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Selection Approaches to Catalytic Systems
Abstract
The key feature of enzymic catalysis is recognition of the transition state. Synthesis of designed systems rarely leads to successful catalysts as the rules for conformation and intermolecular interactions are to imperfectly understood. This review describes several current ‘selection’ approaches to the generation of systems that can recognise transitionstate analogues. Examples covered include catalytic antibodies, ribozymes, imprinted polymers. Combinatorial chemistry, and thermodynamic templating. All have the potential to yeild effective catalysts without prior design of every detail.
... Following the technique described above, recent years have seen remarkable progress in the design of molecularly imprinted catalysts [20]. Numerous reviews on the molecular imprinting procedure have been published [21][22][23][24][25][26][27]. However, a comparison between these catalysts and enzymes [22], shows that enzymes are still in every case several orders of magnitude catalytically more efficient, but in a few cases, the efforts have reached the activity of catalytic antibodies, e.g., in the hydrolysis of carbamates [28]. ...
A critical appraisal of the current strategies for the synthesis of enantiopure drugs is presented, along with a systematic background for the computational design of stereoselective porous polymers. These materials aim to achieve the enantiomeric excess of any chiral drug, avoiding the racemic separation. Particular emphasis is given to link statistical mechanics methods to the description of each one of the experimental stages within the catalyst’s synthesis, setting a framework for the fundamental study of the emerging field of molecularly imprinted catalysts.Graphical abstractThe envisaged modelling tools in the EMIC toolbox: quantum mechanics (QM), molecular dynamics and Monte Carlo (in the NPT and NVT ensembles), grand canonical Monte Carlo (GCMC) and kinetic Monte Carlo (kMC), for the synthesis of an enantiopure drug via our proposed EMIC catalyst.
... The problem with this approach is that successful design is often identified only after the event: one designs and makes many different structures, and then discovers by experiment which, if any, was the right design (Sanders 1998Sanders , 2000). An alternative approach, inspired by the example of evolution and selection in biology, is to chemically or biologically generate a range of different structures and then to select the most effective (Brady & Sanders 1997). This article explores one of these approaches, dynamic combinatorial chemistry (DCC), which has been developed in our laboratory and elsewhere over the past few years. ...
The principles of an evolution-selection approach to the synthesis of systems capable of molecular recognition are described. Using this dynamic combinatorial self-assembly concept in bulk solution, a variety of successful synthetic receptors have been prepared. The reversible chemistries employed include metalloporphyrin-ligand coordination, hydrazone exchange and disulfide exchange. The prospects for extension of the approach to surfaces are briefly considered.
Through molecular mechanics using the force field along with the quantum dynamical aspect of mechanically interlocked compounds, rotaxanes (defined as macromolecular rings that are threaded on a dumbbell-shaped axle molecule) are investigated with advanced quantum mechanical methods, including the atom-centered density matrix propagation simulation technique, at different temperatures like 300, 500, 700, 900, 2000, and 2500 K for 1.2 ps. Ab initio molecular dynamics simulation is carried out. In addition to, we investigate the noncovalent interaction present in the rotaxane compound 2R-D-2PF6 with the help of reduced density gradient, average reduced density gradient, density overlap region indicator, and interaction region indicator as well as Hirshfeld surface analyses. Furthermore, the stability of 2R-D-2PF6 at room temperature and higher temperatures is elucidated by analyzing the thermal fluctuation index through a dynamic process. In order to check the optical behavior of our selected rotaxane compound, an evaluation of the electronic dipole moment, static and frequency-dependent average polarizability, and first- and second-order hyperpolarizability is carried out. The rotaxane compound shows very promising linear and nonlinear optical responses, which indicates its utility as a very good optical material. The calculation of the time-dependent density-functional theory highlights the broad absorption band of rotaxane spanning the UV-visible domain. Therefore, we also unravel that this can tap into solar radiation or harnessing of solar energy.
Dynamic combinatorial chemistry (DCC) has repeatedly proven to be an effective approach to generate directed ligand libraries for macromolecular targets. In the absence of an external stimulus, a dynamic library forms from reversibly reacting building blocks and reaches a stable thermodynamic equilibrium. However, upon addition of a macromolecular host which can bind and stabilize certain components of the library, the equilibrium composition changes and induces an evolution‐like selection and enrichment of high‐affinity ligands. A valuable application of this so‐called target‐directed DCC (tdDCC) is the identification of potent ligands for pharmacologically relevant targets. Over time, the term tdDCC has been applied to describe a number of different experimental setups, leading to some ambiguity concerning its definition. This article systematically classifies known procedures for tdDCC and related approaches, with a special focus on the methods used for analysis and evaluation of experiments.
Different research works have been described in this thesis. The research works can be summarized as the following. The first chapter deals with the identification of effective potent inhibitors for the human carbonic anhydrase I (hCAI) isozyme. Considering the pharmacological importance to find selective CA inhibitors (CAIs) and CA activators (CAAs), human carbonic anhydrase I (hCAI) has been subjected to a parallel screening of various constitutional dynamic libraries (CDL). In the second chapter, constitutional dynamic networks have been used in liquid and solid membrane systems as a carrier network for transporting lanthanides. The transport isbased on the complexing ability of lanthanides metals (La+3, Lu+3, Eu+3) with the functional polyether groups in the membrane materials. In the third chapter, the proposed approach consists in using supported ionic liquid membranes (SILMs) comprising two different carbonic anhydrase enzymes, the thermo-resistant SspCA enzyme and the Bovine-CA enzyme, which catalyze the reaction of reversible conversion of CO2 to bicarbonate, enhancing the driving force for CO2 transport. Membrane stability, CO2 and N2 permeability and (CO2/N2) ideal selectivity weredetermined for the membranes developed. In the fourth chapter, the research work consists in the synthesis and characterization of dense polymeric membranes for gas separation application. The gas permeability measurements for the synthesized polymeric membranes showed that the permeability of CO2 is higher than other used gases (N2 and CH4). In the last chapter, two different methods of PVDF membrane functionalization with a phosphotriesterase (PTE) enzyme have been developed to construct biocatalytic membrane reactor (BMR) for bioconversion andselective separation of paraoxon substrate. The first method employs reversible dispersion of magnetic nanoparticle immobilized with PTE using an external magnetic field on the surface of native PVDF membrane. On the contrary, the second method comprises chemical grafting of the PTE enzyme after surface modification of the native PVDF membrane (DAMP-GA-Enzyme).Both methods of enzyme immobilization showed good efficiency and sensitivity towards the bioconversion of paraoxon substrate at different conditions applied in a biocatalytic membrane reactor (BMR).In general, the concepts developed in this thesis research work will help bring new tracks on the way to the development of a polymeric membrane for selective ion and gas separation but also for selective catalytic reaction under bio(molecular) control.
