structure-activity relationship, which will be used, in turn-as in homogeneous catalysis-to design better catalysts.By the transfer of the concepts and tools of molecular organometallic chemistry to surfaces, surface organometallic chemistry can generate well-defined surface species by understanding the reaction of organometallic complexes with the support, which can be considered as a rigid ligand. This new approach to heterogeneous catalysis can bring molecular insight to the design of new catalysts and even allow the discovery of new reactions (Ziegler-Natta depolymerization and alkane metathesis). After more than a century of existence, heterogeneous catalysis can still be improved and will play a crucial role in solving current problems. It offers an answer to economical and environmental problems faced by industry in the production of molecules (agrochemicals, petrochemicals, pharmaceuticals, polymers, basic chemicals).     

Isomer effects in the excess enthalpies of mixtures of alkanes and cycloalkanes

Using the Picker flow calorimeter, excess molar enthalpies H ^E have been obtained at 25°C for mixtures of 1,2-, 1,3- and 1,4-cis- and trans-dimethylcyclohexane and cis- and trans-decalin with n-hexadecane and the highly branched C₁₆ isomer, 2,2,4,4,6,8,8-heptamethylnonane. Values of H ^E are also obtained for cis- and trans-decalin mixed with C₆, C₇, and C₉ isomers. Anomalously low values of H ^E occur for normal alkanes mixed with cycloalkanes in the di-equatorial configuration, suggesting the presence of a negative contribution in H ^E possibly due to a restriction of n-alkane molecular motion by the flat, plate-like cycloalkane.     

Reactivity of ditert-butyldimethoxystannane with carbon dioxide and methanol: X-ray structure of the resulting complex

The synthesis of dimethyl carbonate from carbon dioxide and methanol was studied with ditert-butyldimethoxystannane under pressure at temperatures ?423 K. The formation of dimethyl carbonate is accompanied by transformation of the stannane into a trinuclear complex, the structure of which has been determined by single-crystal X-ray diffraction technique. The relevance of this specie in the catalytic cycle is demonstrated by conducting recycling runs. A preliminary kinetic study underlines the steric influence of the tert-butyl ancillary ligands in the stabilisation of intermediates, by comparison with the n-butyl homologue.     

Self-enhanced multicolor electrochemiluminescence by competitive electron-transfer processes

Controlling electrochemiluminescence (ECL) color(s) is crucial for many applications ranging from multiplexed bioassays to ECL microscopy. This can only be achieved through the fundamental understanding of high-energy electron-transfer processes in complex and competitive reaction schemes. Recently, this field has generated huge interest, but the effective implementation of multicolor ECL is constrained by the limited number of ECL-active organometallic dyes. Herein, the first self-enhanced organic ECL dye, a chiral red-emitting cationic diaza [4]helicene connected to a dimethylamino moiety by a short linker, is reported. This molecular system integrates bifunctional ECL features (i.e. luminophore and coreactant) and each function may be operated either separately or simultaneously. This unique level of control is enabled by integrating but decoupling both molecular functions in a single molecule. Through this dual molecular reactivity, concomitant multicolor ECL emission from red to blue with tunable intensity is readily obtained in aqueous media. This is done through competitive electron-transfer processes between the helicene and a ruthenium or iridium dye. The reported approach provides a general methodology to extend to other coreactant/luminophore systems, opening enticing perspectives for spectrally distinct detection of several analytes, and original analytical and imaging strategies.

Controlling electrochemiluminescence (ECL) color(s) is crucial for many applications ranging from multiplexed bioassays to ECL microscopy.     

Electrochemical and chemical formation of [Mn4(IV)O5(terpy)4(H2O)2]6+, in relation with the photosystem II oxygen-evolving center model [Mn2(III,IV)O2(terpy)2(H2O)2]3+

To examine the real ability of the binuclear di-mu-oxo complex [Mn2(III,IV)O2(terpy)2(H2O)2]3+ (2) to act as a catalyst for water oxidation, we have investigated in detail its redox properties and that of its mononuclear precursor complex [Mn(II)(terpy)2]2+ (1) in aqueous solution. It appears that electrochemical oxidation of 1 allows the quantitative formation of 2 and, most importantly, that electrochemical oxidation of 2 quantitatively yields the stable tetranuclear Mn(IV) complex, [Mn4(IV)O5(terpy)4(H2O)2]6+ (4), having a linear mono-mu-oxo{Mn2(mu-oxo)2}2 core. Therefore, these results show that the electrochemical oxidation of 2 in aqueous solution is only a one-electron process leading to 4 via the formation of a mono-mu-oxo bridge between two oxidized [Mn2(IV,IV)O2(terpy)2(H2O)2]4+ species. 4 is also quantitatively formed by dissolution of the binuclear complex [Mn2(IV,IV)O2(terpy)2(SO4)2] (3) in aqueous solutions. Evidence of this work is that 4 is stable in aqueous solutions, and even if it is a good synthetic analogue of the "dimers-of-dimers" model compound of the OEC in PSII, this complex is not able to oxidize water. As a consequence, since 4 results from an one-electron oxidation of 2, 2 cannot act as an efficient homogeneous electrocatalyst for water oxidation. This work demonstrates that a simple oxidation of 2 cannot produce molecular oxygen without the help of an oxygen donor.     

Impact of correlation crises in risk theory: Asymptotics of finite-time ruin probabilities for heavy-tailed claim amounts when some independence and stationarity assumptions are relaxed

In the renewal risk model, several strong hypotheses may be found too restrictive to model accurately the complex evolution of the reserves of an insurance company. In the case where claim sizes are heavy-tailed, we relax the independence and stationarity assumptions and extend some asymptotic results on finite-time ruin probabilities, to take into account possible correlation crises like the one recently bred by the sub-prime crisis: claim amounts, in general assumed to be independent, may suddenly become strongly positively dependent. The impact of dependence and non-stationarity is analyzed and several concrete examples are given.     

Three-dimensional characterization of strain localization bands in high-resolution elastoplastic polycrystals

In crystalline materials, the experimental observation of the localization of plastic strains in particular directions is generally restricted to the surface of a sample containing some hundreds of grains, because of the difficulties underlying microstructural analysis. In these conditions, the determination of the morphological characteristics of localization can be limited by the poor statistical representativity of the domain of observation. The purpose of this work is to extend the analysis of localization – localization bands or else – to the 3D elastoplastic strain fields of a high-resolution representative volume element of a polycrystal.