Institute of General Organic Chemistry

San Juan de la Rambla, Spain

Institute of General Organic Chemistry

San Juan de la Rambla, Spain
Time filter
Source Type

Unzeta M.,Autonomous University of Barcelona | Esteban G.,Trinity College Dublin | Bolea I.,Autonomous University of Barcelona | Fogel W.A.,Medical University of Lódz | And 4 more authors.
Frontiers in Neuroscience | Year: 2016

HIGHLIGHTS • ASS234 is a MTDL compound containing a moiety from Donepezil and the propargyl group from the PF 9601N, a potent and selective MAO B inhibitor. This compound is the most advanced anti-Alzheimer agent for preclinical studies identified in our laboratory. • Derived from ASS234 both multipotent donepezil-indolyl (MTDL-1) and donepezil-pyridyl hybrids (MTDL-2) were designed and evaluated as inhibitors of AChE/BuChE and both MAO isoforms. MTDL-2 showed more high affinity toward the four enzymes than MTDL-1. • MTDL-3 and MTDL-4, were designed containing the N-benzylpiperidinium moiety from Donepezil, a metal- chelating 8-hydroxyquinoline group and linked to a N-propargyl core and they were pharmacologically evaluated. • The presence of the cyano group in MTDL-3, enhanced binding to AChE, BuChE and MAO A. It showed antioxidant behavior and it was able to strongly complex Cu(II), Zn(II) and Fe(III). • MTDL-4 showed higher affinity toward AChE, BuChE. • MTDL-3 exhibited good brain penetration capacity (ADMET) and less toxicity than Donepezil. Memory deficits in scopolamine-lesioned animals were restored by MTDL-3. • MTDL-3 particularly emerged as a ligand showing remarkable potential benefits for its use in AD therapy. Alzheimer's disease (AD), the most common form of adult onset dementia, is an age-related neurodegenerative disorder characterized by progressive memory loss, decline in language skills, and other cognitive impairments. Although its etiology is not completely known, several factors including deficits of acetylcholine, β-amyloid deposits, t-protein phosphorylation, oxidative stress, and neuroinflammation are considered to play significant roles in the pathophysiology of this disease. For a long time, AD patients have been treated with acetylcholinesterase inhibitors such as donepezil (Aricept®) but with limited therapeutic success. This might be due to the complex multifactorial nature of AD, a fact that has prompted the design of new Multi-Target-Directed Ligands (MTDL) based on the "one molecule, multiple targets" paradigm. Thus, in this context, different series of novel multifunctional molecules with antioxidant, anti-amyloid, anti-inflammatory, and metal-chelating properties able to interact with multiple enzymes of therapeutic interest in AD pathology including acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases A and B have been designed and assessed biologically. This review describes the multiple targets, the design rationale and an in-house MTDL library, bearing the N-benzylpiperidine motif present in donepezil, linked to different heterocyclic ring systems (indole, pyridine, or 8-hydroxyquinoline) with special emphasis on compound ASS234, an N-propargylindole derivative. The description of the in vitro biological properties of the compounds and discussion of the corresponding structure-activity-relationships allows us to highlight new issues for the identification of more efficient MTDL for use in AD therapy. © 2016 Unzeta, Esteban, Bolea, Fogel, Ramsay, Youdim, Tipton and Marco-Contelles.

Marco-Contelles J.,Institute of General Organic Chemistry | Unzeta M.,Autonomous University of Barcelona | Bolea I.,Autonomous University of Barcelona | Esteban G.,Autonomous University of Barcelona | And 5 more authors.
Frontiers in Neuroscience | Year: 2016

The complex nature of Alzheimer's disease (AD) has prompted the design of Multi-Target-Directed Ligands (MTDL) able to bind to diverse biochemical targets involved in the progress and development of the disease. In this context, we have designed a number of MTD propargylamines (MTDP) showing antioxidant, anti-beta-amyloid, anti-inflammatory, as well as cholinesterase and monoamine oxidase (MAO) inhibition capacities. Here, we describe these properties in the MTDL ASS234, our lead-compound ready to enter in pre-clinical studies for AD, as a new multipotent, permeable cholinesterase/monoamine oxidase inhibitor, able to inhibit Aß-aggregation, and possessing antioxidant and neuroprotective properties. © 2016 Marco-Contelles, Unzeta, Bolea, Esteban, Ramsay, Romero, Martínez-Murillo, Carreiras and Ismaili.

