A class II aldolase mimic

[structures: see text] A class II aldolase-mimicking synthetic polymer was prepared by the molecular imprinting of a complex of cobalt (II) ion and either (1S,3S,4S)-3-benzoyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (4a) or (1R,3R,4R)-3-benzoyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (4b) in a 4-vinylpyridine-styrene-divinylbenzene copolymer. Evidence for the formation of interactions between the functional monomer and the template was obtained from NMR and VIS titration studies. The polymers imprinted with the template demonstrated enantioselective recognition of the corresponding template structure, and induced a 55-fold enhancement of the rate of reaction of camphor (1) with benzaldehyde (2), relative to the solution reactions, and were also compared to reactions with a series of reference polymers. Substrate chirality was observed to influence reaction rate, and the reaction could be competitively inhibited by dibenzoylmethane (6). Collectively, the results presented provide the first example of the use of enantioselective molecularly imprinted polymers for the catalysis of carbon-carbon bond formation.     

Rational design of new bifunctional inhibitors of type II dehydroquinase

Selective inhibitors of type II dehydroquinase were rationally designed to explore a second binding-pocket in the active-site. The molecular modelling, synthesis, inhibition studies and crystal structure determination are described.     

Rational design of new class of BH3-mimetics as inhibitors of the Bcl-xL protein

The Bcl-2 family of proteins plays an important role in the intrinsic pathway of cell apoptosis. Overexpression of pro-survival members of this family of proteins is often associated with the development of many types of cancer and confers resistance against conventional therapeutic treatments. Accordingly, antagonism of its protective function has emerged as an encouraging anticancer strategy. In the present work, we use a pharmacophore for describing interaction between the BH3 domain of different pro-apoptotic members and the pro-survival protein Bcl-x(L) in order to identify new lead compounds. In the strategy followed in the present work, the pharmacophore was derived from molecular dynamics studies of different Bcl-x(L)/BH3 complexes. This pharmacophore was later used as query for 3D database screening. Hits obtained from the search were computationally assessed, and a subset proposed for in vitro testing. Two of the 15 compounds assayed were found able to disrupt the Bcl-x(L)/Bak(BH3) complex with IC(50) values in the lower micromolar range. Finally, docking studies were performed to explore the binding mode of these compounds to Bcl-x(L) for further modifications.     

Rational design of large-spin clusters based on the hexacopper(II) siloxanolate core

The hexacopper(II) siloxanolate cage [Cu₆{(PhSiO₂)₆}₂(BuOH)₅]·3 ⁿBuOH has been synthesized by reaction between CuCl₂ and potassium phenylsiloxanolate in n-butanol, and characterized by single-crystal X-ray diffraction, magnetic measurements and high-frequency EPR (HF-EPR). The complex exhibits a torus-like structure featuring a layer of six copper(II) ions sandwiched between two cyclic (PhSiO₂)₆^6– ligands and surrounded by ⁿBuOH molecules. The magnetic properties are characterized by moderate ferromagnetic exchange interactions between the S = 1/2 copper(II) centres to give an S = 3 ground spin state. Variable temperature HF–EPR spectra evidence a hard-axis magnetic anisotropy with g_|| = 2.063, g_⊥ = 2.225 and D = 0.31 cm^–1. The cage is very soluble in organic solvents and, upon exchange of the labile ⁿBuOH ligands, it functions as a high-spin hexatopic receptor for monodentate units. Reaction with the trigonal bipyramidal copper(II) mononuclear [Cu(tmpa)CN]⁺ in CHCl₃/MeOH solution (tmpa = tris(2-pyridylmethyl)amine) affords the decacopper(II) complex [Cu₆{(PhSiO₂)₆}₂{NCCu(tmpa)}₄](PF₆)₄, whose X-ray structure and magnetic behaviour are presented. To cite this article: G.L. Abbati et al., C. R. Chimie 6 (2003).     

