Hydroxamic acid derivatives as histone deacetylase inhibitors: a DFT study of their tautomerism and metal affinities/selectivities.

Hydroxamic acids are regarded as potent inhibitors of histone deacetylases (HDAC), and can therefore be used to reduce malignancy growth and size in affected organisms. Although there is a substantial body of information on the structures, syntheses, and biological activities of HDAC inhibitors, several important questions regarding their physicochemical properties and metal affinities/selectivities remain answered. First, how do the conformation and ionization of the hydroxamic group depend on its chemical composition and the dielectric properties of the medium? Second, how do these factors affect the affinities and selectivities of HDAC inhibitors for essential biogenic metal cations? Third, what is the preferred deprotonation site of the hydroxamic moiety and its mode of binding to the metal cation? The present work addressed these questions by performing density functional calculations combined with polarizable continuum model computations.

Combretastatin A-4 analogues with benzoxazolone scaffold: Synthesis, structure and biological activity.

In order to design and synthesize a new class of heterocyclic analogues of natural combretastatin A-4 and its synthetic derivative AVE8062, the benzoxazolone ring was selected as a scaffold for a bioisosteric replacement of the ring B of both molecules. A library of 28 cis- and trans-styrylbenzoxazolones was obtained by a modified Wittig reaction under Boden's conditions. Structures of the newly synthesized compounds bearing the 3,4,5-trimethoxy-, 3,4-dimethoxy-, 3,5-dimethoxy-, and 4-methoxystyryl fragment at position 4, 5, 6 or 7 of benzoxazolone core were determined on the basis of spectral and X ray data.

[Characteristics of sexual maturation in girls in Bratislava region].

Objective: Evaluation of puberty onset and menarche in girls in Bratislava region in the years 2006-2007 and 2011-2013.

Design: Regional retrospective epidemiological study.

Setting: 1st Department of Gynaecology and Obstetrics, School of Medicine, Comenius University and University Hospital Bratislava, Slovenské republika.

Endolysin of bacteriophage BFK20: evidence of a catalytic and a cell wall binding domain.

A gene product of ORF24' was identified on the genome of corynephage BFK20 as a putative phage endolysin. The protein of endolysin BFK20 (gp24') has a modular structure consisting of an N-terminal amidase_2 domain (gp24CD) and a C-terminal cell wall binding domain (gp24BD). The C-terminal domain is unrelated to any of the known cell wall binding domains of phage endolysins.

Isolation and characterization of bacteriophage PhiBP from Paenibacillus polymyxa CCM 7400.

A bacteriophage PhiBP infecting Paenibacillus polymyxa CCM 7400 was isolated from culture lysate. Electron microscopy of lysate samples revealed the presence of bacteriophage particles with polyhedral heads 56 nm in diameter and flexible noncontractile tails 144 nm in length. The profile of PhiBP structural proteins resembles that of other bacteriophages.

Hypotrophic effect of long-term neuronal NO-synthase inhibition on heart and conduit arteries of the Wistar rats.

We demonstrate the effect of long-term nNOS inhibition with 7-nitroindazole (7NI) on the heart and conduit arteries. Ten weeks old Wistar rats were used: two groups of controls and rats receiving 7-NI (10 mg/kg b.w.

Effect of chronic nNOS inhibition on blood pressure, vasoactivity, and arterial wall structure in Wistar rats.

While the unequivocal pattern of endothelial nitric oxide (NO) synthase (eNOS) inhibition in cardiovascular control has been recognised, the role of NO produced by neuronal NOS (nNOS) remains unclear. The purpose of the present study was to describe the cardiovascular effects of NO production interference by inhibition of nNOS with 7-nitroindazole (7-NI). Wistar rats (10 weeks old) were used: control and experimental rats were administered 7-NI 10 mg/kg b.

Synthesis and antioxidant potential of novel synthetic benzophenone analogues.

