Search for influence of spatial properties on affinity at α1-adrenoceptor subtypes for phenylpiperazine derivatives of phenytoin

A series of phenylpiperazine derivatives of phenytoin was evaluated for their affinity at α₁-adrenoceptor subtypes in functional bioassays (rat tail artery: α_1A and/or α_1B; guinea pig spleen: α_1B; rat aorta: α_1D). The most potent compounds at α_1A-, α_1B- and α_1D-adrenoceptors, 11, 18 and 8, showed affinities in the submicromolar range. The role of a hydrogen bond donor group for affinity and selectivity at α_1B-adrenoceptors, postulated by Bremner’s pharmacophore model, was confirmed by functional and molecular modelling studies.     

Synthesis and SAR-study for novel arylpiperazine derivatives of 5-arylidenehydantoin with α₁-adrenoceptor antagonistic properties

The study is focused on a series of 5-arylidenehydantoin derivatives with a phenylpiperazine-hydroxypropyl fragment at N3 of the hydantoin ring. The compounds were assessed on their affinity for α(1)-adrenoceptors and evaluated in functional bioassays for their antagonistic properties. Crystal structures of (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)imidazolidine-2,4-dione (7) and hydrochloride of (Z)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)imidazolidine-2,4-dione (10a) were solved using the X-ray diffraction method. Classical molecular mechanics (MMFFs force field, MCMM, MacroModel) were used to predict 3D structure of compounds 5a-18a using a crystal structure of 7. SAR analysis was performed on the basis of Barbaro's pharmacophore model and structural properties of previously investigated α(1)-adrenoceptor antagonists possessing a hydantoin fragment. Most of the compounds exhibited significant affinities for α(1)-ARs in nanomolar range (40-290 nM). The highest activities (K(i)<75 nM) were observed for compounds possessing a 2-alkoxyphenylpiperazine fragment and two methoxy substituents at the benzylidene moiety. The results indicated that chemical properties, number and positions of substituents at the 5-arylidene fragment influenced the power of α(1)-affinities as follows: 3,4-di CH(3)O>2,4-di CH(3)O>4-Cl>2,3-di CH(3)O>H>4-N(CH(3))(2).     

Synthesis of a quinazoline derivative: a new α₁-adrenoceptor ligand for conjugation to quantum dots to study α₁-adrenoceptors in living cells

Quantum dots (QDs) that are conjugated to small molecule derivatives of drugs and endogenous ligands may be useful tools to study the distribution and dynamic of membrane bound receptors, ion channels and transporters in live cells. In order to use these tools, it is necessary to functionalize QDs with bioactive ligands. In this paper, we successfully synthesized a ligand of α(1)-adrenoceptor that could be conjugated to QDs. In addition, the conjugation of the ligands to QDs and their biological activity were evaluated through binding assay with 30 nM QD conjugates in living human embryonic kidney 293 cells.     

Fullerenes and their derivatives as inhibitors of tumor necrosis factor-α with highly promoted affinities

Tumor necrosis factor-α (TNF-α) is a cell signalling protein involved in systemic inflammation in infectious and other malignant diseases. Physiologically, it plays an important role in regulating host defence, but its overexpression can lead to serious illnesses including cancer, autoimmune disease and inflammatory disease. Gadolinium-based metallofullerenols, e.g., Gd@C₈₂(OH) _x (x?≈?22), are well known for their abundant biological activities with low toxicity experimentally and theoretically; however, their activity in direct TNF-α inhibition has not been explored. In this work, we investigated the inhibiting effects of four types of fullerene-based ligands: fullerenes, fullerenols, metallofullerenes, and metallofullerenols. We reported previously that fullerenes, metallofullerenes and their hydroxylated derivatives (fullerenols) can reside in the same pocket of the TNF-α dimer as that of SPD304—a known inhibitor of TNF-α [He et al. (2005) Science 310:1022, 18]. Ligand docking and binding free energy calculations suggest that, with a similar nonpolar interaction dominated binding pattern, the fullerene-based ligands, C₆₀, C₆₀(OH)₁₂, Gd@C₆₀, C₈₂, C₈₂(OH)₁₂, Gd@C₈₂, Gd@C₈₂(OH)₁₃ and Gd@C₈₂(OH)₂₁, have larger affinity than currently known inhibitors, and could be used to design novel inhibitors of TNF-α in the future.

