Sergey N. Podyachev

The Preorganization Effect of the Calix[4]arene Platform on the Extraction Properties of Acetylhydrazide Groups with Transition Metal Ions

The binding properties of the cone conformer of O,O,O,O-tetrakis[hydrazinocarbonylmethyl]-4-tert-butylcalix[4]arene, the cone and the 1,3-alternate conformers of the corresponding thia analogue have been evaluated by means of liquid–liquid extraction for a large variety of metal ions. The extraction constants and the stoichiometries of the complexes formed have been determined. Comparison of the extraction properties of calix[4]arenes with their acyclic monomeric analogue clearly demonstrated, that the preorganization of acetylhydrazide groups on the calix[4]arene platform is the cause for a significant improvement of its binding properties. The presence of additional “soft” nitrogen binding sites in acetylhydrazide derivatives of calix[4]arenes compared to their amide derivatives leads to a shift from their classical selectivity for alkali and alkaline earth cations to transition metals. The cone conformer of tetrathiacalix[4]arene shows higher selectivity in a series of d-metal ions compared with its “classical” analogue. The 1,3-alternate conformer exhibits an excellent extraction selectivity for Cu2+ and Hg2+.

A facile synthetic route to convert Tb(III) complexes of novel tetra-1,3-diketone calix[4]resorcinarene into hydrophilic luminescent colloids

The work presents the synthesis of a novel calix[4]resorcinarene cavitand bearing four 1,3-diketone groups at the upper rim and its complex formation with Tb(III) ions in DMF and DMSO solutions. Electrospray ionization mass spectra, 1H NMR, UV-Vis and luminescence spectra indicate a long (three hours at least) equilibration time for the complex formation between the cavitand and Tb(III) in alkaline DMF and DMSO solutions. These results are explained by the restricted keto–enol conversion, resulting from the steric hindrance effect of the methylenedioxy-groups linking the benzene rings within the cavitand framework. A facile synthetic route to convert luminescent Tb(III) complexes of various stoichiometries into luminescent hydrophilic colloids is disclosed in this work. The route is based on the reprecipitation of the Tb(III) complexes from DMF to aqueous solutions with further polyelectrolyte deposition without prior separation of the luminescent complexes. The luminescent colloids exhibit high stability over time and in buffer systems, which is a prerequisite for their applicability in analysis and biolabeling.

High performance magneto-fluorescent nanoparticles assembled from terbium and gadolinium 1,3-diketones

Polyelectrolyte-coated nanoparticles consisting of terbium and gadolinium complexes with calix[4]arene tetra-diketone ligand were first synthesized. The antenna effect of the ligand on Tb(III) green luminescence and the presence of water molecules in the coordination sphere of Gd(III) bring strong luminescent and magnetic performance to the core-shell nanoparticles. The size and the core-shell morphology of the colloids were studied using transmission electron microscopy and dynamic light scattering. The correlation between photophysical and magnetic properties of the nanoparticles and their core composition was highlighted. The core composition was optimized for the longitudinal relaxivity to be greater than that of the commercial magnetic resonance imaging (MRI) contrast agents together with high level of Tb(III)-centered luminescence. The tuning of both magnetic and luminescent output of nanoparticles is obtained via the simple variation of lanthanide chelates concentrations in the initial synthetic solution. The exposure of the pheochromocytoma 12 (PC 12) tumor cells and periphery human blood lymphocytes to nanoparticles results in negligible effect on cell viability, decreased platelet aggregation and bright coloring, indicating the nanoparticles as promising candidates for dual magneto-fluorescent bioimaging.

6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.

Novel 6‐methyluracil derivatives with ω‐(substituted benzylethylamino)alkyl chains at the nitrogen atoms of the pyrimidine ring were designed and synthesized. The numbers of methylene groups in the alkyl chains were varied along with the electron‐withdrawing substituents on the benzyl rings. The compounds are mixed‐type reversible inhibitors of cholinesterases, and some of them show remarkable selectivity for human acetylcholinesterase (hAChE), with inhibitory potency in the nanomolar range, more than 10 000‐fold higher than that for human butyrylcholinesterase (hBuChE). Molecular modeling studies indicate that these compounds are bifunctional AChE inhibitors, spanning the enzyme active site gorge and binding to its peripheral anionic site (PAS). In vivo experiments show that the 6‐methyluracil derivatives are able to penetrate the blood–brain barrier (BBB), inhibiting brain‐tissue AChE. The most potent AChE inhibitor, 3 d (1,3‐bis[5‐(o‐nitrobenzylethylamino)pentyl]‐6‐methyluracil), was found to improve working memory in scopolamine and transgenic APP/PS1 murine models of Alzheimers disease, and to significantly decrease the number and area of β‐amyloid peptide plaques in the brain.

Improvement of selective d-cation binding by tetrathiacalix[4]arene hydrazides: synthesis and extraction properties

New de-tert-butyltetrathiacalix[4]arenes with acetylhydrazide substituents in cone and 1,3-alternate conformations have been synthesised with good yield by the hydrazinolysis of calix[4]arene ester derivatives. The recognition ability of synthesised macrocycles towards transition and alkali metals has been investigated by the picrate extraction method. The stoichiometry of complexes and the extraction constants have been determined. It has been found that tetrahydrazides do not extract alkali metal ions, but show an excellent affinity towards transition and heavy metal cations. The 1,3-alternate conformer of de-tert-butyltetrathiacalix[4]arene has revealed a remarkable selectivity for Ni2+ and Ag+ in the row of d-elements and for Cd2+ ion among the toxic heavy metals. The experimental data show that the removal of tert-butyl groups from tetrathiacalix[4]arene framework leads to the drastic improvement of extraction efficiency and selectivity of new tetrahydrazides.

