Phase-transfer dynamic combinatorial chemistry

A two-phase approach to dynamic combinatorial chemistry is described using disulfide exchange chemistry; the use of two phases significantly increases the possibilities and the scope of dynamic combinatorial chemistry by facilitating the combination of otherwise incompatible building blocks.     

Resin-bound dynamic combinatorial chemistry

[reaction: see text] Dynamic combinatorial chemistry (DCC) is a promising technique for receptor-aided selection of high-affinity ligands from equilibrating combinatorial libraries. Identification of the specific ligand(s) selected is often challenging, however, due to difficulties associated with chromatographic separation and/or mass degeneracy within the library. Herein, we describe proof-of-concept experiments demonstrating a new technique termed resin-bound DCC (RB-DCC), which provides a solution to this problem.     

Metal-containing nanofibers via coordination chemistry

One-dimensional fibrous nanostructures may exhibit unique mechanical, optical, magnetic, and electronic properties as a result of their nanoscale dimensions. Various approaches have been used to prepare nanofibers (e.g., electrospinning, vapor deposition), but this review focuses on the research and development of self-assembled nanofibers formed through coordination chemistry. By employing metal–ligand interactions that extend along the backbone of the aggregates, nanofibrous, often gel-forming, materials with appealing properties have been formed. Other fibers formed through electrostatic interactions between charged coordination complexes are also discussed. The optical, electronic, and magnetic properties conferred upon the materials by the embedded coordination complexes render the nanofibers useful for applications in the fields of catalysis, sensors, and gas storage, and potentially for developing nanosized devices.     

The dark side of disulfide-based dynamic combinatorial chemistry

During the last two decades, disulfide-based dynamic combinatorial chemistry has been extensively used in the field of molecular recognition to deliver artificial receptors for molecules of biological interest. Commonly, the nature of library members and their relative amounts are provided from HPLC-MS analysis of the libraries, allowing the identification of potential binders for a target (bio)molecule. By re-investigating dynamic combinatorial libraries generated from a simple 2,5-dicarboxy-1,4-dithiophenol building block in water, we herein demonstrated that multiple analytical tools were actually necessary in order to comprehensively describe the libraries in terms of size, stereochemistry, affinity, selectivity, and finally to get a true grasp on the different phenomena at work within dynamic combinatorial systems.

We show that multiple analytical tools are necessary in order to describe the different phenomena within disulfide-based dynamic combinatorial libraries in terms of size, stereochemistry, affinity and selectivity.     

Polymer blend complexes based on coordination chemistry

The preparation, rheology, and mechanical properties of a family of blends composed of transition-metal neutralized sulfonated ethylene-propylene-diene elastomers (S-EPDM) and styrene-4 vinylpyridine copolymers (SVP) are described. These polymeric materials contain relatively low levels of interacting groups (≤ 10 mol%), which are, however, sufficient for forming an intermolecular complex. A distinguishing characteristic of these blends is that the rheology and mechanical properties are strongly influenced by a coordination-type bonding between the transition metal and the basic nitrogen unit. As a result, markedly improved and enhanced physical properties are observed, especially when the stoichometric ratio of the interacting moieties are approached (SO/N = 1/1). This enhancement in properties is clearly exhibited in melt viscosity data, dynamic mechanical data, and thermal data. The blend morphology is also altered by complex formation, as is observed in scanning electron microscopy of the blends from which one of the ingredients was selectively extracted. At the stoichometric ratio, the blend of the olefinic elastomeric ionomer and the styrenic thermoplastic copolymer approaches a single-phase system. Such blends are otherwise completely immiscible when the coordination-type interacting groups are absent from either of the individual components. Accordingly, it was observed that nontransition-type (Na, Mg) counterions have only a marginal effect on the compatibility of these blends, as is the case in the completely unfunctionized blend components.     

Discovery of glutathione S-transferase inhibitors using dynamic combinatorial chemistry

Protein-directed dynamic combinatorial chemistry (DCC) relies on reversible chemical reactions that can function under the near-physiological conditions required by the biological target. Few classes of reaction have so far proven effective at generating dynamic combinatorial libraries (DCLs) under such constraints. In this study, we establish the conjugate addition of thiols to enones as a reaction well-suited for the synthesis of dynamic combinatorial libraries (DCLs) directed by the active site of the enzyme glutathione S-transferase (GST). The reaction is fast, freely reversible at basic pH, and easily interfaced with the protein, which is a target for the design of inhibitors in cancer therapy and the treatment of parasitic diseases such as schistosomiasis. We have synthesized DCLs based on glutathione (GSH, 1) and the enone ethacrynic acid, 2a. By varying either set of components, we can choose to probe either the GSH binding region ("G site") or the adjacent hydrophobic acceptor binding region ("H site") of the GST active site. In both cases the strongest binding DCL components are identified due to molecular amplification by GST which, in the latter system, leads to the identification of two new inhibitors for the GST enzyme.     

