Biomedical subjects

L Costantino

Publications and source records attributed to L Costantino.

At least 19 recordsLinked to original sources

PubMed2006

Thienocinnolinone alkanoic acid derivatives as aldose reductase inhibitors.

A new series of 8-halogen-4,4a,5,6-tetrahydrothieno[2,3-h]cinnolinone-N2-alkanoic acids was prepared and tested for aldose reductase (ALR2) inhibitory activities. These compounds showed significant inhibitory activity against bovine lens ALR2, with the best compound 2e showing an IC(50) value of 31.4 microM. The presence of the C8-substituents here studied (Cl, Br) on the thienocinnolinone scaffold caused a decrease of the inhibitory potency by a factor of about 4 with respect to the unsubstituted parent compound, while the presence of a C8-methyl group, considered in a previous paper decreased the activity by a factor of about 2. Moreover, the length of the N2 alkanoic chain influences strongly the enzyme inhibitory activity. While most of the carboxylic acids ALR2 inhibitors are acetic acid derivatives, in the case of thienocinnolinone compounds, homologues higher than acetic acids showed to be more active.

Aldehyde Reductase↗

PubMed2005

Conjugated poly(D,L-lactide-co-glycolide) for the preparation of in vivo detectable nanoparticles.

Cellular localization of nanoparticles (Np) represents an important target in the understanding of their distribution after endovenous injection. The need of suitable devices and methodologies capable to detect Np in tissues or in cellular districts can be satisfied by Np which have to be easily recognizable by simple methods. Conjugations of poly(D,L-lactide-co-glycolide) with fluorescein and biotin allow fluorescent and immuno-histochemically active Np to be obtained. The fluorescein Np are detectable using fluorescent microscopy whereas biotin Np can be detected by optical microscopy after streptavidin-biotin-peroxidase complexation. In vivo experiments confirm the ability of these particles to be easily detected in the brain parenchyma or in the liver cell population according to the infusion pathway.

Animals↗

PubMed2004

Synthesis and aldose reductase inhibitory activities of novel thienocinnolinone derivatives.

A novel series of tetrahydrothieno[2,3-h]cinnolinone derivatives were synthesized and evaluated in vitro for their ability to inhibit aldose reductase (ALR2), an enzyme involved in the appearance of diabetic complications. Compounds 2e and 2j exert a remarkable inhibitory effect, with IC(50) of 7.6 and 18 microM, respectively. These compounds incorporate a valid pharmacophore for aldose reductase inhibitory activity represented by a thienocinnolinone template linked through a pentamethylene spacer to a carboxylic function.

Aldehyde Reductase↗

PubMed2003

Characterization and pharmacological actions of tecostanine, an alkaloid of Tecoma stans.

Tecostanine (1) was isolated from Tecoma stans leaves. Its sterochemistry was elucidated as well as its antihyperglycemic activity and its affinity to opioid and nicotinic receptors. The oxalate salt of 1 did not significantly affect blood glucose levels in normoglycaemic and hyperglycaemic rats. It did not appear to interact with opioid receptors (mu type) and showed only moderate affinity to the nicotinic receptor.

Alkaloids↗

PubMed2003

TT virus has a ubiquitous diffusion in human body tissues: analyses of paired serum and tissue samples.

The tissue tropism and possible correlation with liver disease of the TT virus (TTV) as well as its prevalence and genotype distribution remain undefined. TTV-DNA was investigated in paired sera and tissue samples from 144 patients, and sera and cerebrospinal fluids (CSF) from additional six subjects. Of the 144 tissue samples, 128 were liver biopsy specimens from subjects with hepatic disease while 16 were surgically obtained nonliver specimens from patients with extrahepatic disease. TTV cloning, sequencing and genotype analyses were performed on isolates from sera, tissue specimens and peripheral blood mononuclear cells of two patients with hepatic and four patients with extrahepatic pathologies, as well as from sera and CSFs of two subjects. TTV was found in 100% of the examined tissues and in 60.1 and 50% of sera from patients with hepatic and extrahepatic pathologies, respectively. Moreover, TTV was detected in four of the six CSFs analysed but only in two correspondent sera. Genotyping revealed the coexistence of multiple TTV genotypes and genetic variants in each infected individual, and the analysis of TTV mRNA showed the presence of transcripts in all the six different tissues studied. These results indicate that the entire adult population in our area is more likely infected by TTV, although several subjects are not viraemic and that TTV infects many different human tissues and is able to invade the central nervous system.

Adult↗

PubMed2002

Synthesis and aldose reductase inhibitory activity of 5-arylidene-2,4-thiazolidinediones.

