Publications by authors named "Alberto A C C Pais"

60 Publications

Methods for unsupervised contribution analysis of raw EEM data in water monitoring. Contaminant identification and quantification.

Spectrochim Acta A Mol Biomol Spectrosc 2022 Jan 4;264:120226. Epub 2021 Aug 4.

Department of Hydraulic and Sanitation, Federal University of Parana, Centro Politecnico, Bl. 5, Av. Cel Francisco H. dos Santos, 81531-990 Curitiba, PR, Brazil.

Fluorescence EEM spectra provide the "fingerprint" of water contamination and is a very efficient way to access the quality of water bodies. These multivariate datasets correspond to complex mixtures and are very rich in information. Graphical approaches have been used for decades to characterize and quantify different contamination sources. It is very important to resolve mixed signals in raw EEM spectra in terms of signal sources and respective composition profiles - signal sources allow the identification of contamination type, while concentration profiles quantify the respective contribution inside the mixtures. In order to be able to use robust modeling algorithms, the first task is to accurately estimate the number of contributions that are present. We demonstrate the ability of Singular value Decomposition (SVD) in accessing this information content in raw EEM datasets. To decompose raw EEM information, several algorithms are tested: PARAFAC, MCR-ALS and ICA. In this work we suggest a systematic unsupervised algorithm to process raw EEM spectra of water samples.
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http://dx.doi.org/10.1016/j.saa.2021.120226DOI Listing
January 2022

Removal of Imidacloprid from Water by Microalgae Nannochloropsis sp. and Its Determination by a Validated RP-HPLC Method.

Bull Environ Contam Toxicol 2021 Jul 13;107(1):131-139. Epub 2021 Apr 13.

CQC, Department of Chemistry, University of Coimbra, Coimbra, Portugal.

The large-scale use of pesticides is one of the main causes of the dramatic degradation of our environment. Pesticides such as imidacloprid (IMID) have been linked to declines in bee health and toxicity to other beneficial insects. They pose a threat to human health due to their persistence in the environment and accumulation in the food chain. Therefore, it is essential to test possible environmentally-friendly solutions for their elimination. The present study evaluates the efficiency of microalgae Nannochloropsis sp. for the removal of IMID from synthetic wastewater. The influence of aeration, light, and the presence of UV radiation on the degradation of IMID were factors considered in the study. A rapid RP-HPLC method was developed and validated for the analysis and quantification of IMID in the context of bioremediation with microalgae. Nannochloropsis sp. removed 4.39 µg mL from an initial content of 9.59 µg mL (reaching approximately 50%) of IMID in the first 20 h. This study demonstrated that the removal of IMID by the marine microalgae Nannochloropsis sp. is both effective and light-dependent.
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http://dx.doi.org/10.1007/s00128-021-03228-1DOI Listing
July 2021

Poly(β-cyclodextrin)-Activated Carbon Gel Composites for Removal of Pesticides from Water.

Molecules 2021 Mar 6;26(5). Epub 2021 Mar 6.

Coimbra Chemistry Centre, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.

Pesticides are widely used in agriculture to increase and protect crop production. A substantial percentage of the active substances applied is retained in the soil or flows into water courses, constituting a very relevant environmental problem. There are several methods for the removal of pesticides from soils and water; however, their efficiency is still a challenge. An alternative to current methods relies on the use of effective adsorbents in removing pesticides which are, simultaneously, capable of releasing pesticides into the soil when needed. This reduces costs related to their application and waste treatments and, thus, overall environmental costs. In this paper, we describe the synthesis and preparation of activated carbon-containing poly(β-cyclodextrin) composites. The composites were characterized by different techniques and their ability to absorb pesticides was assessed by using two active substances: cymoxanil and imidacloprid. Composites with 5 and 10 wt% of activated carbon showed very good stability, high removal efficiencies (>75%) and pesticide sorption capacity up to ca. 50 mg g. The effect of additives (NaCl and urea) was also evaluated. The composites were able to release around 30% of the initial sorbed amount of pesticide without losing the capacity to keep the maximum removal efficiency in sorption/desorption cycles.
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http://dx.doi.org/10.3390/molecules26051426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962014PMC
March 2021

Photoacoustic method for real-time assessment of salt content in aqueous solutions.

