Molecular Recognition Studies Research Articles

Templated Organic Synthesis. Edited by F. Diederich (diederich@org.chem.ethz.ch) and Peter J. Stang (stang@chemistry.chem.utah.edu). Wiley-VCH: Weinheim. 1999. XX+411 pp. 268 DM. ISBN 3-527-29666-2

Physicochemical theoretical development has been dwarfed by the abundant experimental achievements in molecular recognition studies, including the template effects reported in this book [1-3].[...]

Correlation of structural and physico-chemical parameters with the bioactivity of alkylated derivatives of indole-3-acetic acid, a phytohormone (auxin).

As part of molecular recognition studies on the phytohormone indole-3-acetic acid (IAA) a series of alkylated IAAs has been examined. Phenyl-ring substitution (alkyl = methyl and ethyl) at positions 4-, 6- or 7- as well as pyrrole substitution at the 2-site resulted in the six compounds which are analyzed: 2-Me-IAA, 4-Me-IAA, 6-Me-IAA, 7-Me-IAA, 4-Et-IAA and 6-Et-IAA. The structure-activity relationships investigated include those between the geometrical parameters of the molecular structures determined by X-ray analysis, the growth-promoting activities in the Avena coleoptile straight-growth bioassay and relative lipophilicities calculated from retention times on a reversed-phase HPLC column and from R(F) values in reversed-phase TLC. Lipophilicities are correlated with the moments of inertia, average polarizability, molecular mass, and the van der Waals radii of the ring substituents. The influence of substitution on the electronic properties of the indole ring and its geometry is discussed on the basis of the UV and 1H NMR spectra.

Disulfide Bonded Cyclic Peptide Dimers and Trimers: An Easy Entry to High Symmetry Peptide Frameworks

The preparation of the large molecules required for molecular recognition studies in practical quantities is possible by assembling large building blocks with the desired chemical and conformational properties. The versatility of solid-phase peptide synthesis and the present knowledge of the rules that govern the adoption of particular secondary structures by peptides can be usefully exploited in this context. The analysis of the symmetry properties of many target geometrical structures naturally leads to their materialization as cyclic oligomers. Disulfide bond formation under either kinetic or thermodynamic control offers an easy entry to these systems.

Molecular Assemblies of Cholic Acid Derivatives and Use of Their Inclusion Spaces

Cholic acid derivatives form crystalline inclusion compounds with various organic substances. More than two hundred their crystal structures have been used in the study of molecular recognition through their assemblies. Host molecules were noted to combine via intermolecular hydrogen bonds to produce diversible assemblies comprised of layers and helices. The explanation for these assemblies is that the hosts have characteristic facial structures with chirality, directionality and amphiphilicity. Multiple hydrogen bonding groups are essential to the formation of the assemblies. Slight change in the host and guest molecules may frequently lead to great change in the assemblies due to exchange of the corresponding hydrogen bonding network. Different intermolecular hydrogen bonding networks produced polymorphic crystals, depending on the particular guest components. The hosts exhibited very different inclusion ability toward aliphatic alcohols due to additional hydrogen bonding groups situated between host and guest molecules rather than among host molecules. Inclusion spaces are effective as fields for enantioselective resolution and polymerization reactions. This study has demonstrated on analogy between cholic acid derivatives and proteins, and on the basis of which, chiral and sequential carbon chains may be concluded to express their information through molecular assemblies with multiple hydrogen bonds.

Molecular recognition study on a supramolecular system. Part 21. Inclusion complexation thermodynamics of aliphatic alcohols by organoselenium modified β-cyclodextrins

The spectrophotometric titrations have beenperformed at 25–40 °C in aqueous solution to give the complexstability constants and the thermodynamic parametersfor the stoichiometric 1 : 1 inclusion complexation ofvarious aliphatic alcohols withmono[6-(phenylseleno)-6-deoxy]-β-cyclodextrin (2),mono[6-(o-, m-,p-tolylseleno)-6-deoxy]-β-cyclodextrin (3–5),mono[6-(p-chloro-phenyl-seleno)-6-deoxy]-β-cyclodextrin(6), mono[6-(benzylseleno)-6-deoxy]-β-cyclodextrin (7) and mono[6-(naphthaleneseleno)-6-deoxy]-β-cyclodextrin(8). On thebasis of the present and previous results, themolecular binding abilities and selectivities forguest aliphatic alcohols of the host β-cyclodextrinderivatives (2–8) are discussed comparatively and globallyfrom the thermodynamic point of view. Thethermodynamic parameters obtained are criticalfunctions of the size/shape of aliphatic alcohols, andthe position and type of the substituent introduced tothe aromatic ring of β-cyclodextrin's sidearm,which are elucidatedin terms of the conformational, electrostatic,hydrogen-bonding, and hydrophobic effects.