Considering that oxidative stress is strongly implicated in the toxicity of chemotherapy, much effort is focused on the research of diverse antioxidants as protective agents. An efficient synthesis of three novel benzophenones containing 1,3-thiazol moiety (6a-c) is described. Their antioxidant power was evaluated in vitro and in three cell lines (the cancerous MCF7 and the non-cancerous hTERT-HME1 mammary cells, and the H9c2 cardiomyoblastic cells).

Self-assembly properties of some chiral N-palmitoyl amino acid surfactants in aqueous solution.

Various chiral N-palmitoyl amino acid surfactants (AAS) derived from methionine, proline, leucine, threonine, phenylalanine and phenylglycine were prepared and converted to their sodium salt. The properties of the aggregates formed in aqueous solution were studied for both the optically-active compounds and their racemic mixture. Characterization was made by surface tensiometry, fluorimetry, dynamic light scattering, circular dichroism (CD) and transmission electron microscopy.

Integrative pattern of vasomotor efficiency in SHR during ontogenesis.

Numerous studies concerning the cardiovascular system in SHR often yield controversial data. The background of this diversity has various roots, ranging from different vascular segments or areas studied up to the different age of experimental animals. Our study aimed to follow the BP as an integrated response of vascular system.

Systemic blood pressure response to the inhibition of two hyperpolarizing pathways: a comparison to NO-synthase inhibition.

The impact on blood pressure of two vasodilating mechanisms, underlied by vascular smooth muscle hyperpolarization, was studied and compared to that induced by nitric oxide NO mechanism. Systemic blood pressure, after inhibitory intervention in arachidonic acid metabolism cytochrome P-450 inhibition by miconazole 0.5 mg/100 g b.

Acetylcholine and bradykinin enhance hypotension and affect the function of remodeled conduit arteries in SHR and SHR treated with nitric oxide donors.

Discrepancy was found between enhanced hypotension and attenuated relaxation of conduit arteries in response to acetylcholine (ACh) and bradykinin (BK) in nitric oxide (NO)-deficient hypertension. The question is whether a similar phenomenon occurs in spontaneously hypertensive rats (SHR) with a different pathogenesis. Wistar rats, SHR, and SHR treated with NO donors [molsidomine (50 mg/kg) or pentaerythritol tetranitrate (100 mg/kg), twice a day, by gavage] were studied.

Rilmenidine prevents blood pressure increase in rats with compromised nitric oxide production.

Aim: To search tools of high blood pressure in the model of nitric oxide (NO)-defective hypertension, and the study focused on the effect of rilmenidine, agonist of imidazoline receptors, which was suggested to modulate central sympathetic outflow.

Methods: Three experimental groups, each consisting of 7 rats, were used: (I) rats with inhibition of NO synthase (NOS) by N(G)-nitro-L-arginine methyl ester (L-NAME) 40 mg.kg(-1).

Hypotensive effect of agmatine, arginine metabolite, is affected by NO synthase.

The metabolites of arginine were recently shown to be involved in cardiovascular control. The study addresses the general cardiovascular response of anaesthetized rats to agmatine, a decarboxylated arginine. The relation between two arginine metabolic pathways governed by arginine decarboxylase and nitric oxide synthase was investigated.

Hypotrophy of conduit artery walls of the offspring of nitric oxide-defective rats.

The objective of the present study was to investigate the structure of the arterial walls of the offspring stemming from nitric oxide (NO)-defective hypertensive parents. The parents were treated with NG-nitro-L-arginine methyl ester (40 mg kg-1 day-1) for 5 weeks. Blood pressure was measured noninvasively in six 30-day-old rats and nine age-matched controls.

Short-term NO synthase inhibition and the ATP affinity of cardiac Na,K-ATPase.

It was previously shown that 4 hours lasting inhibition of nitric oxide synthesis by administration of an L-arginine analogue, the A(G)-nitro-L-arginine methyl ester (L-NAME) changed the affinity of the Na-binding site of Na,K-ATPase thus resulting in elevation of enzyme activity especially at higher concentrations of sodium. Using the same experimental model, we focused our attention in the present study to the question of binding of ATP to the enzyme molecule in the left ventricle (LV), ventricular septum (S) and the right ventricle (RV) of the dog heart. Activation of the enzyme by increasing concentrations of ATP revealed a significant increase of the Vmax only in septum (by 38 %).

