Host-guest interaction between cyclen based macrotricyclic ligands and phosphate anions. A potentiometric investigation

The host-guest interaction between orthophosphate, pyrophosphate and triphosphate anions and three cyclen based macrotricyclic ligands possessing ortho- (TOC), meta- (TMC) and para-xylenyl (TPC) linkers was investigated by potentiometric measurements. The ternary species present in solution and their stability constants have been determined. The different behaviours are explained in terms of hydrogen bond formation and coulombic attraction between the organic host and the inorganic guest. The selectivity, illustrated with species distribution diagrams, is discussed. The results unambiguously showed the importance of the distance between the two cyclen cores and emphasized the increasing of the triphosphate species selectivity together with the cavity size of the ligand. A comparison of the present results with those obtained with their mono-bridged homologues is also discussed.     

Multisite molecular receptors and co-systems ammonium cryptates of macrotricyclic structures

Macrotricyclic receptor molecules incorporating [18]-N₂O₄ units have been synthesized. They form mono- and dinuclear ammonium cryptates. Such structures are prototypes of CO-SYSTEMS, whose wide scope as co-receptors, co-catalysts and co-carriers is briefly outlined.     

Oxime-based receptors for mono- and disaccharides

Representatives of a new series of acyclic oxime-based receptors were prepared and their binding properties toward neutral sugar molecules studied. 1H NMR and fluorescence titrations revealed that receptors 2a and 2b, incorporating suitable positioned amine and oxime moieties, are able to form strong 1:1 complexes (Ka1 approximately 10(5) M-1) with dodecyl alpha- and beta-maltoside in chloroform solutions. Furthermore, the binding studies with beta-glucopyranoside indicated the formation of complexes with 1:1 and 1:2 receptor-monosaccharide binding stoichiometry (with overall binding constant beta2 approximately 10(5) M-2). Both hydrogen bonding and interactions of the sugar CH's with the phenyl rings of the receptor contribute to the stabilization of the receptor-sugar complexes. Molecular modeling calculations, synthesis, and binding studies are described.     

Solvent dependent conformational isomerism and ligand oxidation of novel Ru(II) cyclen complexes

The synthesis of cis-[Ru(II)(cyclen)(L)(x)](n+) (cyclen = 1,4,7,10-tetraazacyclododecane and L = 2,2'-bipyridine (bpy), phenanthroline (phen) or 4-cyanopyridinium (4-NCpyH(+))) is reported. The freshly prepared complexes are stable in aprotic solvents and cyclen undergoes oxidative dehydrogenation reaction at high pH. These compounds also present solvent dependent conformational isomerization.     

Tuning selectivity in macrotricyclic carbohydrate receptors; CH-->N mutations in aromatic spacers

Dipicolinoyl spacer groups are used to control the conformational and H-bonding properties of tricyclic carbohydrate receptors 3 and 4. Binding selectivities are changed in relation to all-isophthaloyl system 1b.     

Molecular dynamics and conformational kinetics of mono- and disaccharides in aqueous solution.

Acoustical attenuation spectra between 10 kHz and 2 GHz, complex dielectric spectra between 300 kHz and 40 GHz, and time-resolved non-equilibrium measurements are reported for aqueous solutions of various mono- and disaccharides with and without 2:1 valent salts. The spectra reveal a variety of relaxation regimes with relaxation times between 1 micros and 10 ps. In addition, the time-resolved observations enable the study of the mutarotation with relaxation times on the order of 10(3) s. Variation of the concentration and temperature as well as a careful choice of the saccharides allow a discussion of the relaxation processes in terms of a chair-chair ring inversion, two modes of pseudorotation, an exocyclic hydroxymethyl group rotation, a carbohydrate-carbohydrate association, and, in the disaccharide solutions, a rotation of the rings relative to another. Salt-containing solutions show also relaxation phenomena reflecting different steps cation-carbohydrate association and variations in the carbohydrate conformational isomerizations and associations due to interactions with cations.     