IntroductionIsolation and Epoxidation Activity of a Coordinatively Unsaturated Ru Complex at a SiO2 SurfaceChiral Self-Dimerization of V Complexes on a SiO2 Surface for Asymmetric CatalysisMolecular Imprinting Rh-Dimer and Rh-Monomer CatalystsRe Clusters in HZSM-5 Pores for Direct Phenol SynthesisConclusion
References
In this study, we report a dynamic combinatorial approach along with a highly efficient in situ screening to identify inhibitors of UDP-galactopyranose mutase (UGM), an essential enzyme involved in the mycobacterial cell wall biosynthesis. These two technologies converged to the identification of a new UGM inhibitor chemotype. Importantly, the best molecule not only displayed high affinity for the target enzyme but also exhibited in vitro growth inhibition against whole Mycobacterium tuberculosis cells. The strategy described here provides an avenue to explore a novel inhibitor class for UGMs and paves the way for further pharmacological studies on tuberculosis treatment.
This chapter describes approaches towards organocatalyst discovery relying on dynamic chemistry, that is, chemistry relying on reversible bond formation. The use of dynamic chemistry is an attractive option as it allows for self-assembly and self-selection processes. Self-assembly implies that catalyst formation occurs spontaneously upon mixing subunits equipped with complementary recognition elements. It will be shown that this permits the straightforward formation of large catalyst libraries simply by mixing a limited number of subcomponents. Typically, the activity of the catalytic complex is higher in terms of activity and selectivity compared to the separate subunits. Self-assembly can also be used in a more indirect manner by creating molecular cages able to encapsulate reagents. This is a highly attractive strategy for several reasons. Encapsulation increases the effective concentration of reagents and fixes their relative orientation depending on the geometry of the cage. Additionally, the interior of the cage represents a local chemical environment that is different from the bulk, which can be beneficial for the chemical reaction occurring in the cage. The final part of the chapter is dedicated to examples in which catalyst discovery occurs by means of self-selection processes. This approach relies on the exposure of a dynamic library of potential catalysts to a transition state analog of a chemical reaction. This causes a shift in the thermodynamic composition of the library in favor of the catalyst that can most strongly interact with the transition state. The advantage is that it relies on self-selection and that, in principle, no a priori knowledge about the nature of the interaction between catalyst and transition state is required.
Rational and generalisable methods for engineering surface functionality will be crucial to realising the technological potential of nanomaterials. Nanoparticle-bound dynamic covalent exchange combines the error-correcting and environment-responsive features of equilibrium processes with the stability, structural precision, and vast diversity of covalent chemistry, defining a new and powerful approach for manipulating structure, function and properties at nanomaterial surfaces. Dynamic covalent nanoparticle (DCNP) building blocks thus present a whole host of possibilities for constructing adaptive systems, devices and materials that incorporate both nanoscale and molecular functional components. At the same time, DCNPs have the potential to reveal fundamental insights regarding dynamic and complex chemical systems confined to nanoscale interfaces.
Whereas combinatorial chemistry is based on extensive libraries of prefabricated molecules, dynamic combinatorial chemistry (DCC) implements the reversible connection of sets of basic components to give access to virtual combinatorial libraries (VCLs), whose constituents comprise all possible combinations that may potentially be generated. The constituent(s) actually expressed among all those accessible is(are) expected to be that(those) presenting the strongest interaction with the target, that is, the highest receptor/substrate molecular recognition. The overall process is thus instructed (target-driven), combinatorial, and dynamic. It bypasses the need to actually synthesize the constituents of a combinatorial library by letting the target perform the assembly of the optimal partner. It comprizes both molecular and supramolecular events. The basic features of the DCC/VCL approach are presented together with its implementation in different fields and the perspectives it offers in a variety of areas of science and technology, such as the discovery of biologically active substances, of novel materials, of efficient catalysts, and so forth. Finally, it participates in the progressive development of an adaptive chemistry.
A simple route to new diphosphane ligands: Merrifield's resin was used to construct diphosphanes of the general formula 1 that could be cleaved by reaction with PCl3, alcohols, or thioalcohols to provide ligands such as 2–4 in solution.
Supramolecular chemistry has over the last quarter of a century grown into a major field of chemistry and has fueled numerous developments in the related areas of biology and physics, thus giving rise to the emergence and establishment of supramolecular
science (and technology), as a broad multi- and inter-disciplinary domain providing a highly fertile ground for the creativity of scientists from all origins. Its impact has been analyzed in a recent commentary on the theme of the present meeting [1], and illustrated by the perceptive presentation of five selected topics of supramolecular chemistry by some of the major players in the field [2–6]. The chapters in this book provide further extensive coverage and markedly widen the scope.
This chapter outlines key developments of the combination of key supramolecular principles and polymer chemistry, notably in the realization of novel catalyst systems. Novel catalysts have been produced that offer reactivity under conditions that more traditional hetero- or homogeneous catalysts do not tolerate. In particular, molecularly imprinted polymer networks have been used successfully and notable examples are described in this chapter. In addition to cross-linked polymer networks, the combination of hyperbranched polymer architectures with molecular recognition has also afforded novel catalyst systems, and recent developments in this area are outlined. Finally, the application of sonochemistry to self-assembled latent catalysts is reviewed.Keywords:molecular imprinting;polymer;catalysis;dendrimer;supramolecular;template;transition-state analogue;enzyme mimic
Molecular recognition for a specific cation depending on the change of the oxidation state of the metal catalyst component contained in the hydrogel network has been studied in a self-oscillating hydrogel. The self-oscillating hydrogels are synthesized by the copolymerization of N-isopropylacrylamide (NIPAAm), lead methacrylic acid (Pb(MAA) 2), and Ru(bpy) 3 2+ monomer as a metal catalyst component. The recognition for a specific cation (in this study, Ca 2+ has been used) is characterized by the adsorbed amount of Ca 2+ into the gel. The recognition of the gels for Ca 2+ is higher at the temperature below the LCST, and also higher at the oxidized state than at reduced state of the metal catalyst component which corresponds to a more swollen state. Moreover, a propagating wave induced by a periodic change of the oxidation state with the diffusion phenomena in the oscillating hydrogel shows a possibility for temporal and site-specific molecular recognition due to the local swelling of the gel.