Talanta 2021 Jan 8;222:121497. Epub 2020 Aug 8.

Faculty of Pharmacy, University of Coimbra, Pólo Das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal; CQC, Department of Chemistry, University of Coimbra, Rua Larga, 3004-535, Coimbra, Portugal; Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Rua Larga, Faculty of Medicine, Pólo I, 1st Floor, 3004-504, Coimbra, Portugal. Electronic address:

In 2004, the Food and Drug Administration established the foundations for the application of process analytical technologies (PAT) in real-time control of the drug manufacturing process, where progress has been essentially directed to solid formulations. In order to enlarge the application of PAT principles to injectable drug products, the development of appropriate manufacturing process control tools is mandatory. Photoacoustics is a non-invasive technique with the potential for application in real-time control of the manufacturing process of injectable drug products. Herein, we applied a photoacoustic method for the determination of the concentration of salts (sodium chloride) in mono-salt formulations by measuring the changes induced in the speed of sound by density changes. This method was explored using two modes of generating the photoacoustic wave and two detectors with central frequencies of 10 MHz and 100 MHz. The results were analyzed using a 2 full-factorial design, considering the generation mode and detection as independent variables. The optimized method was subsequently validated according to the International Council for Harmonisation (ICH) standards. The method showed good linearity, precision, and accuracy, with a lower limit of quantification of 0.05% (w/v) of NaCl and a limit of detection of 0.02% (w/v) of NaCl. Due to its simplicity and high throughput, this method has potential applicability as PAT in the manufacturing of injectable drug products.
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http://dx.doi.org/10.1016/j.talanta.2020.121497DOI Listing
January 2021

Development and validation of a RP-HPLC method for the simultaneous analysis of paracetamol, ibuprofen, olanzapine, and simvastatin during microalgae bioremediation.

MethodsX 2020 28;7:101083. Epub 2020 Sep 28.

CQC, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.

A rapid reverse phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the simultaneous quantification of paracetamol, ibuprofen, olanzapine, simvastatin and simvastatin acid in the context of microalgae bioremediation. The method was validated according to the guidelines of the US Food and Drug Administration (FDA), the International Conference on Harmonization (ICH), and Eurachem with respect to system suitability, linearity, accuracy, precision, recovery, limits of detection and quantification, ruggedness, selectivity and specificity. The estimated limits of detection and quantification were, respectively, 0.03 and 0.10 µg mL for paracetamol, 0.03 and 0.09 µg mL for ibuprofen, 0.04 and 0.13 µg mL for olanzapine, 0.27 and 0.83 µg mL for simvastantin, and 0.05 and 0.14 µg mL for simvastantin acid. The inter-day and intra-day precision results were within the acceptance limit of relative standard deviation (%RSD) of less than 2, and the percentage recovery was found to be within the required limits of 80-110%. The developed method is rapid, linear, precise, robust and accurate, and has been successfully applied to the determination of the above common pharmaceutical products during microalgae bioremediation.
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http://dx.doi.org/10.1016/j.mex.2020.101083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569217PMC
September 2020

Diving into Batch-to-Batch Variability of Topical Products-a Regulatory Bottleneck.

Pharm Res 2020 Oct 9;37(11):218. Epub 2020 Oct 9.

Faculty of Pharmacy, University of Coimbra, Portugal, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.

Purpose: Following the recent European Medicine Agency (EMA) draft guideline on quality and equivalence of topical products, a modular framework for bioequivalence assessment is proposed, wherein the qualitative, quantitative, microstructure and product performance sameness is demanded to support generic applications. Strict regulatory limits are now imposed, but, the suitability of these limits has been subject of intense debate. In this context, this paper aims to address these issues by characterizing a panel of 8 reference blockbuster semisolid topical products.

Methods: For each product, three batches were selected and, whenever possible, batches retrieved from different manufacturing sites were considered. Product microstructure was evaluated in terms of globule size, pH, rheological attributes and, if required, the thermal behaviour was also assessed. Performance was evaluated through in vitro release testing (IVRT). Finally, an integrated multivariate analysis was performed to highlight the features that most contribute for product variability.

Results: Marked differences were registered within reference products. Statistical analysis demonstrated that if EMA criteria are applied, none of the same product batches can be considered as equivalent. Rheological parameters as well as IVRT indicators account for the majority of batch-to-batch differences.

