Nucleophilic catalysis of p-substituted aniline derivatives in acylhydrazone formation and exchange.

Hydrazone bond formation is a versatile reaction employed in several research fields. It is one of the most popular reversible reactions in dynamic combinatorial chemistry. Under physiological conditions, hydrazone exchange benefits from the addition of a nucleophilic catalyst. We report a mechanistic study and superior performance of electron-rich p-substituted aniline derivatives as catalysts for efficient hydrazone formation and exchange in both protic and aprotic solvents. Rigorous kinetic analyses demonstrate that imine formation with 3-hydroxy-4-nitrobenzaldehyde and aniline derivatives proceeds with unprecedented third-order kinetics in which the aldehyde consistently shows a partial order of two. Computational investigations provide insights into the mechanisms of these transformations.

Biomimetic selenocystine based dynamic combinatorial chemistry for thiol-disulfide exchange.

Dynamic combinatorial chemistry applied to biological environments requires the exchange chemistry of choice to take place under physiological conditions. Thiol-disulfide exchange, one of the most popular dynamic combinatorial chemistries, usually needs long equilibration times to reach the required equilibrium composition. Here we report selenocystine as a catalyst mimicking Nature's strategy to accelerate thiol-disulfide exchange at physiological pH and low temperatures. Selenocystine is able to accelerate slow thiol-disulfide systems and to promote the correct folding of an scrambled RNase A enzyme, thus broadening the practical range of pH conditions for oxidative folding. Additionally, dynamic combinatorial chemistry target-driven self-assembly processes are tested using spermine, spermidine and NADPH (casting) and glucose oxidase (molding). A non-competitive inhibitor is identified in the glucose oxidase directed dynamic combinatorial library.

Protein-Directed Dynamic Combinatorial Chemistry: An Efficient Strategy in Drug Design.

Protein-directed dynamic combinatorial chemistry (P-D DCC) is considered a powerful strategy to identify ligands to pharmacologically relevant protein targets. The protein selects its affinity ligands in situ through a thermodynamic templated effect in which the library composition shifts to the formation of specific library members at the expense of other (nonbinding) species. The increase in concentration of the selected species is known as amplification and leads to the discovery of new hit compounds for protein targets. This Mini-Review contains an updated overview of the protein-directed DCC applications and the fundamental aspects to take into account when designing a P-D DCC experiment such as the most biocompatible reversible reactions and the methodology used to analyze the experiments.

Insights into real-time chemical processes in a calcium sensor protein-directed dynamic library.

Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speeding the identification of modulators of biological targets. However, the exchange chemistries typically take place under specific reaction conditions, with limited tools capable of operating under physiological parameters. Here we report a catalyzed protein-directed DCC working at low temperatures that allows the calcium sensor NCS-1 to find the best ligands in situ. Ultrafast NMR identifies the reaction intermediates of the acylhydrazone exchange, tracing the molecular assemblies and getting a real-time insight into the essence of DCC processes at physiological pH. Additionally, NMR, X-ray crystallography and computational methods are employed to elucidate structural and mechanistic aspects of the molecular recognition event. The DCC approach leads us to the identification of a compound stabilizing the NCS-1/Ric8a complex and whose therapeutic potential is proven in a Drosophila model of disease with synaptic alterations.

Usefulness of carotid ultrasonography in the assessment of coronary artery disease extension in patients undergoing exercise echocardiography.

OBJECTIVES: To evaluate whether carotid disease is associated with coronary artery disease (CAD) extension in patients undergoing treadmill exercise stress echocardiography (EE). METHODS: We retrospectively studied 156 patients without previous vascular disease who underwent EE, carotid ultrasonography, and coronary angiography between 2002 and 2013. Low-, intermediate-, and high-risk EE were defined as negative, localized ischemia, and multivessel/extensive ischemia EE respectively; carotid disease according to Mannheim and American Society of Echocardiography Consensus and CAD extension from zero to three vessel disease as stenosis ≥50% by visual assessment. RESULTS: Of the 156 patients, 67 (42.9%), 43 (27.6%), 22 (14.1%), and 24 (15.4%) had zero, one, two, and three vessel disease respectively. Age (P = 0.047), male sex (P = 0.010), diabetes mellitus (P = 0.039), smoking habit (P = 0.015), fasting plasma glucose (P = 0.021), European Systematic COronary Risk Evaluation (P = 0.003), pretest CAD probability (P = 0.003), high-risk EE (P < 0.001), and carotid plaque presence (CP) (P < 0.001) were associated in univariate analysis with more extensive CAD. Predictors of CAD extension in multivariate analysis were high-risk EE (odds ratio [OR] 2.42, P < 0.001), CP presence (OR 1.75, P = 0.004), and pretest CAD probability >65% (OR 1.49, P = 0.023). CP was also associated with multivessel CAD in the 53 patients with low- or intermediate-risk EE (P = 0.001). CONCLUSIONS: CP is associated with CAD extension in patients with ischemic heart disease suspicion undergoing EE. Patients with CP could benefit from a more aggressive therapeutic strategy regarding patients without carotid disease and similar risk EE, especially in intermediate- and/or low-risk test where guidelines recommend initially optimal medical treatment.