The deoximation kinetics of some oximes was studied by using cetyltrimethylammonium dichromate (CTADC) in dichloromethane in the presence of acetic acid and a cationic surfactant. The rate of reaction is highly sensitive to the change in [CTADC], [oxime], [acid], [surfactant], polarity of the solvents, and reaction temperature. The reaction is found to be catalyzed by acid with an appreciable uncatalytic rate. The reaction is first order with respect to substrate. With increase in CTADC concentration, rate of the reaction increases with a fractional order dependency with respect to oxidant. Consistent to the observation, a mechanism has been proposed in which the substrate forms a complex with CTADC in the rate determining step followed by decomposition with a fast process to yield corresponding carbonyl compounds. The structure of the substituents has also a significant effect on the rate constant. © 2011 Wiley Periodicals, Inc. Int J Chem Kinet 43: 482–488, 2011
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Acid-catalysed scrambling of the mechanically interlocked components between two different homo[3]rotaxanes, constituted of dumbbells containing two secondary dialkylammonium ion recognition sites encircled by two [24]crown-8 rings, each containing a couple of imine bonds, affords a statistical mixture of a hetero[3]rotaxane along with the two homo[3]rotaxanes, indicating that neither selectivity nor cooperativity is operating during the assembly process.
The progress of dinuclear metallo-phosphoesterase models in recent 10 years is reviewed. A brief discussion about the future research is also given.
Discoveries involving the formation, structure, and behavior of an exciting class of compounds, 1,3,5,7-cis-tetraheterodecalins, are reviewed. These compounds are rich in free electrons and exhibit concave structures. The tetraoxa- and dioxadiaza- members of this class of compounds comprise the underframe of various podand structures, which, along with suitable polyhetero linkers, constitute the building blocks of an entire series of unique classes of macro- and gigantocyclic compounds, capable of cation inclusion and catalytic behavior. In the works presented here, a recurring theme is the pursuit of a fundamental understanding and judicious utilization of the dynamic chemical and stereochemical features of compounds derived from 1,3,5,7-cis-tetraheterodecalins, most of which are members of dynamic combinatorial libraries (DCLs).
Reversible covalent bond formation under thermodynamic control adds reactivity to self-assembled supramolecular systems, and is therefore an ideal tool to assess complexity of chemical and biological systems. Dynamic combinatorial/covalent chemistry (DCC) has been used to read structural information by selectively assembling receptors with the optimum molecular fit around a given template from a mixture of reversibly reacting building blocks. This technique allows access to efficient sensing devices and the generation of new biomolecules, such as small molecule receptor binders for drug discovery, but also larger biomimetic polymers and macromolecules with particular three-dimensional structural architectures. Adding a kinetic factor to a thermodynamically controlled equilibrium results in dynamic resolution and in self-sorting and self-replicating systems, all of which are of major importance in biological systems. Furthermore, the temporary modification of bioactive compounds by reversible combinatorial/covalent derivatisation allows control of their release and facilitates their transport across amphiphilic self-assembled systems such as artificial membranes or cell walls. The goal of this review is to give a conceptual overview of how the impact of DCC on supramolecular assemblies at different levels can allow us to understand, predict and modulate the complexity of biological systems.
Recent progresses in molecularly imprinted metal-complex catalysts
are highlighted in this chapter. Molecular imprinting is a technique to
produce a cavity with a similar shape to a particular molecule
(template), and the molecularly imprinted cavity acts as shape-selective
reaction space for the particular reactant. The application of the
molecular-imprinting technique to heterogeneous metal-complex
catalysts is focused in the viewpoint of a novel approach in the design
of shape-selective catalysis mimicking enzymatic catalysis.
This article attempted to review novel metal-complex catalysts prepared by molecular-imprinting methods, presenting our work on recent catalyst design at surfaces. Molecular imprinting is a way to produce cavity with a particular molecule (template) by polymerization of organic and inorganic materials and removal of the template. The cavity with memory of the template provides shape-selective reaction space for the molecule which has similar shape to the template. Recently, the application to metal-complex catalysts has been achieved to exploit unique property different from homogeneous and simple supported metal-complex catalysts. Imprinting metal-complex catalysts prepared by using reaction intermediate or transition state analogues as templates for asymmetric hydride transfer reduction of ketones, aldol condensation, and shape-selective hydrogenation of simple alkenes without any functional groups are focused in the viewpoint of new approaches in design of shape-selective metal-complex catalysts.
The syntheses of tris(2-nicotinic acid)methanol methyl ether 5 and tris(2-picolinic acid)methanol methyl ether 6, two tridentate ligands designed to also act as scaffolds for constructing chiral environments around their metal binding sites, is described. Improved yields for the essential lithiation–alkylation reactions that generate the trispyridyl core of these types of ligands are reported.
Schiff-base reactions are widely used in the field of chemistry. With many advantages, such as mild reaction conditions and high reaction rates, they were employed for protecting various functional groups and synthesizing a series of organic ligands. In polymer chemistry, they can serve as potential pH-responsive linkers in polymer chains because of their sensitive responses to changes in the pH value. With certain particular designs, the Schiff-base structure can cooperate with other reversible covalent bonds or supra-molecular interactions to form assemblies or gels, providing various functions and applications. This article aims to give a critical review of the recent literature on the Schiff-base reactions used in polymer chemistry and how they serve as a way of linking structures together. We will also cover some of the important developments on the functions and applications of these polymers.
Discrete assemblies of nano-size dimensions were synthesized by non-covalent chemistry. Calix[4]arenes, diametrically substituted at the upper rim with two melamine units, form stable box-like assemblies in solution in the presence of two equivalents of 5,5-diethylbarbituric acid (DEB). Various techniques, such as NMR spectroscopy, MALDI-TOF mass spectrometry, and X-rays crystallography have been used for the characterization of these assemblies held together by 36 hydrogen bonds. Furthermore, assemblies with different types of functionalities at the upper rim of the calix[4]arene and at the melamine units were prepared. The effect of these functional groups on the stability of the assembly has been investigated. Small libraries of functionalized assemblies were formed by mixing the individual components under thermodynamically controlled conditions. This strategy provides access to functional group diversity.
Kinetics and mechanisms of the imine exchange reactions of O-alkyl and O-aryl oximes with O-alkyl- and O-aryloxyamines, respectively, were studied by 1H NMR spectroscopy in aqueous solutions. The reaction between benzaldehyde O-methyloxime and O-ethylhydroxylamine at 60 °C is first order in both oxime and the alkoxylamine (the second-order rate constant k2 = 0.86 0.08 l mol ˇ1 minˇ1 at pD 2.9), the reaction being subject to acidic catalysis. A similar imine transfer was studied in the reaction of 1,3-diaminooxypropane with bifunctional oximes. Testing of various additives as potential catalysts for the reaction revealed imidazole as a moderately effective catalyst. The exchange in O-aryl oximes was studied in the interaction between 3-pyridinealdehyde O- phenyloxime and O-(p-nitrophenyl)hydroxylamine. The reaction is first order in the oxime, but its rate is independent on the aryloxyamine concentration and pD. The proposed mechanism involves a rate-limiting hydration of the oxime molecule. Mechanisms of the exchange reactions are discussed in relation to their possible use to generate diverse pools of compounds for the recently proposed 'dynamic' combinatorial chemistry approach. Copyright © 1999 John Wiley & Sons, Ltd.