Conclusions: Semisolid dosage forms exhibit intrinsic variability. This calls for the attention to the need of establishing reasonable equivalence criteria applied to generic drug products. Graphical abstract.
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http://dx.doi.org/10.1007/s11095-020-02911-yDOI Listing
October 2020

Removal of Pharmaceuticals from Water by Free and Imobilised Microalgae.

Molecules 2020 Aug 10;25(16). Epub 2020 Aug 10.

Centro de Química de Coimbra CQC, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.

Pharmaceuticals and their metabolites are released into the environment by domestic, hospital, and pharmaceutical industry wastewaters. Conventional wastewater treatment technology does not guarantee effluents of high quality, and apparently clean water may be loaded with pollutants. In this study, we assess the performance and efficiency of free and immobilised cells of microalgae sp. in removing four pharmaceuticals, chosen for their occurrence or persistence in the environment. These are paracetamol, ibuprofen, olanzapine and simvastatin. The results showed that free microalgae cells remain alive for a longer time than the immobilised ones, suggesting the inhibition of cell proliferation by the polymeric matrix polyvinyl alcohol. Both cells, free and immobilised, respond differently to each pharmaceutical. The removal of paracetamol and ibuprofen by sp., after 24 h of culture, was significantly higher in immobilised cells. Free cells removed a significantly higher concentration of olanzapine than immobilised ones, suggesting a higher affinity to this molecule than to paracetamol and ibuprofen. The results demonstrate the effectiveness of sp. free cells for removing olanzapine and sp. immobilised cells for removing paracetamol and ibuprofen.
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http://dx.doi.org/10.3390/molecules25163639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464271PMC
August 2020

Luminescent Properties of Lanthanoid-Poly(Sodium Acrylate) Composites: Insights on the Interaction Mechanism.

Polymers (Basel) 2020 Jun 9;12(6). Epub 2020 Jun 9.

CQC, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.

The interaction between polyelectrolytes and metal ions is governed by different types of interactions, leading to the formation of different phases, from liquid state to weak gels, through an appropriate choice of metal ion/polyelectrolyte molar ratio. We have found that lanthanide ions, europium(III) and terbium(III), are able to form polymer composites with poly(sodium acrylate). That interaction enhances the luminescent properties of europium(III) and terbium(III), showing that Eu/poly(sodium acrylate) (PSA) and Tb/PSA composites have a highly intense red and green emission, respectively. The effect of cations with different valences on the luminescent properties of the polymer composites is analyzed. The presence of metal ions tends to quench the composite emission intensity and the quenching process depends on the cation, with copper(II) being by far the most efficient quencher. The interaction mechanism between lanthanoid ions and PSA is also discussed. The composites and their interactions with a wide range of cations and anions are fully characterized through stationary and non-stationary fluorescence, high resolution scanning electronic microscopy and X-ray diffraction.
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http://dx.doi.org/10.3390/polym12061314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362023PMC
June 2020

Deep Learning for Deep Chemistry: Optimizing the Prediction of Chemical Patterns.

Front Chem 2019 26;7:809. Epub 2019 Nov 26.

Coimbra Chemistry Centre, CQC, Department of Chemistry, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal.

Computational Chemistry is currently a synergistic assembly between calculations, simulation, machine learning (ML) and optimization strategies for describing, solving and predicting chemical data and related phenomena. These include accelerated literature searches, analysis and prediction of physical and quantum chemical properties, transition states, chemical structures, chemical reactions, and also new catalysts and drug candidates. The generalization of scalability to larger chemical problems, rather than specialization, is now the main principle for transforming chemical tasks in multiple fronts, for which systematic and cost-effective solutions have benefited from ML approaches, including those based on deep learning (e.g. quantum chemistry, molecular screening, synthetic route design, catalysis, drug discovery). The latter class of ML algorithms is capable of combining raw input into layers of intermediate features, enabling bench-to-bytes designs with the potential to transform several chemical domains. In this review, the most exciting developments concerning the use of ML in a range of different chemical scenarios are described. A range of different chemical problems and respective rationalization, that have hitherto been inaccessible due to the lack of suitable analysis tools, is thus detailed, evidencing the breadth of potential applications of these emerging multidimensional approaches. Focus is given to the models, algorithms and methods proposed to facilitate research on compound design and synthesis, materials design, prediction of binding, molecular activity, and soft matter behavior. The information produced by pairing Chemistry and ML, through data-driven analyses, neural network predictions and monitoring of chemical systems, allows (i) prompting the ability to understand the complexity of chemical data, (ii) streamlining and designing experiments, (ii) discovering new molecular targets and materials, and also (iv) planning or rethinking forthcoming chemical challenges. In fact, optimization engulfs all these tasks directly.
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http://dx.doi.org/10.3389/fchem.2019.00809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988795PMC
November 2019