Chemical shift assignment and conformational analysis of monoalkylated acylguanidines

Monoalkylated acylguanidines are important functional groups in many biologically active compounds and additionally applied in coordination chemistry. Yet a straightforward assignment of the individual NH chemical shifts and the acylguanidine conformations is still missing. Therefore, in this study, NMR spectroscopic approaches for the chemical and especially the conformational assignment of protonated monoalkylated acylguanidines are presented. While NOESY and ³J_{H, H} scalar couplings cannot be applied successfully for the assignment of acylguanidines, ⁴J_{H, H} scalar couplings in ¹H,¹H COSY spectra allow for an unambiguous chemical shift and conformational assignment. It is shown that these ⁴J_{H, H} long‐range couplings between individual acylguanidinium NH resonances are observed solely across all‐trans (w) pathways. Already one cis orientation in the magnetisation transfer pathway leads to signal intensities below the actual detection limit and significantly lower than cross‐peaks from ²J_{NH, NH} couplings or chemical exchange. However, it should be noted that also in the case of conformational exchange being fast on the NMR time scale, averaged cross‐peaks from all‐trans ⁴J_{H, H} scalar couplings are detected, which may lead at first glance to an incomplete or even wrong conformational analysis. Copyright © 2010 John Wiley & Sons, Ltd.     

Effect of lanthanide shift reagents on conformational equilibria

The conformational equilibrium constants for a series of 1-alkyl substituted cyclohexanols have been determined using a lanthanide shift reagent, and the results compared with other methods. In comparison to other technique greater preference is shown by the hydroxyl group for the equatorial position. This is rationalized by the effect on the equilibrium of the bulky shift reagent.     

Synthesis and conformational analysis of 6-C-methyl-substituted 2-acetamido-2-deoxy-beta-D-glucopyranosyl mono- and disaccharides

Several 6-C-substituted 2-acetamido-2-deoxy-beta-D-glucopyranosides (beta-D-GlcNAc monosaccharides 1a-3a and 1,4-linked disaccharides 1b-3b) were studied by solution NMR spectroscopy. Conformational analysis of the (6S)- and (6R)-C-methyl-substituted beta-d-GlcNAc monosaccharides indicates that the stereodefined methyl groups impose predictable conformational biases on the exocyclic C-5-C-6 bond, as determined by (1)H-(1)H and (13)C-(1)H coupling constants. Variable-temperature NMR experiments in methanol-d(4) were performed to determine DeltaDeltaH and DeltaDeltaS values derived from the two lowest energy conformers. These indicate that while the influence of 6-C-methyl substitution on conformational enthalpy is in accord with the classic principles of steric interactions, conformational preference in solution can also be strongly affected by other factors such as solvent-solute interactions and solvent reorganization.     

Use of constrained synthetic amino acids in beta-helix proteins for conformational control

A highly constrained amino acid has been introduced in the turn region of a beta-helix to increase the conformational stability of the native fold for nanotechnological purposes. The influence of this specific amino acid replacement in the final organization of beta-helix motifs has been evaluated by combining ab initio first-principles calculations on model systems and molecular dynamics simulations of entire peptide segments. The former methodology, which has been applied to a sequence containing three amino acids, has been used to develop adjusted templates. Calculations indicated that 1-amino-2,2-diphenylcyclopropanecarboxylic acid, a constrained cyclopropane analogue of phenylalanine, exhibits a strong tendency to form and promote folded conformations. On the other hand, molecular dynamics simulations are employed to probe the ability of such a synthetic amino acid to enhance the conformational stability of the beta-helix motif, which is the first requirement for further protein nanoengineering. A highly regular segment from a naturally occurring beta-helix protein was selected as a potential nanoconstruct module. Simulations of wild type and mutated segments revealed that the ability of the phenylalanine analogue to nucleate turn conformations enhances the conformational stability of the beta-helix motif in isolated peptide segments.     