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Graphical Abstract Fullerene-material/TNF-α

     

Photophysical properties ofβ-homo-tyrosine derivatives

Summary The observed monoexponential fluorescence decay of N-acetyl--homo-tyrosine methylamide (Ac-Hty-NHMe) (I) and N-acetyl-(O-methyl)--homo-tyrosine methylamide (Ac-Hty(OMe)-NHMe) (II) is supporting the rotamer population theory, according to which rotamers are responsible for heterogeneity of the fluorescence decay of N-acetyl-tyrosine amide or tyrosine incorporated within a peptide chain, in general.     

Importance of pH and disulfide bridges on the structural and binding properties of human α₁-acid glycoprotein

Human α₁-acid glycoprotein (AGP) is an acute phase plasma glycoprotein containing two disulfide bridges. As a member of the lipocalin superfamily, it binds and transports several basic and neutral ligands, but a number of other activities have also been described. Thanks to its binding properties, AGP is also a good candidate for the development of biosensors and affinity chromatography media, and in this context detailed structural information is needed. The structural properties of AGP at different p²Hs and under reducing conditions were analysed by FT-IR spectroscopy. The obtained data indicate that AGP, when denatured, does not aggregate at neutral or basic p²Hs whilst it does at acidic p²Hs. Under reducing conditions the protein is remarkably less thermostable than its oxidized counterpart and presents an enhanced tendency to aggregate, even at neutral p²H. A heat-induced molten globule-like state (MG) was detected at 55 °C at p²H 7.4 and 5.5. At p²H 4.5 the MG occurred at 45 °C with an onset of formation at 40 °C. The MG was not observed under reducing conditions. A lower affinity of chlorpromazine and progesterone for the MG formed at p²H 4.5 and 40 °C was observed, suggesting that ligand(s) may be released near the negative surfaces of biological membranes. Furthermore, the reduced AGP displays an enhanced affinity for progesterone, indicating the importance of disulfide bonds for the binding capacity of AGP.     

Structure, solution equilibria and magnetic properties of copper(II) complexes with new sulfurated triazoline derivatives of α-amino acids

Two new sulfurated triazoline ligands have been synthesized by functionalization of glycine and l-alanine (HL¹ and HL², respectively) at the carboxylate site with retention of chirality in the latter case. The ligands and their copper(II) complexes have been characterized by spectroscopic methods and their structures were determined by X-ray diffraction. The compound [Cu(H₂L²)₂](H₅O₂)(SO₄)₂(HSO₄) presents a very disordered structure with regard to the anionic counterion and a very unusual elongated crystal cell. In all the complexes the ligands are (N,S) coordinated to copper(II), while the amino groups remain protonated and uncoordinated. The ligands have also been studied in solution and their dissociation constants were determined both by potentiometry and ¹H NMR titrations. Potentiometric studies on the complex [Cu(H₂L²)₂](H₅O₂)(SO₄)₂(HSO₄) were performed to determine the dissociation constants of the ligand once coordinated to the metal. The complex [CuCl₂(H₂L¹)]Cl was studied also by magnetic susceptibility measurements, showing an interesting antiferromagnetic behavior at low temperature which has been interpreted on the basis of its crystal packing.     

Pharmacophore models based studies on the affinity and selectivity toward 5-HT1A with reference to α1-adrenergic receptors among arylpiperazine derivatives of phenytoin

The study is focused on (2-alkoxy)phenylpiperazine derivatives of 1-(2-hydroxy-3-(4-arylpiperazin-1-yl)propyl)-5,5-diphenylimidazolidine-2,4-dione with alkyl or ester substituents at N3 of hydantoin ring, as well as a new designed and synthesized series of compounds with a free N3H group or N3-acetic acid terminal fragment. The compounds were assessed on their affinity for 5-HT_1A and ??₁-adrenoceptors and evaluated in functional bioassays for antagonistic properties. Classical molecular mechanics (MMFFs force field, MCMM, MacroModel) and DFT methods (B3LYP functional, Gaussian 0.3) were used to investigate 3D structure of the compounds. SAR analysis was based on two pharmacophore models, the one described by Barbaro et al. for ??₁-adenoceptor antagonist and the model of Lepailleur et al. for 5-HT_1A receptor ligands. All compounds exhibited significant to moderate affinities for 5-HT_1A receptors in nanomolar range (7-610 nM). The highest activity (7 nM) and selectivity (17.38) for 5-HT_1A was observed for 1-(3-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione (13a). Among new synthesized compounds 1-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5,5-diphenylimidazolidine-2,4-dione hydrochloride (20a) displayed the highest affinity (16.6 nM) and selectivity (5.72) for ??₁-AR.     