Antibacterial Photodynamic Inactivation of Antibiotic-Resistant Bacteria and Biofilms with Nanomolar Photosensitizer Concentrations.

ACS Infect Dis 2020 06 16;6(6):1517-1526. Epub 2020 Jan 16.

Chemistry Department, University of Coimbra 3004-535 Coimbra, Portugal.

Gram-negative bacteria and bacteria in biofilms are very difficult to eradicate and are the most antibiotic-resistant bacteria. Therapeutic alternatives less susceptible to mechanisms of resistance are urgently needed to respond to an alarming increase of resistant nosocomial infections. Antibacterial photodynamic inactivation (PDI) generates oxidative stress that triggers multiple cell death mechanisms that are more difficult to counteract by bacteria. We explore PDI of multidrug-resistant bacterial strains collected from patients and show how positive charge distribution in the photosensitizer drug impacts the efficacy of inactivation. We demonstrate the relevance of size for drug diffusion in biofilms. The designed -imidazolyl porphyrins of small size with positive charges surrounding the macrocycle enabled the inactivation of bacteria in biofilms by 6.9 log units at 5 nM photosensitizer concentration and 5 J cm, which offers new opportunities to treat biofilm infections.
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http://dx.doi.org/10.1021/acsinfecdis.9b00379DOI Listing
June 2020

aQbD as a platform for IVRT method development - A regulatory oriented approach.

Int J Pharm 2019 Dec 16;572:118695. Epub 2019 Sep 16.

Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Coimbra Chemistry Center, Department of Chemistry, University of Coimbra, Rua Larga, 3004-535 Coimbra, Portugal; Centre for Neurosciences and Cell Biology (CNC), University of Coimbra, Rua Larga, Faculty of Medicine, Pólo I, 1st Floor, 3004-504 Coimbra, Portugal. Electronic address:

The EMA draft guideline on quality and equivalence of topical products and the FDA non-binding product specific guidances release has encouraged the establishment of a regulatory background for in vitro release testing (IVRT). Herein, a novel framework applicable to the development of a discriminatory IVRT method is described, according to analytical quality by design (aQbD) principles. A commercially available diclofenac emulgel formulation was used as model product. Through the definition of IVRT analytical target profile, a risk assessment analysis was carried out, in which the critical analytical attributes (in vitro release rate, cumulative amount released at an initial/final point and dose depletion) and critical method variables (medium, membrane and dosage regimen) were identified. Based on this information, a 3 × 2 × 3 full factorial design was performed. Statistical modeling and system desirability assessment enabled the selection of the most suitable IVRT parameters, which were fully validated according with new EMA requirements. These consisted of PBS:Ethanol (80:20, pH = 7.4), Tuffryn membranes and 300 mg of applied product. aQbD provided a comprehensive framework for developing a reliable and effective IVRT method. A thorough analysis of the new EMA draft guideline requirements revealed that some of the established criteria may be challenging to attain.
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http://dx.doi.org/10.1016/j.ijpharm.2019.118695DOI Listing
December 2019

A novel Pd-catalysed sequential carbonylation/cyclization approach toward bis--heterocycles: rationalization by electronic structure calculations.

R Soc Open Sci 2018 Sep 12;5(9):181140. Epub 2018 Sep 12.

Coimbra Chemistry Centre, Departamento de Química, Universidade de Coimbra, Rua Larga, 3004-535 Coimbra, Portugal.

