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Biomedical subjects

G Rastelli

Publications and source records attributed to G Rastelli.

At least 19 recordsLinked to original sources
PubMed2006

Tunable Fröhlich polarons in organic single-crystal transistors.

In organic field-effect transistors (FETs), charges move near the surface of an organic semiconductor, at the interface with a dielectric. In the past, the nature of the microscopic motion of charge carriers--which determines the device performance--has been related to the quality of the organic semiconductor. Recently, it was discovered that the nearby dielectric also has an unexpectedly strong influence. The mechanisms responsible for this influence are not understood. To investigate these mechanisms, we have studied transport through organic single-crystal FETs with different gate insulators. We find that the temperature dependence of the mobility evolves from metallic-like to insulating-like with increasing dielectric constant of the insulator. The phenomenon is accounted for by a two-dimensional Fröhlich polaron model that quantitatively describes our observations and shows that increasing the dielectric polarizability results in a crossover from the weak to the strong polaronic coupling regime. This represents a considerable step forward in our understanding of transport through organic transistors, and identifies a microscopic physical process with a large influence on device performance.

Journal Article↗
PubMed2001

Synthesis and cytotoxicity of bis(benzo[g]indole-3-carboxamides) and related compounds.

A series of bis(benzo[g]indoles) bridged by CX-(CH2)nN(Me)(CH2)n-CX (X = O, S, H2; n = 2,3) was synthesized as bifunctional antitumor agents and evaluated for cytotoxic activity against diverse human cancer cell lines by the National Cancer Institute. The parent compounds 2a,b exhibited a good level of activity and derivates 2c-g,i,k demonstrated significant inhibitory effects, all with IC50 values in the low micromolar range. The thioamide analogue 2j showed less potency. It is interesting to note that introduction of substituents on the benzene ring of the benzo[g]indole portion of 2a,b did not affect activity, with the only exception of the 7,8-dichloro derivative 2h which became less potent. One member of this series, 2i, was then tested in the hollow fiber cell assay to evaluate, in a preliminary fashion, its in vivo antineoplastic activity. Molecular modelling studies were performed on amide 2a and thioamide 2j to explain the loss of activity of 2j as to 2a. Finally, compound 2a behaved as a typical DNA intercalating agent, as judged from viscosity measurements with Poly(dA-dT)...poly(dA-dT).

Amides↗
PubMed2001

7-Hydroxy-2-substituted-4-H-1-benzopyran-4-one derivatives as aldose reductase inhibitors: a SAR study.

On the basis of the results of molecular modelling studies performed on the aldose reductase (ALR2) inhibitor 7-hydroxy-2-(4'-hydroxybenzyl)-4H-1-benzopyran-4-one (compound A) bound at the active site of the enzyme, we synthesised and tested on bovine and human ALR2 several derivatives modified at position 2 of the benzopyran moiety, in order to confirm the hypothesised binding mode of this compound. The substitution of the methylene bridge with the isosteric sulphur substituent gives an active derivative, while substitution with a polar NH causes a decrease in inhibitory activity; this is in accordance to the previously reported structure in which the methylene linker was found to be adjacent to a hydrophobic aminoacid (Leu300). Among the substituents at 4' position examined, the most favourable for inhibitory activity are those able to act as hydrogen bond donors, supporting the hypothesis of the importance of the interaction with Thr113 for the inhibition of the enzyme.

Aldehyde Reductase↗
PubMed2000

Preparation of thieno[3,2-h]cinnolinones as matrix metalloproteinase inhibitors.

A new series of thieno[3,2-h]cinnolinone analogues was synthesized which is structurally related to 2,3,4,4a,5,6-hexahydrothieno [3,2-h]cinnolin-3-one 1, a weak inhibitor of the matrix metalloproteinase MMP-8 (human neutrophil collagenase). Preliminary SAR studies have shown that while C4a-methyl, C7-acetylamino, C7 and C8-nitro substitution, and C4-C4a olefination provided no increase in activity relative to 1, C8-acetylamino substitution as in 5 and 8 was favourable. Moreover, to predict how the thieno[3,2-h]cinnolinone inhibitors might bind to MMP-8, the unsubstituted compound 9 was docked into the MMP-8 crystal structure. These studies revealed that inhibitor 9 does not seem to be able to coordinate the catalytically-active zinc ion but preferably interact with the peptide-binding region of the active site.

Binding Sites↗
PubMed2000

Aldose reductase does catalyse the reduction of glyceraldehyde through a stoichiometric oxidation of NADPH.