Adamantyl analogues of paracetamol as potent analgesic drugs via inhibition of TRPA1.

Paracetamol also known as acetaminophen, is a widely used analgesic and antipyretic agent. We report the synthesis and biological evaluation of adamantyl analogues of paracetamol with important analgesic properties. The mechanism of nociception of compound 6a/b, an analog of paracetamol, is not exerted through direct interaction with cannabinoid receptors, nor by inhibiting COX. It behaves as an interesting selective TRPA1 channel antagonist, which may be responsible for its analgesic properties, whereas it has no effect on the TRPM8 nor TRPV1 channels. The possibility of replacing a phenyl ring by an adamantyl ring opens new avenues in other fields of medicinal chemistry.

Enantioselective synthesis of PPAR (peroxisome proliferator-activated receptors) agonists and antagonists.

This review deals with stereoselective issues in PPAR ligands some of which are in clinical use for treating certain metabolic disorders. After a short introduction of these nuclear receptor and their agonists, some cases of enantioselective separations are reported. The main part concerns stereoselective synthesis first starting with asymmetric synthesis from chiral precursors followed by what we refer to as "true" enantioselective methods. Some examples are discussed in detail for each particular heading.

Prognostic significance of six-minute walk test in non-group 1 pulmonary hypertension.

OBJECTIVE: To assess the value of the six-minute walk test (6MWT) to predict outcome in non-group 1 pulmonary hypertension (PH). BACKGROUND: Distance walked during 6MWT has been widely used as a prognostic test in pulmonary arterial hypertension (group 1 pulmonary hypertension); however, little is known regarding its prognostic value in other groups of PH. METHODS: This was a retrospective study of 60 patients diagnosed of PH, Dana Point classification groups 2-5. 6MWT and echocardiography were performed in all cases. RESULTS: Forty patients (66.6%) were females. Mean age was 70.8 ± 10.7 years (range: 32-85). Seven patients died after a mean follow-up of 23.2 ± 16.7 months. Distance <400 m during 6MWT was associated with a higher risk for death (RR: 4.39; 95% CI: 1.13-17.05; p = 0.03) and for clinical deterioration (death or need for hospitalization) (RR: 2.76; 95% CI: 1.18-6.42; p = 0.02). CONCLUSIONS: 6MWT is useful to predict outcome in non-group 1 PH.

Haemodynamic effects of non-invasive ventilation in patients with obesity-hypoventilation syndrome.

BACKGROUND AND OBJECTIVE: Although it has been reported that pulmonary hypertension is more frequent in patients with obesity-hypoventilation syndrome than in patients with 'pure' obstructive sleep apnoea syndrome, little is known about the haemodynamic repercussions of this entity. The aim was to describe the haemodynamic status, as assessed by echocardiography and 6-min walk test (6MWT), of patients with a newly diagnosed, most severe form of obesity-hypoventilation syndrome, and to evaluate the impact of non-invasive ventilation in these patients. METHODS: A prospective, descriptive, and single-centre follow-up study was conducted. At baseline, patients underwent echocardiography, spirometry, static lung volume measurement, 6MWT, overnight pulse-oximetry and polygraphic recording. Changes in echocardiography and 6MWT were assessed after 6 months of non-invasive ventilation. Right ventricular overload was defined on the basis of right ventricular dilatation, hypokinesis, paradoxical septal motion and/or pulmonary hypertension. RESULTS: Thirty patients (20 women; mean age 69 ± 11) were tested. The percentage of patients with right ventricular overload did not change significantly after non-invasive ventilation (43.3-41.6%; P = 0.24). In patients with right ventricular overload at diagnosis, pulmonary artery systolic pressure decreased significantly at six months (58 ± 11 to 44 ± 12 mm Hg; P = 0.014), and mean distance on 6MWT increased from 350 ± 110 to 426 ± 78 m (P = 0.006), without significant changes in body mass index. CONCLUSIONS: Right ventricular overload is a frequent finding in patients with the most severe form of obesity-hypoventilation syndrome. Treatment with non-invasive ventilation is associated with a decrease in pulmonary artery systolic pressure at six months and an increase in the distance covered during the 6MWT.