Hydration number: crucial role in nuclear magnetic relaxivity of Gd(III) chelate-based nanoparticles

Today, nanostructure-based contrast agents (CA) are emerging in the field of magnetic resonance imaging (MRI). Their sensitivity is reported as greatly improved in comparison to commercially used chelate-based ones. The present work is aimed at revealing the factors governing the efficiency of longitudinal magnetic relaxivity (r1) in aqueous colloids of core-shell Gd(III)-based nanoparticles. We report for the first time on hydration number (q) of gadolinium(III) as a substantial factor in controlling r1 values of polyelectrolyte-stabilized nanoparticles built from water insoluble complexes of Gd(III). The use of specific complex structure enables to reveal the impact of the inner-sphere hydration number on both r1 values for the Gd(III)-based nanoparticles and the photophysical properties of their luminescent Tb(III) and Eu(III) counterparts. The low hydration of TTA-based Gd(III) complexes (q ≈ 1) agrees well with the poor relaxivity values (r1 = 2.82 mM−1s−1 and r2 = 3.95 mM−1s−1), while these values tend to increase substantially (r1 = 12.41 mM−1s−1, r2 = 14.36 mM−1s−1) for aqueous Gd(III)-based colloids, when macrocyclic 1,3-diketonate is applied as the ligand (q ≈ 3). The regularities obtained in this work are fundamental in understanding the efficiency of MRI probes in the fast growing field of nanoparticulate contrast agents.

Synthesis, metal binding and spectral properties of novel bis-1,3-diketone calix[4]arenes

New bis-1,3-diketone derivatives of calix[4]arene (3–5) have been synthesized with good yields by the addition of a sodium salt of acetylacetone, 1-benzoylacetone and dibenzoylmethane to 5,17-bis-(bromomethyl)-25,26,27,28-tetrahydroxycalix[4]arenes. The structural properties of the obtained compounds and their complexes have been established by means of IR, UV-Vis, NMR spectroscopy and quantum-chemical calculations. The complex ability of bis-1,3-diketones towards Al3+, Ni2+, Cu2+ and lanthanide ions (Nd3+, Eu3+, Tb3+) has been investigated by using a liquid–liquid extraction method. The UV-Vis data indicate thermodynamically favorable 1:1 complex formation of the ligands with Tb3+ in alkaline DMF, although the time required for the equilibration reveals the difference between calix[4]arenes bearing acetylaceton-, benzoylaceton- and dibenzoylmethane-substituents. The steric hindrance effect on keto–enol transformation is the reason for the difference. The ligand-centered emissions of Gd3+ complexes with benzoylaceton- and acetylaceton-substituted calix[4]arenes reveal them both as more convenient antennae for red and infra-red than for green lanthanide luminescence. Indeed, the benzoylaceton-substituted counterpart sensitizes Yb3+-centered luminescence to a good extent. Nevertheless, the luminescence of Tb3+ is sensitized by the acetylaceton-substituted counterpart to a better extent than that of Yb3+, while only poor red Eu3+ emission is observed under sensitization by both the ligands.

Synthesis of 1,3-bis(acetylacetonyloxy)- and 1,3-bis(benzoylacetonyloxy)benzene and their complexation with lanthanide ions

Claisen condensation of 1,3-bis(methoxycarbonylmethoxy)benzene with acetone and acetophenone afforded new chelating ligands consisting of two β-diketonate fragments, viz., 1,3-bis(acetylacetonyloxy)benzene and 1,3-bis(benzoylacetonyloxy)benzene, which are linked to each other through the resorcinol spacer. In the crystal, 1,3-bis(acetylacetonyloxy)benzene, unlike the starting ester, adopts a planar conformation and exists in the enol form. The acidities of these compounds and their complexation with lanthanide ions in aqueous ethanolic solutions were studied by pH-potentiometry. Depending on the concentration conditions and pH, the La3+, Gd3+, and Lu3+ ions form 1 : 1, 1 : 2, or 1 : 3 complexes with bis(β-diketones). The stability of the complexes increases as the atomic number of the lanthanide increases (La3+ < Gd3+ ≤ Lu3+). The complexation constants and selectivity of complexation substantially increase with increasing degree of deprotonation of the ligands, which indicates that both chelate groups of the ligands are simultaneously involved in coordination. The Ph substituents in bis(β-diketone) have a considerable effect on the composition and stability of complexes with lanthanide ions due to additional noncovalent inner-sphere interactions.

Synthesis of new hydrazones based on tetrathiacalix[4]arene in the 1,3-alternate conformation

Reactions of 1,3-alternate stereoisomers of tetrathiacalix[4]arene and 4-tert-butyltetrathiacalix[4]-arene, functionalized by hydrazide groups, with benzaldehyde and pyridin-2-carbaldehyde gave new tetrathiacalix[ 4]arene tetrahydrazone derivatives as promising receptors for transition and toxic heavy metal ions.

Mercury(II) and silver(I) receptors based on tetrathiacalix[4]arene hydrazones

The extraction ability of phenyl hydrazone derivatives of cone- and 1,3-alternate tetrathiacalix[4]arenes towards to some alkali, alkaline earth, transition and heavy metal ions has been investigated by picrate extraction method. The synthesized cone-tetrathiacalix[4]arene hydrazones show a high efficiency coupled with an excellent selectivity towards for Ag+ and Hg2+ ions. The stoichiometry of complexes and the extraction constants have been determined. The influence of calix[4]arene platform’s structure and the electron donor substituents in phenyl fragments on the extraction efficiency has been discussed.