Electronic spectra and conformational states of mono- and diphenyl derivatives of [2.2]paracyclophane

Ultraviolet spectra of 4-phenyl-[2.2]paracyclophane and of the 4,7- and 4,13-diphenyl derivatives were interpreted. MINDO/3 total molecular energy andPPP—CI-1 energies of singlet transitions were calculated for different values of the dihedral angle of the phenyl ring with respect to the benzene ring of paracyclophane. Although most of the theoretical transitions correspond to local excitation within thePCP fragment, some of them result in a transfer of electron charge to the phenyl substituents.

---

Elektronenspektren und Konformationen von Mono- und Diphenylderivaten des [2.2]Paracyclophans

Zusammenfassung Es werden die UV-Spektren von 4-Phenyl-[2.2]paracyclophan, 4,7- und 4,13-Diphenyl-[2.2]paracyclophan interpretiert. Für verschiedene Diederwinkel der Phenylringe relativ zu dem Benzolring des Paracyclophans wurden MINDO/3-Rechnungen für die Gesamtenergie undPPP—CI-1 Rechnungen für die Singlet-Übergänge durchgeführt. Die meisten der berechneten Übergänge gehören zu lokalen Anregungen innerhalb desPCP-Fragments, einige sind jedoch einem Elektronentransfer zu den Phenylsubstituenten zuzuschreiben.

     

Chemical modulation of peptoids: synthesis and conformational studies on partially constrained derivatives

The high conformational flexibility of peptoids can generate problems in biomolecular selectivity as a result of undesired off-target interactions. This drawback can be counterbalanced by restricting the original flexibility to a certain extent, thus leading to new peptidomimetics. By starting from the structure of an active peptoid as an apoptosis inhibitor, we designed two families of peptidomimetics that bear either 7-substituted perhydro-1,4-diazepine-2,5-dione 2 or 3-substituted 1,4-piperazine-2,5-dione 3 moieties. We report an efficient, solid-phase-based synthesis for both peptidomimetic families 2 and 3 from a common intermediate. An NMR spectroscopic study of 2a,b and 3a,b showed two species in solution in different solvents that interconvert slowly on the NMR timescale. The cis/trans isomerization around the exocyclic tertiary amide bond is responsible for this conformational behavior. The cis isomers are more favored in nonpolar environments, and this preference is higher for the six-membered-ring derivative 3a,b. We propose that the hydrogen-bonding pattern could play an important role in the cis/trans equilibrium process. These hydrogen bonds were characterized in solution, in the solid state (i.e., by using X-ray studies), and by molecular modeling of simplified systems. A comparative study of a model peptoid 10 containing the isolated tertiary amide bond under study outlined the importance of the heterocyclic moiety for the prevalence of the cis configuration in 2a and 3a. The kinetics of the cis/trans interconversion in 2a, 3a, and 10 was also studied by variable-temperature NMR spectroscopic analysis. The full line-shape analysis of the NMR spectra of 10 revealed negligible entropic contribution to the energetic barrier in this conformational process. A theoretical analysis of 10 supported the results observed by NMR spectroscopic analysis. Overall, these results are relevant for the study of the peptidomimetic/biological-target interactions.     

Synthesis of 3-aminolactams as X-Gly constrained pseudodipeptides and conformational study of a Trp-Gly surrogate

3-Amino-delta-valerolactams trans-11a-c were synthesized through conjugate addition and Curtius rearrangement and converted into Fmoc-[Trp-Gly], Fmoc-[Ile-Gly], and Fmoc-[Phe-Gly] pseudodipeptides. Conformational analyses of tripeptide analogues Ac-[Trp-Gly]-Leu-NH(2) 17a and 17b by NMR experiments and molecular modeling calculations showed that diastereomer 17a adopted a gamma-turn/distorted type II beta-turn structure, whereas diastereomer 17b adopted mainly a gamma-turn structure.     

Application of paramagnetic shift reagents to the conformational analysis of isomeric dienones

Paramagnetic NMR shift reagents, Eu(fod)₃ and Pr(fod)₃, have been applied to study the one-ene conformations of isomeric dienones. The results obtained using various complex formation models are analysed. The preferred model suggests participation of both carbonyl oxygen Ione pairs in binding with the shift reagents. Criteria for the estimation of errors in the determination of the structure parameters of the substrate-paramagnetic reagent complexes are suggested. The data obtained using NMR shift reagents are consistent with the existence of dienone α,β-cis-isomers as s-cis-conformers only, with the carbonyl group lying out of the plane of all the other atoms of the molecule. Both s-cis and s-trans conformers occur in dienone α,β-trans-isomers.     

