Phosphine-phosphite ligands: chelate ring size vs. activity and enantioselectivity relationships in asymmetric hydrogenation.

A series of new phosphine-phosphite ligands P(C)(n)OP (n = 1-4) have been synthesized and used for rhodium-catalyzed asymmetric hydrogenation of prochiral olefins in order to study the effect of the chelate ring size. Excellent ees (up to 97.5%) were obtained in the hydrogenation of dimethyl itaconate and an increase of activity and enantioselectivity was observed in the hydrogenation of (Z)-α-acetamidocinnamic acid methyl ester with the increasing length of the backbone of the ligands.

Stepwise aromatic nucleophilic substitution in continuous flow. Synthesis of an unsymmetrically substituted 3,5-diamino-benzonitrile library.

Aromatic or heteroaromatic ring precursors with 2-3 identical functionalities are often used in sequential derivatization depending on the reactivity difference or the selective execution of the reaction such as nucleophilic aromatic substitution. Continuous flow chemistry offers an enhanced parameter space (pressure and temperature) with rapid parameter optimization that ensures selectivity in many cases. We developed a flow chemistry procedure to carry out a stepwise aromatic nucleophilic substitution of difluoro-benzenes having an activating group in meta position to the fluorines. The mono-aminated products were obtained in high yield and selectivity in an extremely short reaction time, while applying higher temperature, longer reaction zone (or time), and employing higher excess of another amine reactant, the subsequent introduction of the second amino group was also successfully achieved leading to an unsymmetrically substituted 3,5-diamino-benzonitrile library.

High-efficiency aminocarbonylation by introducing CO to a pressurized continuous flow reactor.

Halogenated aryl carboxylic acids were efficiently converted to the corresponding dicarboxylic acid monoamides by a one-step Pd-catalyzed aminocarbonylation in a micro/meso fluidic continuous flow reactor (X-Cube) operated at high pressure and high temperature with CO gas introduction. Reaction parameters (solvent, base, catalyst, pressure, temperature) were rapidly optimized in the reactions, which required less than 2 min. The method gave improved results over comparable batch techniques and is also suited to automated parallel syntheses of compound libraries.

Enhanced hit-to-lead process using bioanalogous lead evolution and chemogenomics: application in designing selective matrix metalloprotease inhibitors.

The authors describe an innovative approach for designing novel inhibitors. This approach effectively integrates the emerging chemogenomics concept of target-family-based drug discovery with bioanalogous design strategies, including privileged structures, molecular frameworks as well as bioisosteric and bioanalogous/isofunctional modifications. The authors applied this method in the design of selective inhibitors of matrix metalloproteases (MMPs), also referred to as matrixins, on the basis of a unique analysis of the ligand-target knowledge base, the 'matrixinome'. For this analysis, the authors created an annotated MMP database containing ∼ 300 inhibitors with their published activity profile. The ligand space was then arranged into a lead evolution tree, where the substructural transformations in each virtual step led to marked changes in the activity pattern. This allowed subtype-specific privileged fragments to be extracted as well as modifications, which improve activity and/or selectivity. Furthermore, the compounds with the preferred activity profile were correlated with sequence homology as well as binding site similarity within the target family, thereby leading to the identification of substructural modifications that turn non-selective, biohomologous structures into selective inhibitors. The matrixinomic application of the authors' approach, therefore, provides an example of how the combination of ligand space knowledge with sequence-related data can radically improve the outcome of the lead optimisation process to achieve higher selectivity within a given target family.

[Comparative chemical proteomics: simultaneous identification of disease-specific protein targets and their small molecule-binding partners, suitable as drug candidates]. / Osszehasonlító kémiai proteomika: Betegség-specifikus molekuláris célpontok és ezekre ható gyógyszerjelötek párhuzamos azonosítása.

The simultaneous identification of disease-specific protein targets and their small molecule binding partners, suitable as drug candidates, could radically reduce the timeline and costs of drug discovery and development. Comparative chemical proteomics provides a novel approach to achieve this goal through rapid detection of overexpressed proteins in diseased samples by the application of small molecule microarrays. The interacting small molecules enables direct affinity-based isolation and identification of the proteins. In the present paper we report comparative chemical proteomics studies on melanocytes and melanoma cell-lines, which led to the identification of 3 overexpressed proteins (e.g. -tubulin) together with their small molecule binding partner.

Explicit Diversity Index (EDI): a novel measure for assessing the diversity of compound databases.

A novel diversity assessment method, the Explicit Diversity Index (EDI), is introduced for druglike molecules. EDI combines structural and synthesis-related dissimilarity values and expresses them as a single number. As an easily interpretable measure, it facilitates the decision making in the design of combinatorial libraries, and it might assist in the comparison of compound sets provided by different manufacturers. Because of its rapid calculation algorithm, EDI enables the diversity assessment of in-house or commercial compound collections.

Solution-phase parallel synthesis of a pyridinium pyrazol-3-olate inner salt library using a three-component reaction.