Tandem driven dynamic combinatorial resolution via Henry-iminolactone rearrangement

An unexplored type of tandem reaction is used to kinetically resolve a dynamic combinatorial library resulting in quantitative amplification of an interesting 3-substituted isoindolinone,     

Optimizing the reversibility of hydrazone formation for dynamic combinatorial chemistry

Hydrazones from hydrazines bearing electron withdrawing groups, and aromatic or aliphatic aldehydes form and hydrolyse rapidly in water at neutral pH.     

Novel intramolecular coordination chemistry of some new metallocene complexes

The metabolic thermogenic curves of liver mitochondria isolated from the livers of Cyprinus Carpio vol and its parents were determined at 28°C by using an LKB‐2277 Bioactivity Monitor. The results indicated that their thermogenic curves are different The total heat output and total time of the metabolism of the liver mitochondria of the hybrid F₁ (Cyprinus Carpio val) are more than those of its parents, and its maximum heat power is between that of the female parent and male parent. The relationship between their metabolic thermogenic curves and character of mitochondrial metabolism, and thermokinetics and the heterosis were analyzed and discussed. The character of the mitochondrial thermogenic curves reflected the physiologic character of heterosis. The microcalorimetric method proved to be a probable and sensitive tool for the assessment of heterosis.     

Dynamic combinatorial chemistry

Dynamic combinatorial chemistry is based on the reversible combination of initial building blocks to form dynamic combinatorial libraries. It has recently emerged as an efficient strategy to detect and to evaluate affinity between the library products and a target molecule. In this review, examples from various fields of chemistry and biochemistry are presented and extensively discussed. The last section deals with the practical aspects for implementing this approach.     

Reversible aqueous metathesis reactions for potential application in dynamic combinatorial chemistry

Solutions of heterocycles having an allyl sulfide unit and simple alkenes in 50% t-BuOH/H₂O undergo reversible olefin metathesis reactions with the second generation Hoveyda-Grubbs catalyst. The choice of functional groups is limited by competitive chelation of some heterocycles with the catalyst, and other stereoelectronic effects.     

Synthesis of cyclic oligomers from histidine-derived building blocks using dynamic combinatorial chemistry

Histidine-derived hydrazide acetal monomers (3-dimethoxymethylbenzoyl)-L-histidine methyl ester 1 and (3-dimethoxymethylbenzoyl)-tau-benzyl-L-histidine methyl ester 2 were prepared from a histidine methyl ester and a tau-benzyl-histidine methyl ester by N-acylation with 3-(dimethoxymethyl)benzoic acid (3) followed by hydrazinolysis. Acid-promoted hydrolysis of each acetal hydrazide initially produced a library of cyclic oligomers that eventually converted to a cyclic dimer. The cyclic dimers 12 and 22 were spectroscopically characterized and found to direct their imidazole-bearing sidechains outward (exo). No evidence for templating the cyclic oligomers was observed using various metal ions and anionic substrates. The average of pKa1 and pKa2 of dimer 12 was determined by potentiometric titration to be 6.6. Dimer 12 was found to catalyze the hydrolysis of p-nitrophenylacetate 10 times faster than 4-methyl imidazole.     

Photoinversion of sulfoxides as a source of diversity in dynamic combinatorial chemistry

Photochemical interconversion of the two diastereoisomers cis- and trans-thianthrene dioxide (1) can be considered an example of photodynamic combinatorial chemistry (PDCC) in which the interconversion among diastereomeric equilibrating species is brought about by electromagnetic irradiation. Photoequilibrium can be shifted by irradiation at different wavelengths or by addition of SnCl(2) that binds cis-1 more efficiently than trans-1.     

Combinatorics of combinatorial chemistry

The hot topic among medicinal chemists today is a novel technique for chemical synthesis in drug research called combinatorial chemistry, where usually a core structure and some building‐block molecules are given and all combinatorially possible combinations are produced. The resulting set of compounds (called a library) can afterwards be systematically screened for a desired biological activity. In this paper we discuss the applications of the mathematical discipline of combinatorics to this process, especially an algorithm for the exhaustive and redundancy‐free generation of a combinatorial library as well as equations for the enumeration of library sizes. This revised version was published online in July 2006 with corrections to the Cover Date.