Maria E. Amato

Synthesis of New Arylpiperazinylalkylthiobenzimidazole, Benzothiazole, or Benzoxazole Derivatives as Potent and Selective 5-HT1A Serotonin Receptor Ligands†

A series of new compounds containing a benzimidazole, benzothiazole, or benzoxazole nucleus linked to an arylpiperazine by different thioalkyl chains was prepared. They were tested in radioligand binding experiments to evaluate their affinity for 5-HT 1A and 5-HT 2A serotonergic, alpha 1 adrenergic, D1, and D2 dopaminergic receptors. Many of tested compounds showed an interesting binding profile; in particular, 36 displayed very high 5-HT 1A receptor affinity and selectivity over all the other investigated receptors. Selected compounds, evaluated in functional assays, showed antagonistic or partial agonistic activity at 5-HT 1A receptor. An extensive conformational research using both NMR and modeling techniques indicated that extended conformations predominated in vacuum, in solution and during interactions with 5-HT 1A receptor. Finally, the elaborated binding mode of selected compounds at 5-HT 1A receptor was used to explain the influence of spacer length on ligands affinity.

Studies on the stereoselective selenolactonization, hydroxy and methoxy selenenylation of α- and β-hydroxy acids and esters. Synthesis of δ- and γ-lactones

Abstract The diastereoselective synthesis of hydroxy substituted γ- and δ-lactones was accomplished following two approaches. A 5- or 6-endo cyclization promoted by electrophilic selenium reagents of α- or β-hydroxy acids and a 5- or 6-exo cyclization of hydroxy esters obtained through a diastereoselective hydroxy selenenylation reaction of α- or β-hydroxy esters. Moreover, the diastereoselective methoxy selenenylation of the above compounds was investigated showing a case in which the compound that was unreactive in the hydroxy selenenylation conditions gave, in the methoxy selenenylation conditions, the deprotected diol. The usefulness of the methoxy selenenylation procedure was proven by the preparation of a symmetric compound unsymmetrically functionalized. Yields and selectivities were found to depend on substituents (Ph or alkyl groups at the carbon atom that undergoes the nucleophilic attack), mode of cyclization, kinetic or thermodynamic control conditions. In the latter case, silica gel played an important role.

Threading the Calix[5]arene Annulus

Among the fast-expanding collection of molecular systems available for nanoscale applications, mechanically interlocked molecules, such as rotaxanes and catenanes, have already moved towards becoming technological realities. Rotaxanes (and their pseudorotaxane precursors), in particular, have been constructed by using the most diverse macrocyclic receptors as wheel components. Crown ethers, cyclodextrins, cyclic amides, and more recently cucurbiturils have all been threaded onto suitable complementary linear axle components. Calix[n]arenes, on the other hand, have received much less attention as building blocks for the construction of interlocked supermolecules, despite their tunable size, their versatility of derivatization (both at the wide and narrow rims), and their ready availability. The only notable exceptions are the findings of Arduini, Pochini, and co-workers, who have extensively investigated pseudorotaxanes and rotaxanes based on heterotopic calix[6]arene receptors adorned with ureido groups and viologen-derived linear components. Leaving aside calix[4]arenes, the cavity of which is too small to be threaded by a linear guest, the slightly larger calix[5]arenes are the next potential candidates for pseudorotaxane formation. Although calix[5]arenes have previously been shown to efficiently perform a number of tasks, which range from the complexation of alkyl(di)ammonium ions and ion pairs to the self-assembly of supramolecular polymers, to the best of our knowledge, no studies have so far been carried out to evaluate whether or not a linear thread can interpenetrate the calix[5]arene annulus. Herein we describe the first examples of [2]pseudorotaxanes derived from a calix[5]arene and linear secondary alkylammonium ions and we show that the ease of formation of these species is predominantly determined by salt ion-pairing effects, whereas the time course of the threading/dethreading process depends on the length of the cation alkylammonium chains. Very recently we have reported the solid-state structure of a calix[5]arene/n-butylammonium endo-cavity complex. Inspection of this structure revealed that the spatial arrangement of the oxygen atoms around the nitrogen atom of the included guest is reminiscent of the oxygen array present in crown ether/secondary ammonium ion complexes. Even though the cavity size of a calix[5]arene (at its narrow rim) appears to be slightly smaller than that found in the solidstate structure of the dibenzo[24]crown-8 encircling the dibutylammonium ion (ca. 5 vs. 6 , respectively), calix[5]arenes were judged to be sufficiently flexible to allow for the inclusion of secondary alkylammonium cations. After a preliminary screening, penta-tert-butylpentakis(tert-butoxycarbonylmethoxy)calix[5]arene (1) was selected as the prototype wheel component, whereas di-n-butylammonium (2·H) and di-n-hexylammonium (3·H) were chosen as axle components. The axle components were all tested as chloride, picrate (Pic ), and hexafluorophosphate salts to evaluate the influence of ion pairing on the pseudorotaxane assembly process.