The Paternò-Büchi Reaction ofN-Acyl Enamines and Aldehydes - The Development of a New Synthetic Method and its Application to Total Synthesis and Molecular Recognition Studies

The Paterno-Buchi reaction of aldehydes and N-acyl or N-alkoxycarbonyl enamines represents a short and efficient method for the stereoselective synthesis of cis-3-aminooxetanes. Consecu- tive ring opening reactions facilitate the preparation of cyclic and acyclic 1,2-amino alcohols. The application of a photocycloaddi- tion/ring opening sequence to the synthesis of an enantiomerically pure pyrrolidinol alkaloid is discussed. The use of cyclic NH-acidic lactams as alkene components in the photocycloaddition allows the study of host-guest interactions. An achiral guest can be attached to a chiral host by two hydrogen bonds in such a way that a dis- crimination of enantiotopic faces is possible.

Molecular recognition studies on supramolecular systems. 26. Inclusion complexation of natural and amino acid modified β-cyclodextrins with model substances: ANS and RhB molecules

The three novel amino acid β-cyclodextrin derivatives, l-methionine ( l-Met-β-CD, 2), l-proline ( l-Pro-β-CD, 3), and l-isoleucine ( l-Ile-β-CD, 4) modified β-cyclodextrins have been synthesized, and their inclusion complexation behavior was investigated through fluorescence spectrometry. Selecting both 8-anilino-1-napthalenesulfonic acid ammonium salt (ANS) and Rhodamine B (RhB) as spectral probes, spectrofluorometric titrations have been performed in aqueous phosphate buffer solution (pH 7.20) to calculate the complex stability constants ( K s) for 1:1 inclusion complexation of amino acid modified β-cyclodextrins ( 2–4) with the two guest molecules. The results obtained indicate that the binding ability of modified β-cyclodextrins ( 2–4) with ANS increased as compared with the parent β-CD ( 1), where decreased with RhB. The molecular binding ability of ANS and RhB guests by natural ( 1) and modified β-cyclodextrins ( 2–4) was discussed from the size/shape fit concept.

Density functional study of molecular recognition and reactivity of thiourea derivatives used in sensors for heavy metal polluting cations

The geometry and electronic structure of four thiourea derivatives, 1,3-diphenylthiourea, 1-furoyl-3-phenylthiourea, 1-furoyl-3-bencyl-3-phenylthiourea, and 1-furoyl-3-hydroxyethylthiourea, were determined by means of the DGauss program, which is a density functional theory based method. Calculations performed were of the all-electron type at the local spin density level of theory. Orbital basis sets of DZVP2 quality were used for the H, C, N, O, and S atoms. The frontier molecular orbitals were characterized. They account for the observed selectivity of these molecules toward the following cations: Pb2+, Hg2+, Cd2+, Ag+, Cu2+, Ni2+, Zn2+, and Mn2+. Moreover, the localization of the highest occupied molecular orbital coupled with a high negative charge over the sulfur center accounts for the softness of the active sulfur site. Indeed, a metal-sulfur interaction is mainly responsible for the observed electrochemical behaviors in ion-selective electrodes toward the different cations. These results agree with the estimated softness reported previously for these cations. Our calculations explain the observed differences of reactivity for these neutral carriers through their interactions with heavy metal cations. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 80: 609–622, 2000

P2-receptor agonists: From molecular recognition studies to potential clinical applications