Eleganz und Präzision zeichnen die Selbstorganisationsstrategie aus, die Stoddart, Atwood et al. zur Synthese von molekularen Borromäischen Ringen entworfen haben. Metallion-Templateffekte dirigieren die dynamische Knüpfung kovalenter Bindungen, bei der das symbolträchtige Ringmotiv als energetisch günstigstes Produkt entsteht (siehe Bild).
Eine nichtplanare Struktur charakterisiert den größten bislang beschriebenen, ringförmigen Eisencluster mit chemisch äquivalenten verbrückenden Einheiten, den Komplex [Fe(OCH3)2(dbm)]12 (im Bild links schematisch dargestellt). Er wird durch zwölf antiferromagnetisch gekoppelte High-spin-Eisen(III)-Zentren aufgebaut und reagiert mit NaI- oder LiI-Ionen (Templateffekt) in organischen Lösungsmitteln unter Bildung von Hexaeisen(III)-Kronenverbindungen (im Bild rechts dargestellt). Fe=•, O=○, NaI oder LiI=• Hdbm = Dibenzoylmethan.
Die molekulare Prägung der Oberflächen mesoporöser Sorbentien ist eine neue Methode, um templatselektive Erkennungsstellen einzuführen. Diese Methode nutzt die einzigartige geometrische Umgebung, die die Oberflächen hexagonal gepackter Mesoporen mit ausgewählten Porenweiten bieten (siehe schematische Darstellung), und bedeckt diese Oberflächen mit funktionellen Liganden, die an ein Metallionentemplat gebunden sind.
We prepare a series of homologues of novel binaphthyl derivatives, (R)‐2, 2′‐bis{ω‐[4‐(4‐(octyloxycarbonyl)phenyl)phenyloxycabonyl]alkyloxy}‐1, 1′‐binaphthyl [(R)‐Bi‐n], and investigate their induced helical senses and pitches in different host nematic liquid‐crystalline compounds. Pronounced odd–even effects were observed for the induced helical structure in each mixture with 5‐heptyl‐2‐(4‐hexyloxyphenyl)pyrimidine. Temperature‐dependent helical twist inversion was observed for the mixture doped with the odd members, whereas a right‐handed helix was observed for the mixture doped with the even members. On the other hand, a left‐handed helix was induced in each mixture with 4‐methyloxyphenyl 4‐pentylcyclohexane. We discuss the change in sign of the induced pitch in terms of chirality transfer from the binaphthyl derivative to a host nematic liquid crystal.
It has become clear over the past two decades that, in order to create functional synthetic nanoscale structures, the chemist must exploit a fundamental understanding of the self-assembly of large-scale biological structures, which exist and function at and beyond the nanoscale. This mode of construction of nanoscale structures and nanosystems represents the so-called ‘bottom-up’ or ‘engineering-up’ approach to fabrication. Significant progress has been made in the development of nanoscience by transferring concepts found in the biological world into the chemical arena. The development of simple chemical systems that are capable of instructing their own organisation into large aggregates of molecules through their mutual recognition properties has been central to this success. By utilising a diverse array of intermolecular interactions as the information source for assembly processes, chemists have successfully applied biological concepts in the construction
of complex nanoscale structures and superstructures with a variety of forms and functions. More recently, the utility of assembly processes has been extended through the realisation that recognition processes can be used to select a single structure from a library of equilibrating structures. These developments open the way for the design and implementation of artificial assembly processes that are capable of adapting themselves to the local environment in which they are conducted.
A diboradiazaaromatic—2,7-di-tert-butyl-5,9-dihydroxy-5,9-dibora-4,10-diazapyrene-4,10-diium-5,9-diuide—which is a structural analogue of isophthalic acid has been designed and synthesised. This compound is capable of spontaneous dehydration in solution to form linear oligoanhydrides. These oligoanhydrides can be readily hydrolysed to the starting diboradiazaaromatic under appropriate conditions. This unusual reactivity is mirrored in the solid-state behaviour of 2,7-di-tert-butyl-5,9-dihydroxy-5,9-dibora-4,10-diazapyrene-4,10-diium-5,9-diuide. A complex network of hydrogen bonds present in the solid-state structure of the borazaaromatic serve to facilitate a facile solid-state dehydration reaction, once again forming oligoanhydrides of molecular weight greater than 3000 Da.
Bis(10-hydroxy-10,9-boraza-2-phenanthryl) ether is capable of covalent self-assembly upon dehydration in solution to form the corresponding cyclic dimer.
A new active SiO2-attached Rh-dimer catalyst for the hydrogenation of alkenes was designed by combining two ways of metal-complex immobilization and molecular imprinting on an oxide surface. The preparation was conducted step-by-step in three steps: (i) the attachment of Rh dimer precursor on an Ox.50 surface; (ii) coordination of the template P(OCH3)3 to the attached Rh dimer; and (iii) subsequent molecular imprinting by hydrolysis-polymerization of Si(OCH3)4 to form SiO2-matrix overlayers on the surface. Characterizations at each step were performed by means of elemental analysis, FFIR, XPS, ICP, solid-state MAS NMR, BET, EXAFS, and DFT calculation. The attached Rh dimer was converted to a pair of Rh monomers by coordination of two P(OCH3)3 on a Rh atom. The surface-imprinting process by Si(OCH3)4 drove the rebonding of the Rh monomer pair and extraction of half of the template ligands. Removal of the template ligands provided both highly active unsaturated Rh dimer with a Rh–Rh bond distance of 0.268 nm and a space of the size of the template around the dimer inside the SiO2-matrix overlayers on the surface. The template P(OCH3)3 was regarded as an analogue to a half-hydrogenated species of 3-ethylpent-2-ene. The catalytic activity of the imprinted Rh dimer catalyst for hydrogenation of 3-ethylpent-2-ene was 35 times higher than that of the Rh monomer pair before imprinting. For hydrogenation of 4-methylhex-2-ene which possesses an ethyl group at the 4-carbon position of the pent-2-ene main chain and oct-2-ene with a long alkyl chain, promotion of the catalytic activity by the imprinting was relatively slight, indicating shape discrimination of the alkenes by the surface molecular imprinting.