Elaidyl-sulfamide, an oleoylethanolamide-modelled PPARα agonist, reduces body weight gain and plasma cholesterol in rats.

We have modelled elaidyl-sulfamide (ES), a sulfamoyl analogue of oleoylethanolamide (OEA). ES is a lipid mediator of satiety that works through the peroxisome proliferator-activated receptor alpha (PPARα). We have characterised the pharmacological profile of ES (0.3-3 mg/kg body weight) by means of in silico molecular docking to the PPARα receptor, in vitro transcription through PPARα, and in vitro and in vivo administration to obese rats. ES interacts with the binding site of PPARα in a similar way as OEA does, is capable of activating PPARα and also reduces feeding in a dose-dependent manner when administered to food-deprived rats. When ES was given to obese male rats for 7 days, it reduced feeding and weight gain, lowered plasma cholesterol and reduced the plasmatic activity of transaminases, indicating a clear improvement of hepatic function. This pharmacological profile is associated with the modulation of both cholesterol and lipid metabolism regulatory genes, including the sterol response element-binding proteins SREBF1 and SREBF2, and their regulatory proteins INSIG1 and INSIG2, in liver and white adipose tissues. ES treatment induced the expression of thermogenic regulatory genes, including the uncoupling proteins UCP1, UCP2 and UCP3 in brown adipose tissue and UCP3 in white adipose tissue. However, its chronic administration resulted in hyperglycaemia and insulin resistance, which represent a constraint for its potential clinical development.

Non-peptidic cell-penetrating agents: synthesis of oligomeric chiral bicyclic guanidinium vectors.

Polycationic oligo(chiral bicyclic guanidines) constitute useful non-peptidic penetrating agents for cell uptake and protein surface recognition. We report herein improved and selective procedures for the preparation of oligoguanidinium scaffolds linked through thioether bonds, with similar or different groups and functions at both ends of the chain. Two synthetic strategies were developed to obtain these compounds in relatively good yields from a common thioacetate precursor: generation of a disulfide intermediate or thiolate formation. Thus, tetraguanidinium intermediates 8 and 22 are best synthesized by the disulfide route, whereas hexamer 29, octamer 31, and trimer 37 arise from a combination of both the disulfide and the thioacetate routes. Finally, tetramer 28 can be readily obtained from either strategy.

Long-term clinical outcome of patients with persistent right ventricle dysfunction or pulmonary hypertension after acute pulmonary embolism.

AIMS: Persistent, echocardiography-assessed right ventricle dysfunction (RVD) and/or pulmonary hypertension (PHT) are relatively frequent findings after an acute pulmonary embolism (PE). It has been suggested that echocardiography might predict long-term adverse events. Our objectives were to evaluate the prognostic value of RVD or isolated PHT 6 months after an acute PE with regard to all-cause mortality or venous thromboembolism (VTE) recurrence. METHODS AND RESULTS: In a previous study, echocardiography was used to assess RVD or PHT on admission and 6 months after an acute PE in 101 consecutive, haemodynamically stable pulmonary patients. We assessed the subsequent vital status and incidence of recurrent VTE in these patients. Six patients were lost for follow-up. The other 95 patients were categorized as those (i) with RVD or PHT 6 months after PE (17 cases, 17.8%) and (ii) patients with neither RVD nor PHT (78 cases, 82.1%). After a mean±SD of 2.8±1.06 years, there were 9 (9.4%) deaths and 12 (12.6%) VTE recurrences. At multivariate analysis, only age predicted all-cause mortality [hazard ratio (HR): 1.081, 95% confidence interval (CI): 1.003-1.166, P=0.004]. RVD or PHT persistence did not appear to increase the risk of mortality or recurrent VTE. CONCLUSION: Persistent echocardiographic signs of right ventricular pressure overload 6 months after an acute PE did not predict long-term adverse outcome events in this study.

"Giant R wave" electrocardiogram pattern during exercise treadmill test: A case report.

INTRODUCTION: The exercise treadmill test is widely used in the evaluation of patients with suspected or known coronary artery disease. The typical ischemic response used to be ST-segment depression. CASE PRESENTATION: We describe a case of a 51-year-old Caucasian man with an unusual ischemic response during the exercise treadmill test: a "giant R wave" electrocardiogram pattern as a manifestation of hyperacute ischemia that resolved with sublingual nitroglycerin. Coronary catheterization showed a severe stenosis in a proximal dominant circumflex coronary artery. We hypothesize that, in this case, the "giant R wave" pattern was related to severe hyperacute ischemia due to coronary spasm superimposed on the atherosclerotic lesion, which probably caused complete occlusion of the artery. The patient was successfully treated with coronary percutaneous revascularization. CONCLUSIONS: This is a dramatic and rare ischemic response during the exercise treadmill test, in which, a rapid administration of nitroglycerin can prevent life-threatening events.