In order to define the ability of bovine lens aldose reductase (ALR2) to generate polyols from aldoses, the quantitative determination of glycerol in the presence of glyceraldehyde was performed by gas chromatography after derivatization with trifluoroacetic anhydride. The proposed method appears to be useful in quantifying low amounts of glycerol in the presence of relatively high concentrations of glyceraldehyde and in following glycerol formation in enzyme assay conditions. The generation of one equivalent of glycerol in the presence of ALR2, is paralleled by the oxidation of one equivalent of NADPH. A similar result was obtained when S-glutathionyl-modified ALR2 was used, instead of the native enzyme, as a catalyst of glyceraldehyde reduction. Sorbinil, a classical ALR2 inhibitor, present in the enzyme assay mixture, inhibits to the same extent both NADPH oxidation and glycerol formation. The demonstration of the stoichiometric ratio of 1:1 occurring in the presence of bovine lens ALR2 between the synthesis of glycerol from D, L -glyceraldehyde and the oxidation of NADPH, rules out doubts concerning the ability of the enzyme to catalyse the reduction of aldoses to the corresponding polyalcohols. Possible autooxidation processes of glyceraldehyde, in the enzyme assay conditions, appear to be irrelevant with respect to the enzyme-catalysed reduction of the aldose. This would indicate that the spectrophotometric monitoring of NADPH oxidation at 340 nm, in the presence of ALR2, is a reliable method to assay the enzyme activity.

Aldehyde Reductase↗
PubMed2000

Synthesis and aldose reductase inhibitory activity of a new series of benz[h]cinnolinone derivatives.

Following our previous studies on pyridazinone carboxylic acids as potent and selective aldose reductase (ALR2) inhibitors, a new series of benzo[h]cinnolinone carboxylic acids, variously substituted at the positions 4, 7-10 and differently modified both at the central ring and at the acidic side chain, were synthesized and tested as inhibitors of ALR2. Comparison with previously synthesized compounds allows us to define more precisely structure-activity relationships for this class of compounds. In fact, in addition to the importance of the acidic side chain, their properties are highly influenced by the substituents present on the benzo[h]cinnolinone nucleous, with potency ranging from that of Sorbinil to very weakly active compounds.

Aldehyde Reductase↗
PubMed2000

Interaction of pyrimethamine, cycloguanil, WR99210 and their analogues with Plasmodium falciparum dihydrofolate reductase: structural basis of antifolate resistance.

The nature of the interactions between Plasmodium falciparum dihydrofolate reductase (pfDHFR) and antimalarial antifolates, i.e., pyrimethamine (Pyr), cycloguanil (Cyc) and WR99210 including some of their analogues, was investigated by molecular modeling in conjunction with the determination of the inhibition constants (Ki). A three-dimensional structural model of pfDHFR was constructed using multiple sequence alignment and homology modeling procedures, followed by extensive molecular dynamics calculations. Mutations at amino acid residues 16 and 108 known to be associated with antifolate resistance were introduced into the structure, and the interactions of the inhibitors with the enzymes were assessed by docking and molecular dynamics for both wild-type and mutant DHFRs. The Ki values of a number of analogues tested support the validity of the model. A 'steric constraint' hypothesis is proposed to explain the structural basis of the antifolate resistance.

Amino Acid Sequence↗
PubMed2000

Structural bases for the inhibition of aldose reductase by phenolic compounds.

Aldose reductase (ALR2) is an enzyme involved in the development of long-term diabetic complications. In the search for aldose reductase inhibitors less acidic than carboxylic acids, phenolic compounds related to benzopyran-4-one and chalcone are particularly interesting because they possess good inhibitory properties. In order to investigate the similarities between these two classes of compounds and to provide a structural basis for their inhibition of ALR2, the existing structure-activity relationships were reconsidered. To this end, the acidity constants of a set of chalcones were measured and compared with those of benzopyran-4-one derivatives. Then, having established the relevant protonation state of these phenolics at physiological pH, a conformational analysis was performed on the most active benzopyran-4-one and chalcone derivatives and the results were compared with the crystal structures of some analogues. Finally, molecular docking of the most active chalcone into the ALR2 binding site was performed, and the structure of the enzyme-inhibitor complex was compared with that of the complex formed between ALR2 and a previously-obtained benzopyran-4-one derivative.

Aldehyde Reductase↗
PubMed1999

1-Benzopyran-4-one antioxidants as aldose reductase inhibitors.

Starting from the inhibitory activity of the flavonoid Quercetin, a series of 4H-1-benzopyran-4-one derivatives was synthesized and tested for inhibition of aldose reductase, an enzyme involved in the appearance of diabetic complications. Some of the compounds obtained display inhibitory activity similar to that of Sorbinil but are more selective than Quercetin and Sorbinil with respect to the closely related enzyme, aldehyde reductase, and also possess antioxidant activity. Remarkably, these compounds possess higher pKa values than carboxylic acids, a characteristic which could make the pharmacokinetics of these compounds very interesting. Molecular modeling investigations on the structures of inhibitors bound at the active site of aldose reductase were performed in order to suggest how these new inhibitors might bind to the enzyme and also to interpret structure-activity relationships.