We present here the discovery of a novel, versatile, multicomponent reaction leading to various 4-[4-(pyridinium-1-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-2H-pyrazol-3-olate inner salts. The structure of the unusual zwitterionic inner salts was elucidated, and the scope of the novel reaction was investigated. After rapid optimization, the reaction was adapted to parallel synthesis, and an 800-membered compound library was produced.

Continuous-flow high pressure hydrogenation reactor for optimization and high-throughput synthesis.

This paper reports on a novel continuous-flow hydrogenation reactor and its integration with a liquid handler to generate a fully automated high-throughput hydrogenation system for library synthesis. The reactor, named the H-Cube, combines endogenous hydrogen generation from the electrolysis of water with a continuous flow-through system. The system makes significant advances over current batch hydrogenation reactors in terms of safety, reaction validation efficiency, and rates of reaction. The hydrogenation process is described along with a detailed description of the device's main parts. The reduction of a series of functional groups, varying in difficulty up to 70 degrees C and 70 bar are also described. The paper concludes with the integration of the device into an automated liquid handler followed by the reduction of a nitro compound in a high throughput manner. The system is fully automated and can conduct 5 reactions in the time it takes to perform and workup one reaction manually on a standard batch reactor.

Procedure for the parallel preparation of 3-imidazo[1,2-a]pyridin-3-yl-propionic acid derivatives involving Meldrum's acid.

We describe here an efficient and versatile method for the preparation of 3-imidazo[1,2-a]pyridin-3-yl-propionic acids involving, as a key step, a three-component Michael-type reaction. The extended and validated procedure allowed us to prepare various acids with three diversity points. The method was easily adaptable for parallel synthesis and an approximately 2000-membered 3-imidazo[1,2-a]pyridin-3-yl-propionic acid amide library was prepared in a semiautomated manner.

Development of chemically modified glass surfaces for nucleic acid, protein and small molecule microarrays.

Microarrays have become a widely used tool to investigate the living cell at different levels. DNA microarrays enable the expression analysis of thousand of genes simultaneously, while protein arrays investigate the properties and interactions of proteins with other proteins and with non-proteinaceous molecules. One crucial step in producing such microarrays is the permanent immobilization of samples on a solid surface. Our goal was to develop diverse linker systems capable of anchoring different biological samples, especially DNA and drug-like small molecules. We developed 6 different chemical surfaces having a 3-D-like linker system for biomolecule immobilization, and compared them to previously described immobilization strategies. The attachment chemistry utilizes the amino reactive properties of acrylic and epoxy functions. The capacity of the support was increased by creating a branching structure holding the reactive functions. The method of anchoring was investigated through a model reaction. From HPLC and mass spectrometry measurements we concluded that the covalent binding of DNA occurs through nucleobases. The tested systems offer the capability to permanently immobilize several biomolecular species in an array format.

In Silico and Ex silico ADME approaches for drug discovery.

The high attrition rate of drug candidates during clinical trials for poor pharmacokinetic and metabolic properties has created a need to do these studies as early as it is possible during the drug discovery process. In addition the most successful drug is often not the most potent one but the one that has the suitable level of potency, safety, and pharmacokinetics. Science and technology development during the last few years and the generation of last databases and information has created the basis for doing early experimental PK and ADME studies in addition to eADME. Similarly, testing safety features as early as possible is key to affordable drug discovery and development. Throughput and cost are crucial for early application. In silico methods have by far the highest throughput, followed by the in vitro and in vivo approaches. On the other hand, with regard to relevance and reliability of data the ranking is the opposite. The great challenge for in silico methods is generation of models that correlate more closely with in vivo systems. For the in vitro assays increasing the throughput is an absolute must. Ex silico methods that combine in silico predictions with experimental methods are new additions to the scientific repertoire (e.g. Chromatographic Hydrophobicity Index that is deduced from the reverse phase HPLC data can be used for calculation of lipophilicity). The emerging new approaches have clear impact on the design of early stage screening and combinatorial libraries. In addition to the Lipinski's rules descriptors such as number of rotatable bonds, number of aromatic rings, branching behavior and polar surface area (PSA) are commonly used is the drug design process.

Enantioselective plasma protein binding of bimoclomol.

The binding of bimoclomol enantiomers to human plasma, its components, as well as to plasma from monkey, dog, rat, and mouse was investigated by ultrafiltration and equilibrium dialysis. The considerably stronger binding of the (-)-(S)-enantiomer found in human plasma is due to the alpha(1)-acid glycoprotein (AAG) component. The binding parameters for AAG (n(R)K(R) = 1.3 x 10(4) M(-1) and n(S)K(S) = 1.0 x 10(5) M(-1)) revealed high enantioselectivity, while the binding to human serum albumin was found to be weak (nK = 5 x 10(3) M(-1)) and not stereoselective. (-)-(S)-Bimoclomol was extensively displaced in the presence of specific marker ligands for the "FIS" subfraction of human AAG. Comparative binding studies indicated considerable differences between plasma of the five species investigated.