Romero-Romero S.,University of Oviedo | Herrero L.,Institute of General Organic Chemistry | Fernandez M.,Institute of General Organic Chemistry | Gomara B.,Institute of General Organic Chemistry | Acuna J.L.,University of Oviedo
Science of the Total Environment | Year: 2017

Polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and polychlorinated dibenzo-p-dioxins and -furans (PCDD/Fs) were measured in a temperate, deep-sea ecosystem, the Avilés submarine Canyon (AC; Cantabrian Sea, Southern Bay of Biscay). There was an increase of contaminant concentration with the trophic level of the organisms, as calculated from stable nitrogen isotope data (δ15N). Such biomagnification was only significant for the pelagic food web and its magnitude was highly dependent on the type of top predators included in the analysis. The trophic magnification factor (TMF) for PCB-153 in the pelagic food web (spanning four trophic levels) was 6.2 or 2.2, depending on whether homeotherm top predators (cetaceans and seabirds) were included or not in the analysis, respectively. Since body size is significantly correlated with δ15N, it can be used as a proxy to estimate trophic magnification, what can potentially lead to a simple and convenient method to calculate the TMF. In spite of their lower biomagnification, deep-sea fishes showed higher concentrations than their shallower counterparts, although those differences were not significant. In summary, the AC fauna exhibits contaminant levels comparable or lower than those reported in other systems. © 2017 Elsevier B.V.

Bastida A.,Institute of General Organic Chemistry | Revuelta J.,Institute of General Organic Chemistry
Targets in Heterocyclic Systems | Year: 2015

Aminoglycoside compounds represent a family of highly charged naturally occurring pseudooligosaccharides, which have been used for a long time as antibiotics that bind ribosomal RNA, but their use has been hindered by their inherent toxicity and the resistance that has emerged to these compounds. To circumvent this drawback during the last years several synthetic strategies for aminoglycoside preparation have been developed. The present review surveys the recent synthetic efforts that are focused on the preparation of heterocyclic aminoglycosides.

Saiz J.,Institute of General Organic Chemistry | Gomara B.,Institute of General Organic Chemistry
Journal of Agricultural and Food Chemistry | Year: 2017

Plasticizers and plastic monomers are commonly used in packaging. Most of them act as endocrine disrupters and are susceptible to migrate from the packaging to the food. We evaluated the migration of endocrine disrupting compounds from three different household food containers to four food simulants under different domestic treatments and for different periods of time, with the aim of reproducing real domestic conditions. The results showed that the migration to the simulants increased with the storage time, up to more than 50 times in certain cases. The heating power seemed to increase the migration processes (up to more than 30 times), and reusing containers produced an increase or decrease of the concentrations depending on the container type and the simulant. The concentrations found were lower than other concentrations reported (always less than 4000 pg/mL, down to less than 20 pg/mL), which might be a consequence of the domestic conditions used. © 2017 American Chemical Society.

Saiz J.,Institute of General Organic Chemistry | Garcia-Roa R.,CSIC - National Museum of Natural Sciences | Martin J.,CSIC - National Museum of Natural Sciences | Gomara B.,Institute of General Organic Chemistry
Journal of Chromatography A | Year: 2017