Rational design of a novel fluorescent biosensor for beta-lactam antibiotics from a class A beta-lactamase

A rational design strategy was used to construct a sensitive "turn-on" biosensor for beta-lactam antibiotics and beta-lactamase inhibitors from a class A beta-lactamase mutant with suppressed hydrolytic activity. A fluorescein molecule was attached to the 166 position on the Omega-loop of the E166C mutant close to the active site of the beta-lactamase. Upon binding with antibiotics or inhibitors, the flexibility of the Omega-loop allows the fluorescein molecule to move out from the active site and be more exposed to solvent. This process is accompanied by an increase in the fluorescence of the labeled enzyme. The fluorescence intensity of the biosensor increases with the concentration of antibiotics or inhibitors, which can detect penicillin G at concentrations as low as 50 nM in water. This approach opens a possibility for converting highly active and nonallosteric enzymes into substrate-binding proteins for biosensing purposes.     

Rational design of porous titanophosphates

To rationally design new nanoporous materials based on titanophosphates, a small library of titanium phosphate crystalline nanoporous compounds has been build up and its compounds have been investigated by X-ray diffraction and by in- and ex-situ NMR. The main trends of the unusual titanium solution chemistry, of the prenucleation building units and of their assembling have been established. The classical trial and error strategy can therefore be replaced by a better control of the steps leading to the final targeted network.     

Rational design of DNA nanoarchitectures

DNA has many physical and chemical properties that make it a powerful material for molecular constructions at the nanometer length scale. In particular, its ability to form duplexes and other secondary structures through predictable nucleotide-sequence-directed hybridization allows for the design of programmable structural motifs which can self-assemble to form large supramolecular arrays, scaffolds, and even mechanical and logical nanodevices. Despite the large variety of structural motifs used as building blocks in the programmed assembly of supramolecular DNA nanoarchitectures, the various modules share underlying principles in terms of the design of their hierarchical configuration and the implemented nucleotide sequences. This Review is intended to provide an overview of this fascinating and rapidly growing field of research from the structural design point of view.     

Rational design of polymer colloids

Recent advances in understanding of the fundamental mechanistic events in emulsion polymerization give the potential for rational design of new materials based on polymer colloids. It is now possible to design a new industrial process from first principles, based on well‐understood mechanistic principles. An overview of recent developments in the fundamental science of emulsion polymerization is given, with examples of the application of this knowledge to topologically‐controlled synthesis of novel materials based on natural rubber and polybutadiene seed latexes.     

Rational design of allosteric ribozymes

Background: Efficient operation of cellular processes relies on the strict control that each cell exerts over its metabolic pathways. Some protein enzymes are subject to allosteric regulation, in which binding sites located apart from the enzyme's active site can specifically recognize effector molecules and alter the catalytic rate of the enzyme via conformational changes. Although RNA also performs chemical reactions, no ribozymes are known to operate as true allosteric enzymes in biological systems. It has recently been established that small-molecule receptors can readily be made of RNA, as demonstrated by the in vitro selection of various RNA aptamers that can specifically bind corresponding ligand molecules. We set out to examine whether the catalytic activity of an existing ribozyme could be brought under the control of an effector molecule by designing conjoined aptamer-ribozyme complexes.Results: By joining an ATP-binding RNA to a self-cleaving ribozyme, we have created the first example of an allosteric ribozyme that has a catalytic rate that can be controlled by ATP. A 180-fold reduction in rate is observed upon addition of either adenosine or ATP, but no inhibition is detected in the presence of dATP or other nucleoside triphosphates. Mutations in the aptamer domain that are expected to eliminate ATP binding or that increase the distance between aptamer and ribozyme domains result in a loss of ATP-specific allosteric control. Using a similar design approach, allosteric hammerhead ribozymes that are activated in the presence of ATP were created and another ribozyme that can be controlled by theophylline was created.Conclusions: The catalytic features of these conjoined aptamer-ribozyme constructs demonstrate that catalytic RNAs can also be subject to allosteric regulation — a key feature of certain protein enzymes. Moreover, by using simple rational design strategies, it is now possible to engineer new catalytic polynucleotides which have rates that can be tightly and specifically controlled by small effector molecules.     