Three-pulse photon echo peak shift spectroscopy as a probe of flexibility and conformational heterogeneity in protein folding

We investigate the equilibrium unfolding of Zn-cytochrome c in guanidine hydrochloride by three-pulse photon echo peak shift (3PEPS) spectroscopy. Unexpectedly, the measurements reveal that inhomogeneous broadening of the sample at the midpoint of the denaturation is larger than that of either native or unfolded states. To interpret this finding, we present simulations of the peak shift for both two-state and three-state unfolding models. Both the denaturant concentration dependence of the asymptotic peak shift (APS) and the wavelength dependence of the APS at the midpoint of the denaturation are different for the two models. Our data are consistent with two-state unfolding.     

13C NMR spectra of 1,3-dipyridyl- and pyridylphenylthioureas. Chemical shift assignments and conformational implications

The ¹³C NMR spectra of a series of 1,3-dipyridyl- and pyridylphenylthioureas have been obtained. Complete analyses of the experimental spectra have provided the chemical shifts and coupling constants. The spectra of dipyridylthioureas over a temperature range showed important changes which could be attributed to an intramolecular conversion between the two equivalent E,Z and Z,E conformations. The coalescence temperature of the ¹³C signals leads to a ΔG* of ∼ 58.0 kJ mol⁻¹ for the dynamic process involved. The results show that pyridylphenyl thioureas exist in a single conformation at ambient temperature.     

13C and 17O chemical shifts and conformational analysis of mono- and di-methyl-substituted thiane 1-oxide and thiane 1,1-dioxide

The ¹³C and ¹⁷O (natural abundance) chemical shifts of several mono- and di-methyl ring-substituted thiane 1-oxides and thiane 1,1-dioxides are reported. The cis and trans isomers of methyl-substituted thiane 1-oxide are readily identified by ¹³C and ¹⁷O NMR. In particular, the ¹⁷O NMR signals of axial SO groups are found several ppm upfield of those of the equatorial counterparts. The proportion of axial and equatorial conformers of thiane 1-oxide in different solvents has been measured by low-temperature ¹³C NMR. In THF the proportion of the axial conformer is higher than in CD₂Cl₂ whereas in CDCl₃ or CHF₂Cl the conformational preference is reversed and the equatorial conformer is slightly favoured.     

A randomized kinematics‐based approach to pharmacophore‐constrained conformational search and database screening

Computational tools have greatly expedited the pharmaceutical drug design process in recent years. One common task in this process is the search of a large library for small molecules that can achieve both a low‐energy conformation and a prescribed pharmacophore. The pharmacophore expresses constraints on the 3D structure of the molecule by specifying relative atom positions that should be maintained to increase the likelihood that the molecule will bind with the receptor site. This article presents a pharmacophore‐based database screening system that has been designed, implemented, and tested on a molecular database. The primary focus of this article is on a simple, randomized conformational search technique that attempts to simultaneously reduce energy and maintain pharmacophore constraints. This enables the identification of molecules in a database that are likely to dock with a given protein, which can serve as a powerful aid in the search for better drug candidates. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 731–747, 2000     

Synthesis and conformational studies of dipeptides constrained by disubstituted 3-(aminoethoxy)propionic acid linkers

A series of cyclic compounds with dimethyl-substituted 3-(aminoethoxy)propionic acid linkers have been prepared as potential beta-turn mimics. The desired linkers were prepared from disubstituted pyrones, which were coupled with dipeptides and then subjected to macrocyclization using diethylcyanophosphonate to furnish cyclic compounds 1-5. Conformational analysis was carried out using NMR and X-ray crystallography. All of the five cyclic compounds were found to exist in type I or type II beta-turn conformations.