Chemical signaling is a widespread mode of communication among living organisms that is used to establish social organization, territoriality and/or for mate choice. In lizards, femoral and precloacal glands are important sources of chemical signals. These glands protrude chemical secretions used to mark territories and also, to provide valuable information from the bearer to other individuals. Ecologists have studied these chemical secretions for decades in order to increase the knowledge of chemical communication in lizards. Although several studies have focused on the chemical analysis of these secretions, there is a lack of faster, more sensitive and more selective analytical methodologies for their study. In this work a new GC coupled to tandem triple quadrupole MS (GC-QqQ (MS/MS)) methodology is developed and proposed for the target study of 12 relevant compounds often found in lizard secretions (i.e. 1-hexadecanol, palmitic acid, 1-octadecanol, oleic acid, stearic acid, 1-tetracosanol, squalene, cholesta-3,5-diene, α-tocopherol, cholesterol, ergosterol and campesterol). The method baseline-separated the analytes in less than 7. min, with instrumental limits of detection ranging from 0.04 to 6.0. ng/mL. It was possible to identify differences in the composition of the samples from the lizards analyzed, which depended on the species, the habitat occupied and the diet of the individuals. Moreover, α-tocopherol has been determined for the first time in a lizard species, which was thought to lack its expression in chemical secretions. Globally, the methodology has been proven to be a valuable alternative to other published methods with important improvements in terms of analysis time, sensitivity, and selectivity. © 2017 Elsevier B.V.

Perez-Fernandez V.,University of Alcalá | Gonzalez M.J.,Institute of General Organic Chemistry | Garcia M.T.,University of Alcalá | Marina M.L.,University of Alcalá
Analytica Chimica Acta | Year: 2013

A new CE method has been developed for the simultaneous separation of a group of parent phthalates. Due to the neutral character of these compounds, the addition of several bile salts as surfactants (sodium cholate (SC), sodium deoxycholate (SDC), sodium taurodeoxycholate (STDC), sodium taurocholate (STC)) to the separation buffer was explored showing the high potential of SDC as pseudostationary phase. However, the resolution of all the phthalates was not achieved when employing only this bile salt as additive, being necessary the addition of neutral cyclodextrins (CD) and organic modifiers to the separation media. The optimized cyclodextrin modified micellar electrokinetic chromatography (CD-MEKC) method consisted of the employ of a background electrolyte (BGE) containing 25. mM β-CD-100. mM SDC in a 100. mM borate buffer (pH 8.5) with a 10% (v/v) of acetonitrile, employing a voltage of 30. kV and a temperature of 25. °C. This separation medium enabled the total resolution of eight compounds and the partial resolution of two of the analytes, di-n-octyl phthalate (DNOP) and diethyl hexyl phthalate (DEHP) (Rs ~ 0.8), in only 12. min. The analytical characteristics of the developed method were studied showing their suitability for the determination of these compounds in commercial perfumes. In all the analyzed perfumes the most common phthalate was diethyl phthalate (DEP) that appeared in ten of the fifteen analyzed products. Also dimethyl phthalate (DMP), diallyl phthalate (DAP), dicyclohexyl phthalate (DCP), and di-n-pentyl phthalate (DNPP) were found in some of the analyzed samples. © 2013 Elsevier B.V.

Portoles T.,Jaume I University | Sales C.,Jaume I University | Gomara B.,Institute of General Organic Chemistry | Sancho J.V.,Jaume I University | And 4 more authors.
Analytical Chemistry | Year: 2015

The analysis of brominated flame retardants (BFRs) commonly relies on the use of gas chromatography coupled to mass spectrometry (GC-MS) operating in electron ionization (EI) and electron capture negative ionization (ECNI) modes using quadrupole, triple quadrupole, ion trap, and magnetic sector analyzers. However, these brominated contaminants are examples of compounds for which a soft and robust ionization technique might be favorable since they show high fragmentation in EI and low specificity in ECNI. In addition, the low limits of quantification (0.01 ng/g) required by European Commission Recommendation 2014/118/EU on the monitoring of traces of BFRs in food put stress on the use of highly sensitive techniques/methods. In this work, a new approach for the extremely sensitive determination of BFRs taking profit of the potential of atmospheric pressure chemical ionization (APCI) combined with GC and triple quadrupole (QqQ) mass analyzer is proposed. The objective was to explore the potential of this approach for the BFRs determination in samples at pg/g levels, taking marine samples and a cream sample as a model. Ionization and fragmentation behavior of 14 PBDEs (congeners 28, 47, 66, 85, 99, 100, 153, 154, 183, 184, 191, 196, 197, and 209) and two novel BFRs, decabromodiphenyl ethane (DBDPE) and 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), in the GC-APCI-MS system has been investigated. The formation of highly abundant (quasi) molecular ion was the main advantage observed in relation to EI. Thus, a notable improvement in sensitivity and specificity was observed when using it as precursor ion in tandem MS. The improved detectability (LODs < 10 fg) achieved when using APCI compared to EI has been demonstrated, which is especially relevant for highly brominated congeners. Analysis of samples from an intercomparison exercise and samples from the marine field showed the potential of this approach for the reliable identification and quantification at very low concentration levels. © 2015 American Chemical Society.