Oligomerization of preorganized cinchona and xanthene building blocks to produce dynamic combinatorial libraries results in libraries with only a few components. Diversity is generated by the addition of semi-flexible ephedrine and cholate building blocks.
A cyclic Zn-porphyrin trimer with ethyne and butadiyne links stabilises the thermodynamically disfavoured endo transition state and product of a reversible Diels–Alder reaction; at 30°C the endo adduct is formed rapidly and almost exclusively. Linear porphyrin dimers containing ethyne or butadiyne links show related stereochemical preferences to the corresponding cyclic trimers; substantial rate accelerations are observed despite rotational freedom around the linkers. A qualitative correlation is observed between rate acceleration (i.e., transition state binding) and product binding, and the results are rationalised in terms of host geometry and flexibility.
Thermodynamic cyclizations of a series of cinchona alkaloid derivatives are investigated. An extended quinine monomer 2:HO-Ce-OMe is prepared and cyclized to produce a mixture of cyclic oligomers. Combining the extended monomer 2:HO-Ce-OMe with the previously reported cinchonidine monomer 1b:HO- Cc-OMe under thermodynamic control produces a library of quinine-derived macrocycles. Two quinidine-derived methyl ester monomers 10:HO-Cd-OMe and 16:HO-Ca-OMe are also reported. Both are preorganized to form cyclic dimers; upon carrying out the thermodynamic cyclization on a mixture of both monomers only a small percentage (5%) of the hetero-dimer is obtained. Thermodynamic cyclization of the corresponding cinchonidine derived methyl ester 1b:HO-Cc- OMe with 10:HO-Cd-OMe results in the self-sorting of the two diastereoisomers.
A new size- and shape-selective Rh-dimer catalyst was designed by combination of a metal-complex-attaching method and a molecular-imprinting method on an Ox.50 surface. Coordinatively unsaturated, air-stable Rh dimers with a Rh–Rh bond of 0.268 nm were prepared in 0.74-nm micropores of SiO2-matrix overlayers on the Ox.50 silica surface by attaching a Rh2Cl2(CO)4 precursor on the surface (Rh2Cl2(CO)4/SiO2), followed by coordination of template ligands P(OCH3)3 to the attached Rh species (Rhsup catalyst), and then by surface imprinting of the template with SiO2-matrix overlayers formed by hydrolysis–polymerization of Si(OCH3)4 (Rhimp catalyst). The Rh dimers, micropores, and SiO2-matrix overlayers in the molecular-imprinting Rhimp catalyst were characterized by EXAFS, BET analysis, and 29Si solid-state MAS NMR, respectively. It was found that activity of the Rhsup catalyst for hydrogenation of alkenes was promoted remarkably (35–51 times) after the imprinting. The alkene hydrogenation proceeded on the imprinted Rh dimers with a monohydride without any breaking of the Rh–Rh bond. Size and shape selectivities of the molecular-imprinting Rhimp catalyst were examined by measuring the hydrogenation rates of eight alkenes of different sizes and shapes. It was also found that the Rhimp catalyst exhibited not only high activity and stability but also size and shape selectivities for the alkene molecules, probably due to a template-size cavity, created behind the removed template ligand, being used as a reaction site. Activation energies and activation entropies for the hydrogenation of large and branched alkenes were much smaller than those for small alkenes, which implies a shift in the rate-determining step in the reaction sequence for alkene hydrogenation. The performance of the molecular-imprinting Rh-dimer catalyst is discussed from structural and kinetic viewpoints.
A combinatorial library of 125 compounds with a structure consisting of 1-azafagomine linked at N-1 via an acetic acid linker to a variable tripeptide was synthesised.
Schematic of molecular imprinting.
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The selection of the receptor presenting the strongest affinity for a barbiturate substrate from a dynamic combinatorial library of constituents differing in structure and conformation/configuration is described. The gradual addition of the barbiturate to an equilibrating mixture of hydrazone isomers leads to the quantitative shift towards a single species, 3, which presents highest complementarity to the substrate and yields the supramolecular entity 3:4.
An organometallic transition state analog for the asym. redn. of acetophenone with a Cp*Rh complex was synthesized and structurally characterized - rac-[(C5Me5)Rh[OP(O)MePh](R,R-4-CH2:CHC6H4SO2NC6H10NH2)] (3). This complex has a chiral N,N'-chelate ligand with a styrene side chain to allow its incorporation into org. polymers. The remaining coordination site is occupied by a methylphenylphosphinato ligand. This ligand acts as a pseudo substrate which mimics acetophenone. The conformation and configuration of 3 in the crystal are in excellent agreement with the postulated transition structure. Following the protocol of mol. imprinting, complex 3 was co-polymd. with ethylene glycol dimethacrylate in the presence of a porogen. The resulting polymer P3 was ground and sieved and the phosphinato ligand was substituted with a chloro ligand to generate a shape-selective cavity in proximity to the catalytically active metal center. When tested for its ability to catalyze the redn. of acetophenone and related substrates the imprinted polymer P3 showed a significantly higher activity than a control polymer P2 without a cavity. Excellent enantioselectivities (up to 95% ee) were obtained, with the catalyst P3 being more selective than the resp. control catalyst P2 (Dee = 2-9%). Competition expts. with acetophenone and a 2nd co-substrate revealed that the cavity generated with the phosphinato ligand is specific for acetophenone.
Two different approaches are described for the creation of supramolecular systems potentially capable of recognition and catalysis. Using the design approach, we have been able to accelerate and influence two different Diels-Alder reactions within the cavities of porphyrin dimers and trimers; this is templating from the outside inwards. The selection approach is a synthetic chemical attempt to capture some of the key evolutionary features of biological systems: dynamic combinatorial chemistry is used to create equilibrating mixtures of potential receptors, and then a template is used to select and amplify the desired system. Five potential reactions for such dynamic chemistry are discussed: base-catalyzed transes- terification, hydrazone exchange, disulfide exchange, alkene metathesis, and Pd-catalyzed allyl exchange, and preliminary templating results (inside outwards) are presented.
Combinatorial libraries of pseudo-peptide hydrazone macrocycles are formed from amino acid-derived building blocks equipped with hydrazide and aldehyde functionalities; a series of experiments confirm that hydrazone formation is reversible and that the libraries are genuinely dynamic.
Addition of a dinaphtho-crown ether to the components of a chiral metallomacrocycle affords a [2]catenane as the exclusive thermodynamic product; the reversible assembly process is driven by a combination of zinc(II)–bipyridyl ligation and π-donor/π-acceptor interactions between the electronically complementary aromatic components.