Synthesis of new simplified hemiasterlin derivatives with α,β-unsaturated carbonyl moiety

In this Letter, we report a convenient and efficient method for the synthesis of new simplified derivatives of hemiasterlin in which the α,α-dimethylbenzylic moiety A is replaced by α,β-unsaturated aryl groups as Michael acceptor. Most of these derivatives have a strong cytotoxic activity on three human tumor cell lines (KB, Hep-G₂ and MCF₇). Analogs 17b and 17f showed a high cytotoxicity against KB and Hep-G₂ cancer cell lines comparable to paclitaxel and ellipticine.     

Enantioseparation and plant virucidal bioactivity of new quinazoline derivatives with α-aminophosphonate moiety

Enantiomers of some new quinazoline derivatives bearing α-aminophosphonate moiety were separated under normal-phase conditions on two immobilized polysaccharide-based chiral stationary phases (Chiralpak IA and Chiralpak IC). The role of two chiral stationary phases (CSPs), polar modifier and column temperature on retention time and separation factor was studied. Apparent thermodynamic parameters were deduced from Van’t Hoff plots and plausible mechanism of chiral recognition has been discussed. The semi-preparative separation of some compounds was executed successfully in n-hexane/isopropyl alcohol (IPA) on the Chiralpak IA column. The preliminary bioassay showed that both the enantiomers of the investigated series of compounds possessed similar anti-tobacco mosaic virus (TMV) activities.     

Efficient synthesis of phthaloyl derivatives of α-amino carboxamides

A rapid and one-pot synthesis of phthaloyl derivatives of -amino carboxamides is described. In dichloromethane, -amino carboxamides react with mono-methylphthalate in the presence of BOP and i-Pr₂NEt to afford the intermediate N -[(o-methoxycarbonyl)benzoyl]amino carboxamides which undergo cyclization in dichloromethane/water in the presence of aqueous sodium hydroxide and tetrabutylammonium bromide catalyst to afford the corresponding N -phthaloyl amides in excellent yields.     

Synthesis and binding assays of novel 3,3-dimethylpiperidine derivatives with various lipophilicities as σ₁ receptor ligands

Starting from two carbocyclic analogs, a series of 3,3-dimethylpiperidine derivatives was prepared and tested in radioligand binding assays at σ(1) and σ(2) receptors, and at Δ(8)-Δ(7) sterol isomerase (SI) site. The novel compounds mostly bear heterocyclic rings or bicyclic nucleus of differing lipophilicities. Compounds 18a and 19a,b demonstrated the highest σ(1) affinity (K(i)=0.14-0.38 nM) with a good selectivity versus σ(2) binding. Among them, 18a had the lowest ClogD value (3.01) and only 19b was selective versus SI too. Generally, it was observed that more planar and hydrophilic heteronuclei conferred a decrease in affinity for both σ receptor subtypes.     

FTIR 2D correlation spectroscopy of α₁ and α₂ fractions of an alkali-pretreated gelatin

An alkali-pretreated gelatin (pI~4.9) was fractionated by means of alcohol coacervation and semi-preparative gel chromatography. The thermal responses of the isolated α fractions, the coacervate and the total gelatin were investigated by 2D-correlation FTIR spectroscopy in the amide I band region (1600-1700 cm?1). The gelation temperature was the same for all examined samples (24.5°C) while the melting temperature of the α? fraction was lower (30°C) than that of the other samples (32.5°C). The 2D COS plots indicate that on cooling (gelation) the core sequence of conformational changes is the same for all samples. On heating, however, the α? fraction deviates from the α?-containing samples and shows an earlier disappearance of the triple helix signal in the event sequence. The lower melting temperature (less thermostable gelatin gel) of the α? fraction thus results from a different conformational cascade of the α? chains upon melting. In all samples the initial conformational changes take place in the β-turns, providing further evidence for the models proposed previously.     