Recognition of Achiral and Chiral Ammonium Salts by Neutral Ditopic Receptors Based on Chiral Salen-UO2 Macrocycles

A mononuclear (M20) and a dinuclear (M40) uranyl chiral macrocyclic complex, incorporating both a salen unit containing two phenyl rings linked to a chiral diimine bridge and the (R)-BINOL unit, behaves as an efficient ditopic receptor for achiral and chiral quaternary ammonium salts. Binding affinities in chloroform solution have been measured for 1:1 complexes of many quaternary salts encompassing tetramethylammonium (TMA), tetraethylammonium (TEA), tetrabutylammonium (TBA), and acetylcholine (ACh), as well as trimethylanilinium (TriMAn), benzyltrimethylammonium (BnTriMA), (alpha-methylbenzyl)trimethylammonium and pyrrolidinium cations. The anion of the salt is bound by the hard Lewis acidic uranyl site, with an increasing binding efficiency on increasing the anion hardness (I(-) < Br(-) < Cl(-)), whereas CH-pi or pi-pi attractions by binapthyl moiety, or the salicylaldehyde unit, or the phenyl rings of diimine bridge ensure the recognition of the cation partner. Optimized structures of receptor-anion-cation ternary complexes obtained by MM calculations are supported by 2D-ROESY NMR measurements.

Pair of Diastereomeric Uranyl Salen Cavitands Displaying Opposite Enantiodiscrimination of α‑Amino Acid Ammonium Salts

A pair of diastereomeric salen cavitands and their uranyl complexes combine a chiral (R,R) salen bridge and an inherent chiral tris-bridged quinoxaline cup within the same molecule. Whereas the free ligands show a preference for the same enantiomer of an α-amino acid pair, the corresponding UO(2) complexes display opposite enantiodiscrimination and exceptionally high enantioselectivities (K(D)/K(L) = 26.4).

Quality Traits of Conventional and Transgenic Lettuce (Lactuca sativa L.) at Harvesting by NMR Metabolic Profiling

Metabolism of genetically modified (GM) lettuce (Lactuca sativa L.) leaves was investigated by comparing NMR metabolic profiles of three lines (T(3)B12, T(7)B7, and T(7)B14) overexpressing the E. coli asparagine synthetase A gene with those of the wild type (WT) at 24, 56, and 64 days after sowing (DAS). Statistical analyses based on hydro-soluble compound profiles significantly and maximally discriminated the WT from GM-lines at optimal harvest time (56 DAS). The T(7)B14 metabolic variations were opposite to those of both T(3)B12/T(7)B7 lines, suggesting that unexpected effects of transgenesis had occurred. Compared to controls, the T(3)B12/T(7)B7 plants shared the leaf mass increase, higher amino acid (asparagine, glutamine, valine, and isoleucine) and protein levels, and lower nitrate contents, accompanied by a modest sink of organic acids (alpha-chetoglutarate, succinate, fumarate, and malate), sucrose, fructose, and inulins. Incongruously, the T(7)B14 butter heads were less leafy than the controls and showed lowered amino acid/protein contents and overstored inulin. To further investigate the metabolic discrepancies among the GM-lines, a set of key nitrogen and inulin genes was monitored. The T(3)B12/T(7)B7 lines shared comparable gene expression changes, including the induction of the endogenous asparagine synthetase1 and nitrate reductase1 that supported the targeted enhancement of nitrogen status. Transgene product malfunctioning and T-DNA rearrangements throughout generations were proposed to explain the decreased asparagine content and the complex expression pattern of N genes in T(7)B14 leaves. In the latter, the inulin accumulation was associated with the upregulation of fructan biosynthesis genes and the intense repression of fructan hydrolases.