Aldehyde Reductase↗
PubMed1999

Isoxazolo-[3,4-d]-pyridazin-7-(6H)-one as a potential substrate for new aldose reductase inhibitors.

The isoxazolo-[3,4-d]-pyridazin-7-(6H)-one (2) and its corresponding open derivatives 5-acetyl-4-amino-(4-nitro)-6-substituted-3(2H)pyridazinones (3, 4) were used as simplified substrates for the synthesis of new aldose reductase inhibitors with respect to the previously reported 5, 6-dihydrobenzo[h]cinnolin-3(2H)one-2 acetic acids (1). Moreover, a few derivatives lacking the 5-acetyl group were prepared. Several compounds derived from 2 displayed inhibitory properties comparable to those of Sorbinil. In this class the presence at position 6 of a phenyl carrying an electron-withdrawing substituent proved to be beneficial, independently from its position on the ring (5g,j-l). Acetic acid derivatives were more effective than propionic and butyric analogues. On the contrary, all the monocyclic compounds (6-8) were either inactive or only weakly active. The 3-methyl-4-(p-chlorophenyl)isoxazolo-[3,4-d]-pyridazin-7-(6H )-one acetic acid (5g), which proved to be the most potent derivative, was also investigated in molecular modeling studies, to assess possible similarities in its interaction with the enzyme, with respect to the model 1.

Aldehyde Reductase↗
PubMed1999

Diabetes complications and their potential prevention: aldose reductase inhibition and other approaches.

Despite recent advances both in the chemistry and molecular pharmacology of antidiabetic drugs, diabetes still remains a life-threatening disease, which tends to spread all over the world. The clinical profile of diabetic subjects is often worsened by the presence of several long-term complications, namely neuropathy, nephropathy, retinopathy, and cataract. Several attempts have been made to prevent or at least to delay them. The most relevant are reported in this review, including the development of compounds acting as aldose reductase inhibitors, anti-advanced glycation end-product drugs, free radical scavengers, vasoactive agents, essential fatty acid supplementation, and neurotropic growth factors.

Aldehyde Reductase↗
PubMed1999

Platelet alpha2-adrenoceptor alterations in patients with essential hypertension.

AIMS: The purpose of this study was to determine whether human platelet alpha2-adrenoceptors were altered in essential hypertension. A systematic analysis was carried out on 165 normotensives and 124 untreated primary hypertensives. METHODS: The study was performed at different levels: i) density and affinity of platelet alpha2-adrenoceptors were determined by receptor binding assays using the full alpha2-adrenoceptor agonist [3H]-UK 14304 and a thermodynamic analysis of data was carried out to evaluate if binding mechanisms at the molecular level were altered during hypertension; ii) the functionality of Gi proteins coupled to alpha2-adrenoceptors and iii) forskolin-stimulated cAMP levels were measured. RESULTS: Platelet alpha2-adrenoceptors mean density (Bmax) and affinity (Kd) (+/-s.e.mean) were significantly lower and higher, respectively, in normotensive than in hypertensive subjects [Bmax=327+/-4 vs 435+/-5 fmol mg(-1) of protein (P<0.01) and Kd=3.76+/-10.05 vs 6.50+/-0.15 nM (P<0.01), respectively]. The 50% stimulating concentration of adrenaline on [35S]-GTPgammaS binding to Gi proteins was significantly (P<0.01) lower in normotensives (12+/-2 nM) than in hypertensives (110+/-10 nM). The 50% inhibiting concentration of adrenaline on forskolin-stimulated cAMP levels was significantly (P<0.01) lower in normotensive (22+/-2 nM) than in hypertensive subjects (200+/-25 nM). CONCLUSIONS: Present analysis, including receptorial and functional data, provides evidence that marked alterations occur in platelet alpha2-adrenoceptors of hypertensive subjects.

Adrenergic alpha-Antagonists↗
PubMed1998

Oxidative modification of aldose reductase induced by copper ion. Factors and conditions affecting the process.