The elucidation of the parameters governing molecular recognition of modified-adenine nucleotides by P2Y-receptors is described. In addition, parameters effecting the enzymatic stability of these and other P2-R ligands, towards NTPDase, a major enzyme in extracellular nucleotides metabolism, are also discussed. These findings are significant for the development of potent and enzymatically stable P2Y-R ligands. Furthermore, 8-thioether-ATP derivatives, found inactive at P2Y- and P2X-receptors, and stable to NTPDase hydrolysis, were developed as specific and potent NTPDase inhibitors. The latter are important for potentiation of the pharmacological effect of endogenous ATP and ADP and of synthetic P2-R ligands. The knowledge described above was used to develop two new series of pharmacologically active P2-R ligands. Thus, a series of 2-thioether-ATP-α-S derivatives was synthesized. These compounds were identified as potent P2Y 1 -R ligands and potent insulin secretagogues, active at nM concentrations. These analogues also possess relative enzymatic stability and high chemical stability. However, their ability to also induce vascular effects prevents their further use as potential anti-diabetic agents. In addition, a series of non-nucleotide P2X-Rs ligands with cardiac activity was identified. These ligands are xanthine-alkylphosphates, which exert the same effects as ATP regarding Ca 2+ elevation and contractility of cardiac cells. Owing to the selectivity of these ligands to certain P2X-R subtypes, they are expected to serve as prototypes for selective compounds aiming at cardiac disorders mediated through certain P2X-receptors.

Criteria of evaluation and of interpretation of Sepharose drug IgE‐RIA to anaesthetic drugs

The detection of antidrug specific IgE in serum is usually performed by a sandwich-type immunoassay in which the serum IgE is first adsorbed to a reactive phase and subsequently quantified via the binding of an anti-IgE tracer. The preparation of a new drug-reactive phase requires one to establish carefully different steps of validation: 1) criteria of positivity of control sera 2) competitive inhibition assays with the soluble drug, which should include the determination of the inhibition constant rather than estimation of a single inhibition percentage, especially when the assay is performed for the identification of determinants 3) estimation of nonspecific binding of IgE to the solid phase, including hydrophobic binding. The competitive inhibition depends on the concentration of the competitor and of IgE in the test-tube and the concentration of reactive drug bound to the solid phase. We have improved the inhibition assay by performing the Dixon test for calculating the inhibition constant (Ki) of the competitor. The Ki of six different muscle relaxants was determined in 12 patients who experienced an anaphylactic reaction to muscle relaxants. The values ranged between 1.5 nM and 2.5 microM. This confirmed the great heterogeneity of drug IgE cross-reactivity among patients. The Ki value of the incriminated drug was the lowest (affinity, the highest) in eight of the 12 patients. It was better correlated to clinical data than the classical inhibition assay. A hydrophobic environment seemed to be necessary, close to the quaternary ion, to allow IgE binding to the muscle relaxant. By contrast, in tiemonium, a hydroxyl group present at a distance of about 3 A from the quaternary ion may explain why this molecule had a high Ki (microM). In conclusion, it should be recommended, in molecular-recognition studies, that the inhibition constant of the soluble drug and of the related compounds be determined to complement the experiments based only on hapten inhibition assays.

Automated docking of peptides and proteins by using a genetic algorithm combined with a tabu search.

A genetic algorithm (GA) combined with a tabu search (TA) has been applied as a minimization method to rake the appropriate associated sites for some biomolecular systems. In our docking procedure, surface complementarity and energetic complementarity of a ligand with its receptor have been considered separately in a two-stage docking method. The first stage was to find a set of potential associated sites mainly based on surface complementarity using a genetic algorithm combined with a tabu search. This step corresponds with the process of finding the potential binding sites where pharmacophores will bind. In the second stage, several hundreds of GA minimization steps were performed for each associated site derived from the first stage mainly based on the energetic complementarity. After calculations for both of the two stages, we can offer several solutions of associated sites for every complex. In this paper, seven biomolecular systems, including five bound complexes and two unbound complexes, were chosen from the Protein Data Bank (PDB) to test our method. The calculated results were very encouraging-the hybrid minimization algorithm successfully reaches the correct solutions near the best binded modes for these protein complexes. The docking results not only predict the bound complexes very well, but also get a relatively accurate complexed conformation for unbound systems. For the five bound complexes, the results show that surface complementarity is enough to find the precise binding modes, the top solution from the tabu list generally corresponds to the correct binding mode. For the two unbound complexes, due to the conformational changes upon binding, it seems more difficult to get their correct binding conformations. The predicted results show that the correct binding mode also corresponds to a relatively large surface complementarity score. In these two test cases, the correct solution can be found in the top several solutions from the tabu list. For unbound complexes, the interaction energy from energetic complementarity is very important, it can be used to filter these solutions from the surface complementarity. After the evaluation of the energetic complementarity, the conformations and orientations close to the crystallographically determined structures are resolved. In most cases, the smallest root mean square distance (r.m.s.d.) from the GA combined with TA solutions is in a relatively small region. Our program of automatic docking is really a universal one among the procedures used for the theoretical study of molecular recognition.