A combination of two methods for catalyst design, namely metal-complex attaching and molecular imprinting, at oxide surfaces was employed to prepare new SiO2-attached shape-selective Rh-monomer catalysts for hydrogenation of alkenes. Attachment of Rh monomer on SiO2 surface was performed by reaction of RhCl(P(OCH3)3)3 precursor with an Ox.50 surface. The attached Rh monomers were characterized to be coordinated with two P(OCH3)3 ligands (Rh–P=0.225 nm) and two surface oxygens (Rh–O=0.204 nm) by EXAFS, XPS, and FT-IR, independent of Rh loading in the range 0.24–0.60 wt.%. Subsequent molecular imprinting of a P(OCH3)3 ligand in the attached Rh monomers as template ligand by hydrolysis–polymerization of Si(OCH3)4 depended
on the Rh loading; the lower loading Rh-monomers were successfully imprinted in uniform micropores formed in SiO2-matrix overlayers on the Ox.50 surface. Characterizations of the molecular imprinting catalysts with different heights of the SiO2-matrix overlayers were performed by EXAFS, XPS, 29Si solid-state MAS NMR, BET analysis, and H2 adsorption. The hydrolysis–polymerization of Si(OCH3)4 to form the SiO2-matrix overlayers on the surface led to removal of a template ligand P(OCH3)3, and as the result provided a cavity behind the template. Thus, a coordinatively unsaturated active Rh-monomer structure with a remaining P(OCH3)3 ligand per Rh and the template cavity as catalytic reaction space was created in the micropores of the SiO2-matrix overlayers. The catalytic properties of the imprinted Rh monomers were examined by
measuring the hydrogenation rates of nine simple alkenes (C5–C8 alkenes). The catalytic activity of the surface Rh monomers was promoted 2.4–13 times by the imprinting, and shape selectivity for the alkenes also appeared by the effect of template cavity, resulting in a shift of the rate-determining step and a large decrease in the activation energy and the activation entropy for alkenes with the larger shapes.
Molecular-scale design of catalytically active structures at oxide surfaces is highlighted, focusing on our recent challenges for selective heterogeneous catalysis. We found novel structural transformations of supported metal complexes on oxide surfaces and achieved unique selective catalysis for various chemical syntheses. In this account, the advanced design of supported metal-complex catalysts on oxide surfaces and the in situ characterization of their structural kinetics, which means kinetics of structural changes of catalysts themselves, under catalyst-working conditions are reviewed.
Seven families of RNA ligases, previously isolated from random RNA sequences, fall into three classes on the basis of secondary structure and regiospecificity of ligation. Two of the three classes of ribozymes have been engineered to act as true enzymes, catalyzing the multiple-turnover transformation of substrates into products. The most complex of these ribozymes has a minimal catalytic domain of 93 nucleotides. An optimized version of this ribozyme has a kcat exceeding one per second, a value far greater than that of most natural RNA catalysts and approaching that of comparable protein enzymes. The fact that such a large and complex ligase emerged from a very limited sampling of sequence space implies the existence of a large number of distinct RNA structures of equivalent complexity and activity.
Molecular imprinting of morphine and the endogenous neuropeptide [Leu5]enkephalin (Leu-enkephalin) in methacrylic acid-ethylene glycol dimethacrylate copolymers is described. Such molecular imprints possess the capacity to mimic the binding activity of opioid receptors. The recognition properties of the resultant imprints were analyzed by radioactive ligand binding analysis. We demonstrate that imprinted polymers also show high binding affinity and selectivity in aqueous buffers. This is a major breakthrough for molecular imprinting technology, since the binding reaction occurs under conditions relevant to biological systems. The antimorphine imprints showed high binding affinity for morphine, with Kd values as low as 10(-7) M, and levels of selectivity similar to those of antibodies. Preparation of imprints against Leu-enkephalin was greatly facilitated by the use of the anilide derivative rather than the free peptide as the print molecule, due to improved solubility in the polymerization mixture. Free Leu-enkephalin was efficiently recognized by this polymer (Kd values as low as 10(-7) M were observed). Four tetra- and pentapeptides, with unrelated amino acid sequences, were not bound. The imprints showed only weak affinity for two D-amino acid-containing analogues of Leu-enkephalin. Enantioselective recognition of the L-enantiomer of phenylalanylglycine anilide, a truncated analogue of the N-terminal end of enkephalin, was observed.
For the past decade the immune system has been exploited as a rich source of de novo catalysts. Catalytic antibodies have been shown to have chemoselectivity, enantioselectivity, large rate accelerations, and even an ability to reroute chemical reactions. In many instances catalysts have been made for reactions for which there are no known natural or man-made enzymes. Yet, the full power of this combinatorial system can only be exploited if there was a system that allows for the direct selection of a particular function. A method that allows for the direct chemical selection for catalysis from antibody libraries was so devised, whereby the positive aspects of hybridoma technology were preserved and re-formatted in the filamentous phage system to allow direct selection of catalysis. This methodology is based on a purely chemical selection process, making it more general than biologically based selection systems because it is not limited to reaction products that perturb cellular machinery.
Certain stereoisomers of the ionophore antibiotic lasalocid A can be epimerized to the natural configuration using metal ions which form particularly stable complexes with the natural antibiotic.
We report here the isolation and characterization of a 35-nucleotide (nt) RNA that catalyzes the related Cu(II) insertion into mesoporphyrin IX with a k{sub cat}/K{sub m} value of 2100 M{sup -1} s{sup -1}, close to the value for the metalation of mesoporphyrin with Fe(II) catalyzed by recombinant human ferrochelatase. This work demonstrates the ability of RNA to catalyze a reaction closely related to that required for the biosynthesis of the essential cofactor, heme. The small size of the catalytic sequence motif found here should facilitate structural studies. Moreover, mutants of this RNA may be selected to display other porphyrin-based activities: ferrochelatase activity, reversible oxygen binding with RNA-bound heme, peroxidase activity, or complementation of ferrochelatase-deficient (heme H{sup -}) auxotrophs which could ultimately lead to in vivo complementation of ferrochelatase deficiency using gene transfer techniques. 25 refs., 2 figs., 1 tab.
Combinatorial chemistry is a novel way of rapidly generating a large number of related compounds. Screening of such a collection or library for biological activity may be performed in solution or on a solid support. Combinatorial peptide libraries have been most intensively investigated in the search for lead compounds, but the method is so powerful that it seems certain that it will be used increasingly to generate libraries of other types of molecule.
An automated search of thousands of combinatorially-functionalized
polymers bearing dihydropyridine groups defines a few active examples that
can reduce a ketone in water.
Thermodynamically-controlled transesterification of a predisposed
cinchonidine building block with a more flexible extended quinine monomer
leads to a combinatorial mixture of 11 macrocyclic receptors which is
analysed by electrospray mass spectrometry; similar results with
alkaloid–cholate mixtures demonstrate the generality of the
approach.