Gomara B.,University of Stockholm | Gomara B.,Institute of General Organic Chemistry | Athanasiadou M.,University of Stockholm | Quintanilla-Lopez J.E.,Institute of General Organic Chemistry | And 2 more authors.
Environmental Science and Pollution Research | Year: 2012

Introduction Concentrations and congener profiles of polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (OH-PCBs) in placenta samples from a Madrid population (Spain) are reported. Structure dependent retentions of OH-PCBs are known to occur in both humans and wildlife, making it of interest to assess placental transfer of both parent compounds and their metabolites to the developing foetus. Results The ΣPCB concentrations found in placenta samples were in the range 943-4,331 pg/g fresh weight (f. w.), and their hydroxylated metabolites showed a 20-time lower concentration level (53-261 pg/g f. w.). The PCB profiles were surprisingly dominated by CB-52 and CB-101 accounting for more than 44% of the total PCB concentration. This is indicating a source of exposure that is not yet identified. The OH-PCB profiles were dominated by 4-OH-CB187 and 4-OH-CB146, representing >50% of the ΣOH-PCB concentration of the placenta samples. Statistical analysis of the data revealed strong correlations between the PCB congeners, among some OH-PCBs, and between OH-PCB metabolites with a meta- and para- substitution pattern. Both PCB and OH-PCB concentrations presented homogeneous distribution, what allowed the establishment of a partial least squares model that correlated the concentrations of OH-PCB with those of PCBs in placenta samples. In addition, causal correlations were observed between the concentrations of OH-PCBs and those of their corresponding PCB precursors. © 2011 Springer-Verlag.

Gulias M.,University of Santiago de Compostela | Lopez F.,Institute of General Organic Chemistry | Mascarenas J.L.,University of Santiago de Compostela
Pure and Applied Chemistry | Year: 2011

We present a compilation of methodologies developed in our laboratories to assemble polycyclic structures containing small- and medium-sized cycles, relying on the use of transition-metal-catalyzed (TMC) cycloadditions. First, we discuss the use of alkylidene - cyclopropanes (ACPs) as 3C-atom partners, in particular in their Pd-catalyzed (3 + 2) cycloadditions with alkynes, alkenes, and allenes, reactions that lead to cyclopentane-containing polycyclic products in excellent yields. Then, we present the expansion of this chemistry to a (4 + 3) annulation with conjugated dienes, and to inter- and intramolecular (3 + 2 + 2) cycloadditions using external alkenes as additional 2C-π-systems. These reactions allow the preparation of different types of polycyclic structures containing cycloheptene rings, the topology of the products depending on the use of Pd or Ni catalysts. Finally, we include our more recent discoveries on the development of (4 + 3) and (4 + 2) intramolecular cyclo additions of allenes and dienes, promoted by Pt and Au catalysts, and discuss mechanistic insights supported by experimental and density functional theory (DFT) calculations. An enantioselective version of the (4 + 2) cycloaddition with phosphoramidite Au(I) catalysts is also presented. © 2011 IUPAC.

Loading Institute of General Organic Chemistry collaborators
Loading Institute of General Organic Chemistry collaborators