Rational design of InhA inhibitors in the class of diphenyl ether derivatives as potential anti-tubercular agents using molecular dynamics simulations

A series of diphenyl ether derivatives were developed and showed promising potency for inhibiting InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, leading to the lysis of Mycobacterium tuberculosis. To understand the structural basis of diphenyl ether derivatives for designing more potent inhibitors, molecular dynamics (MD) simulations were performed. Based on the obtained results, the dynamic behaviour in terms of flexibility, binding free energy, binding energy decomposition, conformation, and the inhibitor–enzyme interaction of diphenyl ether inhibitors were elucidated. Phe149, Tyr158, Met161, Met199, Val203 and NAD+ are the key residues for binding of diphenyl ether inhibitors in the InhA binding pocket. Our results could provide the structural concept to design new diphenyl ether inhibitors with better enzyme inhibitory activity against M. tuberculosis InhA. The present work facilitates the design of new and potentially more effective anti-tuberculosis agents.     

Rational design of light-controllable polymer micelles

Amphiphilic block copolymer (BCP) micelles are nanocarriers that hold promise for controlled delivery applications. This account highlights our recent works on light-dissociable BCP micelles. We have designed and developed light-responsive amphiphilic BCPs whose micellar aggregates (core-shell micelles and vesicles) can be disrupted by light exposure. The basic strategy is to incorporate a chromophore into the structure of the hydrophobic block, whose photoreaction can result in a conformational or structural change that shifts the hydrophilic/hydrophobic balance toward the destabilization of the micelles. Using various chromophores including azobenzene, pyrene and nitrobenzene, we have achieved both reversible and irreversible dissociation of BCP micelles upon illumination with UV/visible or near infrared light. The demonstrated rational design principle based on light-changeable or light-switchable amphiphilicity is general and can be applied to many polymer/chromophore combinations. This opens the door to developing photocontrollable polymer nanocarriers offering control over when and where the release of loaded agents takes place.     

Rational design of lanthanide binding peptides

Lanthanide-binding peptides are very attractive for the design of bioprobes. Indeed, they combine the amazing properties of lanthanide ions, such as their time-resolved luminescence (Eu, Tb) or electronic relaxation (Gd) to the characteristics of the peptide scaffold, such as large solubility in water and ability to recognize biological substrates. Peptides derived from natural amino acids are reviewed in a first section. Some of their lanthanide complexes have already demonstrated their efficiency in determining protein structures and functions. Then, we will show how insertion of chelating unnatural amino acids modulates peptide-lanthanide complexes properties, such as luminescence and stability.     

Rational design of a calcium-binding protein

Calcium ions play key roles as structural components in biomineralization and as a second messenger in signaling pathways. We have introduced a de novo designed calcium-binding site into the framework of a non-calcium-binding protein, domain 1 of CD2. The resulting protein selectively binds calcium over magnesium with calcium-binding affinity comparable to that of natural extracellular calcium-binding proteins (K(d) of 50 microM). This experiment is the first successful metalloprotein design that has a high coordination number (seven) metal-binding site constructed into a beta-sheet protein. Our results demonstrate the feasibility of designing a single calcium-binding site into a host protein, taking into account only local properties of a calcium-binding site obtained by a survey of natural calcium-binding proteins and chelators. The resulting site exhibits strong metal selectivity, suggesting that it should now be feasible to understand and manipulate signaling processes by designing novel calcium-modulated proteins with specifically desired functions and to affect their stability.     

Rational design of chiral nanoscale adamantanoids

[formula: see text] Utilizing coordination as a motif, the self-organization of six ditopic and four tritopic building blocks leads to the formation of nanoscale adamantanoid frameworks.     