A series of ester-linked macrocyclic oligomers (dimer–pentamer) of cholates equipped with a variety of recognition and reporter elements has been prepared (a) by conventional irreversible chemistry, and (b) using methoxide-catalysed transesterification under reversible equilibrium conditions. Templating by metal ions under these equilibrium conditions is also demonstrated. These results demonstrate the feasibility of creating a dynamic combinatorial library of receptors.
For corrigendum see DOI:10.1002/anie.199619951
Can binding sites be produced in organic or inorganic polymers—similar to those in antibodies—which are able to recognize molecules and which may have catalytic action? In this article we review a method, analogous to a mechanism of antibody formation proposed earlier, by which in the presence of interacting monomers a cross-linked polymer is formed around a molecule that acts as a template. After removal of the template, an imprint containing functional groups capable of chemical interaction remains in the polymer. The shape of the imprint and the arrangement of the functional groups are complementary to the structure of the template. If chiral templates are used, the success of the imprinting process can be assessed by the ability of the polymer to resolve the racemate of the template molecule. Through optimization of the process has led to chromatographic separation factors of α = 4–8, and to base line separations. There is also great interest in the surface imprinting of solid materials and monolayers. In all cases, the structure of the polymeric matrix in the imprinted materials and the function of the binding groups are of crucial importance. The mechanisms of imprinting and molecular recognition of substrates are by now well understood. A large number of potential applications for this class materials are being intensively developed, for example in the chromatogrphic resolution of recemates, and as artificial antibodies, chemosensors, and selective catalysts. The use of similarly produced materials as enzyme models is also of great interest.
For corrigendum see DOI:10.1002/anie.199605541
The combinatorial synthesis and evaluation of inorganic catalysts is described. The catalysts are an array of early-transition-metal-oxygen-anion clusters (polyoxometalates) and the reaction is the aerobic oxidation of a mustard thioether analog, tetrahydrothiophene (THT). Selective oxidation of THT to the desired sulfoxide, THTO, was achieved in high selectivity (τ; 99%) and under relatively mild conditions (95°C, 1.52 atm). Solutions with a molar ratio of 1:2 (phosphorus:vanadium) had the highest catalytic activity. 51V NMR and IR were used not only to identify the self assembling polyoxometalates in several representative precursor combinations (columns in the combinatorial gallery of Fig. 1) but also to assess the stability of one representative polyoxometalate catalyst, 1P:2V:10W, under catalytic conditions (no decomposition after 50 turnovers). Gas chromatography was sufficient to rapidly quantify the product (THTO) yields and selectivities of representative reactions. Combinatorial methodology should be applicable to and provide the same advantages for discovery and optimization of catalysts as it has for pharmaceuticals.
THE synthesis of microporous materials such as aluminosilicates and aluminophosphates, which are widely exploited as solid acid catalysts, ion exchangers and in gas separation, is facilitated by the use of structure-directing agents (often referred to as templates)1. These are generally organic bases, and are included in an inorganic gel medium so that the microporous framework condenses around them; the final structure of the framework reflects, to differing degrees, the shape of the template. Although there is growing confidence2 in being able to target a particular microporous structure by adroit choice of structure-directing agent3–7, no a priori method has been described for generating potential templates for either existing or hypothetical structures. Here we present a method for de novo design of template molecules, which are computationally 'grown' in the desired inorganic framework. Our method is successful in generating known templates for existing microporous materials, and a new candidate suggested by this method succeeds as a template for the target material. Our method should be generally applicable to the field of template-directed hydrothermal synthesis of crystals and to other fields of chemistry involving host–guest recognition.
Monoclonal antibodies (mAbs) were generated against the coplanar transition state (TS) analogue 1 and assayed for their ability to catalyze the isomerization of bridged biphenyls 4, 6, and 7. This is a relatively simple unimolecular reaction whose activation barrier arises from unfavorable steric interactions between the two benzylic methylene groups and strain in the bridging ring system. Seven mAbs were found that catalyzed the isomerization of 4 to 6; the most efficient (mAb 64D8E10) has kcat and KM values of 4.3 × 10-5 s-1 and 420 μM, respectively. This corresponds to a rate enhancement over the unimolecular uncatalyzed reaction (kcat/kuncat) of 2900. The dissociation constant for the TS analogue, Kd, was determined to be 210 nM. For both the antibody (64D8E10) catalyzed and uncatalyzed reactions, the free energy of activation (ΔG) is comprised largely of the enthalpy term; the antibody decreases the enthalpy of activation by 5 kcal/mol. Despite relatively large differences in the values of kcat/kuncat for the five antibodies, the ratios of Kd to KM(4) are very similar. It is likely that the antibodies catalyze this reaction by reducing both ring strain and nonbonded steric interactions in the transition state.
The intramolecular aldol condensation of keto-aldehyde 1 yields a substituted 2-benzyl-3-hydroxy-cyclohexanone 2 and subsequently 2-benzyl-2-cyclohexenone (3). The sequence involves four individual reaction steps, Three of these steps can be accelerated using general acid-base catalysis to effect proton transfer at or near the alpha-carbon of the ketone involved in the condensation, which is at the homobenzylic position relative to the aromatic group of the substrate (Ar). An antibody to the corresponding N-benzyl-N-methylpiperidinium hapten 5 was found to catalyze the entire reaction sequence. This antibody seems to act purely as a general base and does not catalyze the carbon-carbon bond forming step. Catalysis of the aldol elimination is selective for the disfavored trans-elimination with a single enantiomer of stereoisomer 2a. Catalysis is suppressed by incubating the antibody with a carboxyl-specific reagent, suggesting that a carboxyl group acts as a general base to catalyze the sequence. The antibody is approximately 2.0 x 10(5) times more reactive than acetate for catalysis of the sequence. These experiments demonstrate that catalysis of reactions with several consecutive transition states is possible using catalytic antibodies.
Molecular imprinting is a promising technique for the preparation of synthetic polymers of predetermined specificity. Functional monomers are copolymerized with crosslinkers in the presence of the desired molecule, the imprint molecule. The use of these polymers as chiral stationary phases is discussed. Other applications, such as antibody-mimics, enzyme-like catalysts and sensors, are also focused upon.