ChemInform Abstract: Synthesis of Novel Acridino‐ and Phenazino‐18‐crown‐6 Ligands and Their Optically Pure Dimethyl‐Substituted Analogues for Molecular Recognition Studies.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Molecular Recognition Studies on Supramolecular Systems. 22. Size, Shape, and Chiral Recognition of Aliphatic Alcohols by Organoselenium-Modified Cyclodextrins.

A novel cyclodextrin derivative, mono[6-(p-methoxyphenylseleno)-6-deoxy]-beta-cyclodextrin (2), has been synthesized and characterized by elemental analysis and mass, FT-IR, and (1)H NMR spectroscopy. The stability constants (K(S)) of the inclusion complexation of 2 and mono[6-(p-tolylseleno)-6-deoxy]-beta-cyclodextrin (3) with a series acyclic and cyclic alcohols have been determined in phosphate buffer solution (pH 7.20) at 25 degrees C by using the circular dichroism spectral titration method. Although the stability constants obtained for the inclusion complexation of 2 and 3 with aliphatic alcohols are generally smaller than those for native beta-cyclodextrin, the modified cyclodextrins can recognize both the size and chirality of the guest molecules. Interestingly, the complex stability constants (log K(S)), or the Gibbs free energy change (-DeltaG degrees ), increase linearly with increasing number of carbon atoms in the guest molecule (N(C)), irrespective of the topological differences of acyclic, cyclic, and bicyclic guests. The unit increment of complex stability per methylene (-dDeltaG degrees /dN(C)) is not appreciably affected by the difference of the host's substituent but is a critical function of the guest topology, affording distinctly different -dDeltaG degrees /dN(C) values of 2.4 and 2.9 kJ mol(-)(1) for alkanols and cycloalkanols, respectively. In the complexation of chiral guests with 2 and 3, the observed enantioselectivities, as measured by the stability difference (DeltaDeltaG degrees ), are mostly in the range of 1-2 kJ mol(-)(1).

Synthesis of novel acridino- and phenazino-18-crown-6 ligands and their optically pure dimethyl-substituted analogues for molecular recognition studies

Novel acridino- and phenazino-18-crown-6 ligands 5 and 6 were prepared from acridine-4,5-diol ( 9) and phenazine-1,9-diol ( 10) with tetraethylene glycol di- p-tosylate ( 11) using potassium teri-butoxide as a base in THF. New optically pure dimethyl-substituted acridino- and phenazino-18-crown-6 ligands (R,R)-7 and (R,R)-8 were also prepared by treating 9 and 10 with optically pure dimethyl-substituted tetraethylene glycol di- p-tosylate [(S,S)-18] . Molecular recognition studies on these novel ligands are underway.

Molecular recognition study on supramolecular systems. Part 19.† Circular dichroism studies of inclusion complexation of aliphatic alcohols by organoselenium modified β-cyclodextrins

Complex stability constants for the stoichiometric 1∶1 inclusion complexation of various aliphatic alcohols with mono[6-(benzylseleno)-6-deoxy]-β-cyclodextrin (1), mono[6-(phenylseleno)-6-deoxy]-β-cyclodextrin (2), and mono[6-(o-, m-, or p-tolylseleno)-6-deoxy]-β-cyclodextrin (3–5) have been obtained by spectrophotometric titrations at 25 °C in phosphate buffer solution (pH = 7.2). The Cotton effects observed indicate that the aromatic moiety penetrates shallowly into the hydrophobic cavity of cyclodextrin. Therefore, the aromatic moiety can be taken as an induced circular dichroism (ICD) probe to investigate the inclusion phenomena. The results obtained demonstrate that the modified β-cyclodextrin (1) is highly sensitive to the size/shape and conformational rigidity of guest molecules, giving fairly good molecular selectivity up to 114 for adamantan-1-ol/cyclopentanol and relatively high E/Z selectivity up to 2.7 for geraniol/nerol. Interestingly, all of the modified β-cyclodextrins employed displayed relatively good enantioselectivity for (+)-enantiomers of borneol and menthol. The molecular recognition ability and enantioselectivity for aliphatic alcohols of the modified β-cyclodextrins (1–5) are discussed from the viewpoints of the size/shape–fit relationship and the multipoint recognition mechanism.