An unprecedented palladium-catalysed sequential aminocarbonylation/cyclization synthetic strategy, using carbon monoxide and structurally different aliphatic diamines as -nucleophiles, gives access, in one pot, to a new family of indole-based -heterocyclic derivatives (hydropyrazinones, benzodiazepinones and hydroquinoxalines). Optimization of the reaction conditions towards double carbonylation ( = 30 bar, = 80°C, iodoindole/diamine ratio = 1 : 1.5, toluene as solvent) allowed the target cyclic products, which are formed via intramolecular cyclization of the ketocarboxamide intermediates, to be obtained through a nucleophilic addition/elimination reaction with the pendant terminal amine groups. The structure of the diamine nucleophile was revealed to affect the reaction's selectivity, with the best yields for the cyclic products being obtained in the presence of (1,)-(+)-cyclohexane-1,2-diamine () as the nucleophile, using either 5- or 7-iodoindole as the substrate. The reaction's selectivity was rationalized based on electronic structure calculations, which explain the effect of the diamine structure on the predominant formation of the cyclic products.
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http://dx.doi.org/10.1098/rsos.181140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170558PMC
September 2018

Development of levofloxacin-loaded PLGA microspheres of suitable properties for sustained pulmonary release.

Int J Pharm 2019 Feb 7;556:117-124. Epub 2018 Dec 7.

INSERM, U 1070, Pôle Biologie Santé, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers, Cedex 9, France; University of Poitiers, Faculty of Medicine and Pharmacy, 6 rue de la Milétrie, TSA 51115, 86073 Poitiers, Cedex 9, France.

Aerosol antibiotics are an interesting alternative to oral or intravenous therapy in Cystic Fibrosis lung infections. Levofloxacin (LVX) inhaled solution is already an effective option. In this study, the aim was the development of LVX-loaded PLGA microspheres (MS) for pulmonary administration as a dry powder. MS were prepared, for the first time, by a modified double emulsion solvent evaporation method with premix membrane homogenization. Aqueous phases were saturated with LVX and a fatty acid (lauric acid) was added to avoid the drug escaping from the organic phase. MS were characterized in terms of size, drug content, morphology and in vitro release properties. X-ray diffraction, Fourier-transform infrared spectroscopy, differential and gravimetric thermal analysis, and cytotoxicity analyses were performed. Results showed this new method increased the drug loading while maintaining an adequate (∼5 µm) particle size and controlled release. Compared to a solution for inhalation, these properties combined with the dry-powder nature of these MS will improve patient compliance. The incorporation of lauric acid was not advantageous because the particle size was higher and no improvements concerning the sustained release occurred. LVX was molecularly dispersed in the matrix, or it was in amorphous state, as confirmed by the physico-chemical analyses. Calu-3 cell viability assays demonstrated no cytotoxicity for these MS, making them a promising system for LVX pulmonary delivery.
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http://dx.doi.org/10.1016/j.ijpharm.2018.12.005DOI Listing
February 2019

Host flexibility and space filling in supramolecular complexation of cyclodextrins: A free-energy-oriented approach.

Carbohydr Polym 2019 Feb 9;205:42-54. Epub 2018 Oct 9.

Coimbra Chemistry Centre, CQC, Faculty of Science and Technology, University of Coimbra, 3004-535 Coimbra, Portugal. Electronic address:

Cyclodextrins (Cds) are versatile carbohydrate hosts for developing multifunctional nanostructures of pharmaceutical interest. Factors affecting the thermodynamic signatures and stability of β- and γ-Cd complexes are detailed at the atomic level. The MD/PMF-based method is combined with the description of the nature and strength of the inter-partner affinity. Naphthalene, adamantane and lycorine derivatives are used as models of drug-leading structures. Guest size affects Cd-guest contact and the inclusion degree, inducing Cd deformation, which opposes inclusion. Complexation depends on the available Cd cavity volume, as guest fitting variations and the enthalpy penalty from Cd deformation impact on the binding constants (promoting a reduction of up to 10). The often neglected Cd deformation plays, thus, an important role in the interaction behavior of larger cavity Cd-based systems, being crucial in carbohydrate-mediated recognition phenomena. It corresponds to an increase in energy of ca. 90 kJ mol in the simpler analyzed model system.
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http://dx.doi.org/10.1016/j.carbpol.2018.10.009DOI Listing
February 2019

Adsorption of charged macromolecules upon multicomponent responsive surfaces.

Phys Chem Chem Phys 2018 Aug;20(30):19811-19818

Coimbra Chemistry Center, CQC, Faculty of Science and Technology, University of Coimbra, Portugal.