Methylation of imidazoline related compounds leads to loss of α₂-adrenoceptor affinity. Synthesis and biological evaluation of selective I₁ imidazoline receptor ligands

Methylated analogues of imidazoline related compounds (IRC) were prepared; their abilities to bind I(1) imidazoline receptors (I(1)Rs), I(2) imidazoline binding sites (I(2)BS) and α(2)-adrenoceptor subtypes (α(2)ARs) were assessed. Methylation of the heterocyclic moiety of IRC resulted in a significant loss of α(2)AR affinity. Amongst the selective ligands obtained, LNP 630 (4) constitutes the first highly selective I(1)R agent showing hypotensive activity after intravenous administration.     

Design, synthesis and biological evaluation of new arylpiperazine derivatives bearing a flavone moiety as α1-adrenoceptor antagonists

Elaborate study on the three-dimensional model of α₁-adrenoceptor (α₁-AR) antagonists led to the development of a series of new arylpiperazine derivatives bearing a flavone nucleus as α₁-AR antagonists. The in vitro activities were evaluated and compounds 1, 4, 10, 13 and 15 showed activities close to the reference compound (Prazosin).     

Rational design, synthesis, biological evaluation, homology and docking studies of coumarin derivatives as α1 -adrenoceptor antagonists

According to a three-point pharmacophore for some uro-selective α(1) -adrenoceptor (AR) antagonists, a novel class of coumarin (=2H-1-benzopyran-2-one) derivatives have been successfully designed and synthesized with high efficacies for α(1) -AR. These synthesized coumarin derivatives exhibited high efficacies towards α(1) -AR in in vitro pharmacological assays. Compared with prazosin (pK(i) value of 8.77), among those coumarins, tolylpiperazine-substituted derivatives, 7 and 8, have comparable pK(i) values of 8.81 and 8.77, respectively. The trend in efficacies of these coumarin derivatives towards α(1A) -adrenoceptor was further rationalized by intensive molecular docking. Our work demonstrated that the designed coumarin derivatives can inhibit α(1) -AR in vitro. These findings will provide a guide for further studies of the medical therapy of benign prostatic hyperplasia (BPH).     

Activity of Debaryomyces hansenii UFV-1 α-galactosidases against α-D-galactopyranoside derivatives

α-D-Galactopyranosides were synthesized and their inhibitory activities toward the Debaryomyces hansenii UFV-1 extracellular and intracellular α-galactosidases were evaluated. Methyl α-D-galactopyranoside was the most potent inhibitor compared to the others tested, with K(i)(') values of 0.82 and 1.12 mmolL(-1), for extracellular and intracellular enzymes, respectively. These results indicate that the presence of a hydroxyl group in the C-6 position of α-D-galactopyranoside derivatives is important for the recognition by D. hansenii UFV-1 α-galactosidases.     

Biological evaluation of new imidazole derivatives tethered with indole moiety as potent α-glucosidase inhibitors

A series of triarylimidazoles substituted with 2-arylindoles (4a-4j) were prepared and evaluated for their in vitro α-Glucosidase inhibition. α-Glucosidase inhibition assay displayed a new class of highly potent agents The new compounds showed significant α-glucosidase inhibitory activity as compared to the standard inhibitor acrabose. Structures of synthesized compounds were determined by using Mass spectrometry FT-IR, ¹H NMR and ¹³C NMR.     

Mechanistic investigation of anthocyanidin derivatives as α-glucosidase inhibitors

Eight anthocyanidin derivatives (1–8) were evaluated as potential inhibitors of the catalysis of α-glucosidase. Among them, compounds 4 and 8 had the highest levels of inhibitory activity at 100 μM (IC₅₀ values of 14.4 ± 0.1 and 29.7 ± 1.2 μM) and acted in a dose-dependent manner. Enzyme kinetic analysis further revealed that these inhibitors interacted with α-glucosidase in a mixed noncompetitive mode. Moreover, fluorescence quenching studies provided parameters for calculating the binding mechanism between receptor and ligand. On the basis of these studies, and in silico simulations, we determined that the ligand was likely docked in the receptor. Thus, compounds 4 and 8 are excellent potential targets for in vitro cell-based and in vivo assays related to treatment of diabetes.