Nucleic acid syntheses and molecular recognition

Syntheses of nucleic acids are of importance not only in the natural product chemistry but also in the molecular recognition study in biology. This review describes syntheses of RNA and DNA, which were found to be related each other. Deoxyinosine probes were developed for cloning genes with degenerated codons. Synthetic genes for c-Ha-ras and T4 endonuclease V provided new approaches in recognition of nucleic acids by proteins. Antibodies specific for photo-damaged pyrimidines in DNA have been studied by cloning and mutating their genes.

Spectroscopic Study of Molecular Recognition of Ions by Chromogenic Calix[4]arene Derivatives

The complexation properties of three new chromogenic calix[4]arenes ( 1a–c) with aliphatic amines and alkali/alkali earth metal ions have been studied by UV/Vis spectroscopy. 1c shows the greatest complex forming ability and it is selective for Li+, Ca2+ and certain amines in polar solvents.

Unprecedented concentration dependent chemical shift variation in 1H-NMR studies: A caveat in the investigations of molecular recognition and structure elucidation

Our studies show that changes in concentration can lead to significant changes in the 1H chemical shifts of non-exchangeable hydrogens, and thus, in the NMR spectra. An important observation, as described for quinoline and other aromatic compounds, is that different protons shift to different extents in the same solvent as the concentration of the solute is varied, leading to overlap/coalescence or cross over of proton signals. Chemical shift variations can be so pronounced that they lead to misleading 1D and 2D spectral signatures. Such concentration dependent spectral pattern changes have far reaching implications in the use of 1H-NMR spectroscopy for structure elucidation, spectral characterization, determination of purity and the study of molecular recognition. Changes in concentration shift different protons to different extents, leading to coalescence or crossover of 1H-NMR signals. Such spectral changes have far reaching implications for the use of 1H-NMR spectroscopy for structure elucidation and study of molecular recognition. [Display omitted]

Combinatorial libraries: studies in molecular recognition

In recent years, combinatorial libraries have become a major tool for drug discovery and drug development. Along the way, one potential use of combinatorial chemistry libraries almost been neglected: the basic study of intermolecular interactions. Especially "one-bead-one-structure" libraries can be a powerful means for the discovery of ligands to synthetic receptors and vice versa. Encoded combinatorial libraries have been used to disclose ligands for well designed macrocyclic host molecules and to elucidate their specificities for peptide sequences. These studies led via receptors with more flexibility to simple host molecules without elaborate design that are accessible to combinatorial synthesis. These findings open a realm of possibilities and applications. An intriguing one is the development of chemical sensors for analytes that are otherwise hard or only unspecifically detected. Furthermore, such libraries and the techniques that were developed to handle them have been used to find new catalysts and enzyme mimics. In this review we put the emphasis on studies involving "one-bead-one-structure" libraries. We will review the techniques to generate them, to encode and analyze them, and to assay them. We will describe their past usage and the intriguing results of these studies and point out interesting new applications of such libraries for the study of non-covalent intermolecular interactions.

An Easy Entry to a New High-Symmetry, Large Molecular Framework for Molecular Recognition Studies and de Novo Protein Design. Solvent Modulation of the Spontaneous Formation of a Cyclic Monomer, Dimer, or Trimer from a Bis-cysteine Peptide

Spontaneous oxidation of a short palindromic peptide with the sequence Ac-C-X-K-L-H-A-E-L-S-S-L-E-A-H-L-K-B-C-G-NH2 (X = Aib) provides up to three different cyclic products: a monomer with an intrachain disulfide bond, an antiparallel dimer, and a trimer with two parallel and an antiparallel chain. Control over the relative amount of the different products can be achieved by adding different amounts of TFE that modulate the population of the α-helix conformation during the reaction. Regioselective disulfide formation affords also the parallel dimer, which was not formed spontaneously, as well as the three possible noncyclic dimers with two protected cysteines and a single disulfide bond. CD spectroscopic studies of these dimers as well as NMR and CD studies of a peptide with the two cysteines replaced by Leu provide the basis for understanding the control of the spontaneous oxidation by TFE and the strong discrimination between parallel and antiparallel dimers. The special topological properties of this ...