VIRTUALLY all synthetic materials with a dynamic function, from catalysts to integrated circuit elements, degrade irreversibly with time. The inevitability of decay is an implicit consideration in the design of materials or molecules that serve these functions, and fabrication methods tend to aim simply at minimizing the rate of decay. Here, by contrast, we describe a molecular catalyst that experiences a thermodynamic and kinetic driving force for its own reassembly and repair under the conditions of catalysis. We show that the multicomponent polyanion cluster alpha-[(CoII)PW11O39]5- self-assembles from four precursor species, containing a total of 28 molecules, and that as it assembles it starts simultaneously to catalyse the epoxidation of alkenes with high selectivity. This conclusion follows from the observation that the kinetics of self-assembly and those of catalysis are closely correlated as the reactions proceed. Should it be fragmented during operation, this polyanion catalyst will therefore experience a thermodynamic and kinetic driving force for its own repair.
An in vitro evolution procedure was used to obtain RNA enzymes with a particular catalytic function. A population of 10(13) variants of the Tetrahymena ribozyme, a group I ribozyme that catalyzes sequence-specific cleavage of RNA via a phosphoester transfer mechanism, was generated. This enzyme has a limited ability to cleave DNA under conditions of high temperature or high MgCl2 concentration, or both. A selection constraint was imposed on the population of ribozyme variants such that only those individuals that carried out DNA cleavage under physiologic conditions were amplified to produce "progeny" ribozymes. Mutations were introduced during amplification to maintain heterogeneity in the population. This process was repeated for ten successive generations, resulting in enhanced (100 times) DNA cleavage activity.
By combining the enormous molecular diversity of the immune system with basic mechanistic principles of chemistry, one can
produce catalytic antibodies that allow control of reactions in ways heretofore not possible. Mechanistic and structural studies
of these antibodies are also providing insights into important aspects of enzymatic catalysis and the evolution of catalytic
function. Moreover, the ability to rationally direct the immune response to generate selective catalysts for reactions ranging
from pericyclic and redox reactions to cationic rearrangement reactions underscores the chemical potential of this and other
large combinatorial libraries.
General acid-base catalysis contributes substantially to the efficacy of many enzymes, enabling an impressive array of eliminations, isomerizations, racemizations, hydrolyses and carbon-carbon bond-forming reactions to be carried out with high rates and selectivities. The fundamental challenge of exploiting similar effects in designed catalysts such as catalytic antibodies is that of correctly positioning the catalytic groups in an appropriate active-site microenvironment. Charge complementarity between antibody and hapten (the template used to induce an antibody) has been used successfully in a number of instances to elicit acids and bases within immunoglobulin combining sites, but the activities of the catalysts obtained by this strategy are generally considerably lower than those of natural enzymes. Here we report that by optimizing hapten design and efficiently screening the immune response, antibodies can be obtained that act effectively as general base catalysts. Thus a cationic hapten correctly mimicking the transition-state geometry of all reacting bonds and bearing little resemblance to the reaction product has yielded carboxylate-containing antibodies that catalyse an E2 elimination with more than 10(3) turnovers per active site and rate accelerations of greater than 10(8). These results demonstrate that very large effects can be achieved by strategic use of haptenic charge.
In a previous study [Beaudry, A. A., & Joyce, G. F. (1992) Science 257, 635-641], an in vitro evolution procedure was used to obtain variants of the Tetrahymena ribozyme with 100-fold improved ability to cleave a target single-stranded DNA under physiologic conditions. Here we report continuation of the in vitro evolution process to achieve 10(5)-fold overall improvement in DNA-cleavage activity. In addition, we demonstrate that, by appropriate manipulation of the selection constraints, one can optimize specific catalytic properties of the evolved ribozymes. We first reduced the concentration of the DNA substrate 50-fold to favor ribozymes with improved substrate binding affinity. We then reduced the reaction time 12-fold to favor ribozymes with improved catalytic rate. In both cases, the evolving population responded as expected, first improving substrate binding 25-fold, and then improving catalytic rate about 50-fold. The population of ribozymes has undergone 27 successive generations of in vitro evolution, resulting in, on average, 17 mutations relative to the wild type that are responsible for the improved DNA-cleavage activity.
Mimicking the efficiency of enzyme catalysis is a daunting challenge. An enzyme selectively binds and stabilizes the transition state (s) for a particular reaction. Artificial host systems can bind ground states just as efficiently, and rate enhancements comparable to those in enzymatic reactions can be achieved by bringing catalytic and substrate groups together in intramolecular reactions. But the combination of selective binding and efficient catalysis remains elusive. The best enzyme mimics currently known are catalytic antibodies. They bind transition-state analogues with high affinity, but their catalytic efficiency generally falls far short of that of enzymes. Thorn et al. recently described an antibody that catalyses the eliminative ring-opening of a benziosoxazole "exceptionally efficiently" using carboxylate as the general base, raising the intriguing possibility that this high efficiency derives from precise positioning of catalytic and substrate groups. Here we show that familiar 'off-the-shelf' proteins--serum albumins--catalyse the same reaction at similar rates, using a lysine side-chain amino group as the catalytic general base. Comparisons suggest that formal general base catalysis is of only modest efficiency in both systems, and that the antibody catalysis is boosted by a non-specific medium effect.
Molecular and supramolecular diversity may be generated, respectively, by reversible, covalent or noncovalent self-assembly of basic components whose various potential combinations in number and nature represent a virtual combinatorial library. This concept is applied to the induction of inhibitors of carbonic anhydrase (CA) by reversible recombination of aldehyde and amine components. It is found that the presence of CA favors the formation of those condensation compounds that may be expected to present the strongest binding to the CA active site. The virtual combinatorial library approach may represent a powerful methodology for the discovery of substrates, inhibitors, receptors, catalysts, and carriers for a variety of processes.
In Tom Stoppard's famous play [Rosencrantz and Guildenstern are Dead], the ill-fated heroes toss a coin 101 times. The first 100 times they do so the coin lands heads up. The chance of this happening is approximately 1 in 10(30), a sequence of events so rare that one might argue that it could only happen in such a delightful fiction. Similarly rare events, however, may underlie the origins of biological catalysis. What is the probability that an RNA, DNA, or protein molecule of a given random sequence will display a particular catalytic activity? The answer to this question determines whether a collection of such sequences, such as might result from prebiotic chemistry on the early earth, is extremely likely or unlikely to contain catalytically active molecules, and hence whether the origin of life itself is a virtually inevitable consequence of chemical laws or merely a bizarre fluke. The fact that a priori estimates of this probability, given by otherwise informed chemists and biologists, ranged from 10(-5) to 10(-50), inspired us to begin to address the question experimentally. As it turns out, the chance that a given random sequence RNA molecule will be able to catalyze an RNA polymerase-like phosphoryl transfer reaction is close to 1 in 10(13), rare enough, to be sure, but nevertheless in a range that is comfortably accessible by experiment. It is the purpose of this Account to describe the recent advances in combinatorial biochemistry that have made it possible for us to explore the abundance and diversity of catalysts existing in nucleic acid sequence space.