Reversibility effects on the stereoselectivity of Pt(II)-mediated cascade poly-ene cyclizations

Cyclization of 1,5-dienes bearing nucleophilic traps with electrophilic trisphosphine pincer ligated Pt(II) complexes results in the formation of a polycyclic Pt-alkyl via a Pt(eta2-alkene) intermediate. With electron-rich triphosphine ligands, an equilibrium between the Pt(eta2-alkene) and Pt-alkyl was observed. The position of the equilibrium was sensitive to ligand basicity, conjugate acid strength, solvent polarity, and ring size. In cases where the ligand was electron poor and did not promote retrocyclization, the kinetic products adhering to the Stork-Eschenmoser postulate were observed (E-alkenes give trans-ring junctions). When retrocyclization was rapid, alternative thermodynamic products resulting from multistep rearrangements were observed (cis-[6,5]-bicycles). Under both kinetic and thermodynamic conditions, remote methyl substituents led to highly diastereoselective reactions. In the case of trienol substrates, long-range asymmetric induction from a C-ring substituent was considerably attenuated and only modest diastereoselectivity was observed (approximately 2:1). The data suggest that for a tricyclization, the long-range stereocontrol results from diastereo-selecting interactions that develop during the organization of the nascent rings. In contrast, the bicyclization diastereoselectivities result from reversible cascade cyclization.     

Intramolecular weak interactions in the thermodynamic stereoselectivity of copper(II) complexes with carnosine-trehalose conjugates

The interactions of metal ions with chiral molecules are of particular interest for relevant biochemical processes, as many of them are made possible only with a selected chirality of the stereocenters. In this work we report a study of the stereoselectivity of copper(II) complexes with D-trehalose-L-carnosine and D-trehalose-D-carnosine as a prototypical case of natural chirality selection. The interest in L-carnosine dipeptide is compounded by its antioxidant and antitumor properties, which are further enhanced when combined with D-trehalose. Potentiometric, calorimetric, and UV/circular dichroism (CD) spectroscopic measurements show that the copper(II) dimer of D-trehalose-L-carnosine is more stable than the D-trehalose-D-carnosine diastereoisomeric copper(II) dimer (log β(L)(22-2) - log β(D)(22-2) = 3.6). Free-energy calculations highlight that the cause of this different behavior lies with different intramolecular weak interactions between the diastereoisomers. The different pattern of hydrogen bonds and the different CH-π interactions between the π-electron-rich imidazole and the α-glucose rings are more favorable by 5 kcal mol(-1) in the L dimer.     

Rational design of high-spin biradicaloids in the isobenzofulvene and isobenzoheptafulvene series

The relative energies of singlet biradicaloid and of triplet and singlet biradical electronic states for a series of benzannelated isobenzofulvenes and isobenzoheptafulvenes were calculated at the (u-)B3LYP/6-31G(d), full π-space CASSCF-CASPT2 (≤14 π-e(-)s), and full π-space RASSCF-RASPT2 (≤24 π-e(-)s) levels of theory. Both absolute and relative CASPT2 energies were reproduced quite well by the RASPT2 approach, which can be extended to much larger active spaces. RASPT2 (and DFT) calculations find that increasing benzannelation leads to triplet ground states in both hydrocarbon series, in violation of the classical principle of maximum bonding. This confirmed the expectations that the combined effects of resonance energy and aromaticity could compensate for the extra formal π-bond of the biradicaloid singlet, and that the strong exchange coupling inherent to the embedded trimethylenemethane (TMM) would manifest itself in the biradicaloids. The relative energy of the biradicaloid singlet rises rapidly upon benzannelation, as π-bonding between the high-energy delocalized GVB orbitals decreases. The underlying π-orbital topology is revealed when this weak π-bonding is artificially eliminated by a 1:1 mixing of the nondegenerate HOMO and LUMO to produce an overcorrelated valence bond (OCVB) orbital pair. For members of both biradicaloid series, the OCVB pairs are nondisjoint, revealing a limiting triplet preference with increasing benzannelation. Within the two-electron, two-orbital approximation, the effects of π-bonding in the singlet biradicaloids and orbital localization away from the acene π-system in the triplet biradicals can be analyzed as perturbations of the singlet OCVB biradicals. The application of a VB-based spin coupling scheme is discussed, in which the unpaired electrons of these species can be considered both ferromagnetically and antiferromagnetically coupled, with the strength of the latter strongly dependent on the acene subunit.