Several (Z)-5-arylidene-2,4-thiazolidinediones were synthesized and tested as aldose reductase inhibitors (ARIs). The most active of the N-unsubstituted derivatives (2) exerted the same inhibitory activity of Sorbinil. The introduction of an acetic side chain on N-3 of the thiazolidinedione moiety led to a marked increase in lending inhibitory activity, conducting to the discovery of a very potent ARI (4c), whose activity level (IC50=0.13 microM) was in the same range of Tolrestat. Moreover, the corresponding methyl esters (3), devoid of any acidic functionality, showed appreciable inhibitory activity similar to that of the N-unsubstituted compounds. It was also found that the substitution pattern on the 5-benzylidene moiety markedly influenced the activity of N-unsubstituted 2,4-thiazolidinediones 2, compounds with substituents at the meta position being generally more effective than the para-substituted ones; however, this SAR was not evidenced in acetates 3 and acids 4.

Aldehyde Reductase↗

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

Binding of beta-carbolines and related agents at serotonin (5-HT(2) and 5-HT(1A)), dopamine (D(2)) and benzodiazepine receptors.

A large series of beta-carbolines was examined for their ability to bind at [3H]agonist-labeled 5-HT(2A) serotonin receptors. Selected beta-carbolines were also examined at 5-HT(2C) serotonin receptors, 5-HT(1A) serotonin receptors, dopamine D(2) receptors, and benzodiazepine receptors. Indolealkylamines and phenylisopropylamines were also evaluated in some of these binding assays. The beta-carbolines were found to bind with modest affinity at 5-HT(2A) receptors, and affinity was highly dependent upon the presence of ring substituents and ring saturation. The beta-carbolines displayed little to no affinity for 5-HT(1A) serotonin receptors, dopamine D(2) receptors and, with the exception of beta-CCM, for benzodiazepine receptors. Examples of beta-carbolines, indolealkylamines (i.e. N,N-dimethyltryptamine analogs), and phenylisopropylamines have been previously shown to produce common stimulus effects in animals trained to discriminate the phenylisopropylamine hallucinogen DOM (i.e. 1-(2, 5-dimethoxy-4-methylphenyl)-2-aminopropane) from vehicle. Although the only common receptor population that might account for this action is 5-HT(2A), on the basis of a lack of enhanced affinity for agonist-labeled 5-HT(2A) receptors, as well as on their lack of agonist action in the PI hydrolysis assay, it is difficult to conclude that the beta-carbolines behave in a manner consistent with that of other classical hallucinogens.

Animals↗

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

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

Transport Properties for Aqueous Solution of Sodium Sulfonate Surfactants.

Isothermal mutual diffusion coefficients (D) have been measured for binary aqueous solutions of sodium alkylsulfonates at 25 degrees C. The diffusion coefficient values drop as the concentration of micelles in the system increases. As the length of the hydrocarbon chain increases, the observed drop in D becomes increasingly sharp and shifts to lower concentrations. When the micellization process is treated as a chemical equilibrium, diffusion coefficients lead to the calculation of the thermodynamic parameters association number, n, and the equilibrium constant, K. These parameters are briefly discussed in connection with the alkyl chain length of the surfactants. Copyright 1999 Academic Press.

Journal Article↗

PubMed1999

Transport Properties for Aqueous Sodium Sulfonate Surfactants.

Intradiffusion coefficients of sodium alkylsulfonates [CH3-(CH2)n-1SO-3 Na+, CnSNa] (n = 5-9, 11) in mixtures with heavy water were measured by the PGSE-NMR technique at 25 degrees C. A slope change in the experimental trends permits the determination of the critical micelle concentration (CMC). In the micellar composition range, solubilized TMS molecules were used to determine the micelle intradiffusion coefficient, from which the micelle radii were obtained. Both the monomer surfactant and the micelle intradiffusion coefficients show a sharp decrease above the CMC. These results can be interpreted in terms of the obstruction effect due to the micelles. The electrostatic repulsion among charged particles strongly enhances this effect. A simple approach that permits the computation of the Gouy-Chapman layer thickness from the experimental coefficients has been proposed and the results are briefly discussed. Copyright 1999 Academic Press.

Journal Article↗

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↗

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

Microcalorimetric Study of Some Short-Chain Nonionic Surfactants.

Apparent enthalpies of mixing were measured for various surfactants of the general formula CH3-(CH2)n-1-(OCH2-CH2)mOH(CnEm) in aqueous solution at 25 degreesC. From the experimental data the enthalpies of micellization were obtained. The results are briefly discussed. Copyright 1998 Academic Press.

Journal Article↗