Cardiovascular system of offsprings of hypertensive rats with defective nitric oxide production.

The question was addressed of how nitric oxide synthase (NO synthase) inhibition-induced hypertension in rat parents would affect the cardiovascular system in their offsprings. Two experimental groups were set up: Group I -- offsprings of parents who had both been administered NO synthase inhibitor L-nitro-arginine methyl ester (L-NAME 40 mg/kg/day) for 5 weeks, the treatment of dams continued till week 12. Group II -- offsprings fed by dams administered L-NAME after delivery only for a period of 4 weeks.

Efficiency of NO donors in substituting impaired endogenous NO production: a functional and morphological study.

Two exogenous NO donors were used to act as substitutes for impaired endogenous nitric oxide (NO) production due to inhibition of NO synthase in rats. Six weeks' lasting inhibition of NO synthase by NG-nitro-L-arginine methyl ester (L-NAME) induced stabilized hypertension. Simultaneously administered isosorbide-5-mononitrate did not prevent the development of hypertension.

Short-term NO synthase inhibition and the Na+-binding properties of cardiac Na,K-ATPase.

It is known that hypertension is accompanied by increased [Na+]i. The functional properties of Na,K-ATPase, which transports the Na+ out and K+ into myocardial cells during the relaxation phase, were investigated in the left ventricle (LV), septum (SV) and the right ventricle (RV) of anesthetized dogs with moderate acute blood pressure elevation elicited by short-term (4-hour) NO synthase inhibition. The NO-insufficiency was induced by administration of an L-arginine analogue, the N(G)-nitro-L-arginine methyl ester (L-NAME).

Nitric oxide-compromised hypertension: facts and enigmas.

NO concentration in the femoral artery and femoral vein of anesthetized dogs was found to be 154.2+/-5.6 nM and 90.

Acetylcholine and bradykinin induce paradoxically amplified hypotensive response in hypertensive NO-deficient rats.

The hypotensive response to acetylcholine and bradykinin was studied in rats with NO synthase activity inhibited for a short period of 2 h or a long period of 6 weeks. N(G)-nitro-L-arginine-methyl ester (L-NAME) was used as NO synthase inhibitor (given in a dose of 50 mg/kg either into the jugular vein, or daily in drinking water). Blood pressure was measured in the right carotid artery by a Statham pressure transducer in acute experiments, and on the tail artery by the plethysmographic method weekly in chronic experiments.

Early changes of protein synthesis in myocardium and coronary arteries induced by NO synthase inhibition.

The question was addressed whether short-term (4 hour) NO deficiency, inducing an increase in blood pressure in anaesthetized dogs, does influence proteosynthesis in the myocardium and coronary arteries. A potentially positive answer was to be followed by the study of the supporting role of ornithine decarboxylase for the polyamines pathway. N(G)-nitro-L-arginine-methyl ester (L-NAME) (50 mg/kg per hour) was administered i.

NO concentration in the periendothelial area of the femoral artery of the dog measured in vivo.

.NO concentration was measured in the periendothelial area of the femoral artery by Malinski's porphyrinic .NO sensor in seven anaesthetized dogs.

Developmental dynamics of endothelial and neurogenic control of canine thoracic aorta.

The purpose of the study was to confront the range of endothelial relaxation and neurogenic contraction of the thoracic aorta in fetuses (1 week before birth), puppies (1, 2, 4 and 6 weeks old), and in adult dogs. Isometric tension of aortic rings was monitored in organ bath. Acetylcholine-induced dose-dependent relaxation of aortic rings precontracted by phenylephrine was pronounced already in fetuses and puppies and significantly larger than in adults.

Dynamics of endothelium-muscle cell contacts in the coronary artery of the dog in ontogeny.

The myo-endothelial area in the coronary artery conduit was described in 3 developmental stages: in fetuses, newborns, and adult dogs. Transmission and scanning electron microscopy were used for the study, and morphometry was used for quantitative evaluation. In all three stages, the internal elastic lamina was found to be fenestrated.