Discovery of Potent Dual PPARα Agonists/CB1 Ligands.

This letter describes the synthesis and in vitro and in vivo evaluation of dual ligands targeting the cannabinoid and peroxisome proliferator-activated receptors (PPAR). These compounds were obtained from fusing the pharmacophores of fibrates and the diarylpyrazole rimonabant, a cannabinoid receptor antagonist. They are the first examples of dual compounds with nanomolar affinity for both PPARα and cannabinoid receptors. Besides, lead compound 2 proved to be CB1 selective. Unexpectedly, the phenol intermediates tested were equipotent (compound 1 as compared to 2) or even more potent (compound 3 as compared with 4). This discovery opens the way to design new dual ligands.

Two-phase dynamic combinatorial discovery of a spermine transporter.

The discovery, in a two-phase dynamic combinatorial library, of an unexpected linear receptor and transporter for spermine is described.

Phase-transfer dynamic combinatorial chemistry.

A two-phase approach to dynamic combinatorial chemistry is described using disulfide exchange chemistry; the use of two phases significantly increases the possibilities and the scope of dynamic combinatorial chemistry by facilitating the combination of otherwise incompatible building blocks.

Molecular recognition of oxoanions based on guanidinium receptors.

Guanidinium is a versatile functional group with unique properties. In biological systems, hydrogen-bonding and electrostatic interactions involving the arginine side chains of proteins are critical to stabilise complexes between proteins and nucleic acids, carbohydrates or other proteins. Leading examples of artificial receptors for carboxylates, phosphates and other oxoanions, such as sulfate or nitrate are highlighted in this tutorial review, addressed to readers interested in biology, chemistry and supramolecular chemistry.

Controlling the biological effects of spermine using a synthetic receptor.

Polyamines play an important role in biology, yet their exact function in many processes is poorly understood. Artificial host molecules capable of sequestering polyamines could be useful tools for studying their cellular function. However, designing synthetic receptors with affinities sufficient to compete with biological polyamine receptors remains a huge challenge. Binding affinities of synthetic hosts are typically separated by a gap of several orders of magnitude from those of biomolecules. We now report that a dynamic combinatorial selection approach can deliver a synthetic receptor that bridges this gap. The selected receptor binds spermine with a dissociation constant of 22 nM, sufficient to remove it from its natural host DNA and reverse some of the biological effects of spermine on the nucleic acid. In low concentrations, spermine induces the formation of left-handed DNA, but upon addition of our receptor, the DNA reverts back to its right-handed form. NMR studies and computer simulations suggest that the spermine complex has the form of a pseudo-rotaxane. The spermine receptor is a promising lead for the development of therapeutics or molecular probes for elucidating spermine's role in cell biology.

[Congenital apical left ventricular aneurysm]. / Aneurisma congénito apical ventricular izquierdo.

Congenital ventricular aneurysm is an infrequently occurring disease entity that usually affects the left ventricle. Its etiopathology is unknown. Clinical presentation is variable, and the condition is potentially lethal in some cases. Various imaging techniques are useful in diagnosis and enable the condition to be differentiated from congenital left diverticulum. We present a patient with a calcified congenital ventricular aneurysm who presented with supraventricular and ventricular arrhythmias and who was treated by surgical resection.

Aneurisma congénito apical ventricular izquierdo / Congenital apical left ventricular aneurysm

El aneurisma ventricular congénito es una entidad infrecuente que generalmente se localiza en el ventrículo izquierdo y cuya etiopatogenia es desconocida. Su presentación clínica es muy variable, pero hay casos potencialmente letales. Varias técnicas de imagen cardíaca pueden ser útiles para su diagnóstico y permiten diferenciarlo de los divertículos ventriculares congénitos, con los que en ocasiones se confunden. Presentamos el caso de un aneurisma ventricular congénito calcificado que cursó con arritmias supraventriculares y ventriculares, y que requirió resección quirúrgica

Congenital ventricular aneurysm is an infrequently occurring disease entity that usually affects the left ventricle. Its etiopathology is unknown. Clinical presentation is variable, and the condition is potentially lethal in some cases. Various imaging techniques are useful in diagnosis and enable the condition to be differentiated from congenital left diverticulum. We present a patient with a calcified congenital ventricular aneurysm who presented with supraventricular and ventricular arrhythmias and who was treated by surgical resection