Reversible photoswitching of stimuli-responsive Si(100) surfaces engineered with an assembled 1 -cyano-1-phenyl-2-[4/-(10-undecenyloxy)phenyl]-ethylene monolayer

Si(100) surfaces were molecularly engineered by covalent linkage of a monolayer of two stilbene-based chromophores, either 1-cyano-1-phenyl-2-[4′-(10-undecenyloxy)phenyl]-ethylene or its chlorine derivative, 1-cyano-1-(4-Cl-phenyl)-2-[4′-(10-undecenyloxy)phenyl]-ethylene. The hybrid systems have been probed by monochromatized angle-resolved X-ray photoelectron spectroscopy (AR-XPS) and atomic force microscopy (AFM) measurements. Results indicated robust covalent linkage of stilbene molecules to the functionalized substrate surfaces. AFM lithography and contact angle (CA) analysis confirmed that the adopted molecular architectures proved to be well-suited for reversible cis–trans photoswitching promoted by UV irradiation in the solid state.

High field NMR techniques and molecular modelling study of the inclusion complexes of the nootropic drug tenilsetam (CAS-997) in cyclodextrins

The inclusion complexes of the chiral anti-amnesic drug 3-(2-thienyl)piperazin-2-one (Tenilsetam, CAS-997) with α-, β- and γ-cyclodextrins (CDs) were studied by high resolution 1H NMR spectroscopy and molecular modelling (MACROMODEL interactive computer program). The partial inclusion of the guest from the secondary hydroxyl side of α-CD was observed in aqueous solution, as well as a deeper insertion into β-CD from the same side; no interactions were evidenced with γ-CD. Diastereoisomeric pairs were observed for both α- and β-CD inclusion complexes. ROESY experiments allowed us to detect the dipolar contacts between protons of the thiophene ring and those of the internal cavity of β-CD. The possible geometry of the complex edifice derived from experimental results was consistent with those obtained by molecular modelling. The formation of hydrogen bonds provides specific interaction sites to differentiate the diastereoisomeric intermolecular inclusion complexes in terms of conformational host–guest adaptation according to available experimental NMR data.

Novel inhibitors of nitric oxide synthase with antioxidant properties

We previously described a series of imidazole-based inhibitors substituted at N-1 with an arylethanone chain as interesting inhibitors of neuronal nitric oxide synthase (nNOS), endowed with good selectivity vs endothelial nitric oxide synthase (eNOS). As a follow up of these studies, several analogs characterized by the presence of substituted imidazoles or other mono or bicyclic nitrogen-containing heterocycles instead of simple imidazole were synthesized, and their biological evaluation as in vitro inhibitors of both nNOS and eNOS is described herein. Most of these compounds showed improved nNOS and eNOS inhibitory activity with respect to reference inhibitors. Selected compounds were also tested to analyze their antioxidant properties. Some of them displayed good capacity to scavenge free radicals and ability to reduce lipid peroxidation.

High field NMR techniques, molecular modelling and molecular dynamics simulations in the study of the inclusion complex of the cognition activator (±)-1-(4-methoxybenzoyl)-5-oxo-2-pyrrolidinepropanoic acid (CI-933) with β-cyclodextrin

Abstract The formation of the inclusion complex of β-cyclodextrin with the new cognition activator (±)-1-(4-methoxybenzoyl)-5-oxo-2-pyrrolidinepropanoic acid (CI-933) and the chiral discrimination capability of the macrocyclic host towards the racemic guest were evident from 1H NMR studies. The structure, relative host-guest orientation and binding mode of the complex were studied using the ROESY NMR technique complemented by molecular modelling and molecular dynamics simulations ( charmm ). All these methods converged towards the structure attained by inserting the guest, the aromatic ring first, into the hydrophobic cavity of the host from the side of the secondary hydroxyls. Both the R- and S-enantiomers were found deeply inserted into the host, the diastereoisomeric complexes formed featuring different numbers and distribution of intermolecular hydrogen bonds.