Bovine lens aldose reductase (ALR2) is inactivated by copper ion [Cu(II)] through an oxygen-independent oxidative modification process. A stoichiometry of 2 equiv of Cu(II)/enzyme mol is required to induce inactivation. While metal chelators such as EDTA or o-phenantroline prevent but do not reverse the ALR2 inactivation, DTT allows the enzyme activity to be rescued by inducing the recovery of the native enzyme form. The inactive enzyme form is characterized by the presence of 2 equiv of bound copper, at least one of which present as Cu(I), and by the presence of two lesser equivalents, with respect to the native enzyme, of reduced thiol residues. Data are presented which indicate that the Cu-induced protein modification responsible for the inactivation of ALR2 is the generation on the enzyme of an intramolecular disulfide bond. GSH significantly interferes with the Cu-dependent inactivation of ALR2 and induces, through its oxidation to GSSG, the generation of an enzyme form linked to a glutathionyl residue by a disulfide bond.

Aldehyde Reductase↗
PubMed1998

Molecular dynamics simulations of the structure of aldose reductase complexed with the inhibitor tolrestat.

This study reports a molecular dynamics (MD) investigation on the structure of aldose reductase (ALR2) complexed with the potent inhibitor tolrestat. The simulations predict four different orientations of tolrestat into the ALR2 binding site; these orientations have in common a strong interaction of the anionic carboxylate with Tyr48, His110, Trp111 and NADP+, but completely differ for the orientation of the aromatic portion of the inhibitor. Interestingly, the orientation in which tolrestat gives the most attractive interaction energy with the enzyme is in full accord with the x-ray crystal structure of the complex that has been reported in the literature after this work was completed. In addition, the suggestion of more than one orientation of tolrestat during MD is in agreement with recent electrospray mass spectrometry experiments on the ALR2-tolrestat complex.

Aldehyde Reductase↗
PubMed1996

Synthesis, activity, and molecular modeling of a new series of tricyclic pyridazinones as selective aldose reductase inhibitors.

Three new series of tricyclic pyridazinones have been synthesized and tested in vitro in order to assess (i) their ability to inhibit aldose reductase enzyme (ALR2) and (ii) their specificity toward the target enzyme with respect to other related oxidoreductases, such as aldehyde reductase, sorbitol dehydrogenase, and glutathione reductase. The inhibitory capability of the most effective compounds (IC50 values ranging from 6.44 to 12.6 microM) appears to be associated with a rather significant specificity for ALR2. Molecular mechanics and molecular dynamic calculations performed on the ALR2-inhibitor complex give indications of specific interaction sites responsible for the binding, thus providing information for the design of new inhibitors with improved affinity for the enzyme.

Aldehyde Reductase↗
PubMed1996

Conformational analysis of phthalein derivatives acting as thymidylate synthase inhibitors by means of 1H NMR and quantum chemical calculations.

The conformations of a set of phthalein derivatives with bacterial thymidylate synthase (TS) inhibitory activity were investigated by 1H NMR spectra, performed at both room and low temperature, and by quantum chemical calculations. Since the crystal structure of the binary complex of phenolphthalein with the enzyme is known, we set out to study the conformation of various of its analogues in solution in order to observe the effects of the substituents on the phenolic rings, of the alpha-naphthol derivative and of the rigid analogue, fluorescein, and compare the results with the X-ray crystal structure studies. A relationship between the chemical shift of the proton on C4 (H4) of the phthalidic ring and the averaged angle formed by the phthalidic and the aromatic ring planes was found in which the most perpendicular conformations have the lowest H4 chemical shift values. At room temperature, the rotational freedom of all the studied compounds was similar, while at lower temperature the naphthol derivative assumed a partially blocked conformation. Finally, a qualitative relationship between the inhibitory properties of the compounds and their conformations is discussed.

Coloring Agents↗
PubMed1996

Circadian variations in plasma ACTH, cortisol and beta-endorphin levels in normal-weight bulimic women.

In order to establish possible alterations in the secretory patterns of adrenocorticotropic hormone (ACTH), cortisol and/or beta-endorphin in bulimia nervosa, the circadian fluctuations of these hormones were evaluated in blood samples taken at 1-hour intervals over 24 h. Eleven bulimic women with normal body weight and 8 weight- and age-matched normal controls were tested during the follicular phase (days 6-8) of normal menstrual cycles. All women were hospitalized for bulimia or for checkup examinations and were tested 3 days after hospital admission. Both normal and bulimic women showed maximal ACTH, cortisol and beta-endorphin levels at 08.00 h, with minimal ACTH and beta-endorphin levels at midnight and cortisol levels at 02.00 h. The general temporal structure of all hormonal secretions coincided in the two groups. However, whereas all measured ACTH/cortisol levels were quantitatively similar in the two groups, plasma beta-endorphin concentrations were significantly higher in bulimic than in control subjects at all examined time points. The enhancement in the overall 24-hour beta-endorphin secretion suggests the presence of an increased opioid tonus in bulimic women, which might play a role in the pathophysiology of the eating disorder.

Adrenocorticotropic Hormone↗