Adsorption of polyions onto charged surfaces has long been recognized as a crucial phenomenon in biological and technological applications. An intuitive model relating polyelectrolyte adsorption with the imposed features of polarizable surfaces of different compositions and charges is proposed based on Monte Carlo simulations using a coarse-grained approach. The excellent performance of the equation allows simultaneously describing a wide range of adsorption regimes and accounting for specific non-monotonic trends. For a constant surface charge density, the surface composition governs adsorption, promoting variations exceeding 100%. Adsorption increases with the number of attractive charges in the surface until reaching a maximum, decreasing thereafter due to the presence of polyanion-like charged particles. The presence of crowders hampers adsorption. These results can be used to efficiently predict and modulate the interaction between charged macromolecules and different substrates with direct implications in de novo designs of vehicles and biomedical devices.
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http://dx.doi.org/10.1039/c8cp03383hDOI Listing
August 2018

Analysis of raw EEM fluorescence spectra - ICA and PARAFAC capabilities.

Spectrochim Acta A Mol Biomol Spectrosc 2018 Dec 11;205:320-334. Epub 2018 Jul 11.

CQC, Department of Chemistry, University of Coimbra, Coimbra P-3004 535, Portugal.

Excitation-Emission fluorescence spectroscopy is a versatile technique and has been used to detect, characterize and quantify residual Dissolved Organic Matter (DOM) in aquatic domains. PARAllel FACtor Analysis (PARAFAC) has been extensively used in the analysis of excitation-emission matrices (EEM), allowing for a better identification and quantification of contributions resulting from spectral decomposition. In this work we have adapted Independent Component Analysis (ICA) in order to make it suitable to the analysis of three-way EEM datasets, and tested ICA and PARAFAC performances for the study of three available datasets (Claus, Dorrit and drEEM). Semi-empirical simulation allowed us to assess the impact of (a) sample size, (b) signal sources and (c) composition dependencies, and the presence of (d) unspecific signal contributions (e.g. light scattering) upon both algorithms. PARAFAC and ICA have similar performances in processing ideal three-way EEM datasets but, in the presence of non-trilinear responses, ICA leads to a more realistic approach, yielding a better decomposition of contributing sources and their identification and quantification. This makes this algorithm more suitable for the analysis of real, raw EEM data, without the need of preprocessing to remove any unspecific contributions.
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http://dx.doi.org/10.1016/j.saa.2018.07.025DOI Listing
December 2018

Combining Cellulose and Cyclodextrins: Fascinating Designs for Materials and Pharmaceutics.

Front Chem 2018 5;6:271. Epub 2018 Jul 5.

Coimbra Cemistry Centre, CQC, Department of Chemistry, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal.

Cellulose and cyclodextrins possess unique properties that can be tailored, combined, and used in a considerable number of applications, including textiles, coatings, sensors, and drug delivery systems. Successfully structuring and applying cellulose and cyclodextrins conjugates requires a deep understanding of the relation between structural, and soft matter behavior, materials, energy, and function. This review focuses on the key advances in developing materials based on these conjugates. Relevant aspects regarding structural variations, methods of synthesis, processing and functionalization, and corresponding supramolecular properties are presented. The use of cellulose/cyclodextrin conjugates as intelligent platforms for applications in materials science and pharmaceutical technology is also outlined, focusing on drug delivery, textiles, and sensors.
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http://dx.doi.org/10.3389/fchem.2018.00271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041395PMC
July 2018

Exploring PAZ/3'-overhang interaction to improve siRNA specificity. A combined experimental and modeling study.

Chem Sci 2018 Feb 15;9(8):2074-2086. Epub 2018 Jan 15.

Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) , Jordi Girona 18-26 , E-08034 Barcelona , Spain . Email: ; Email: ; Tel: +34 934006145.

The understanding of the dynamical and mechanistic aspects that lie behind siRNA-based gene regulation is a requisite to boost the performance of siRNA therapeutics. A systematic experimental and computational study on the 3'-overhang structural requirements for the design of more specific and potent siRNA molecules was carried out using nucleotide analogues differing in structural parameters, such as sugar constraint, lack of nucleobase, distance between the phosphodiester backbone and nucleobase, enantioselectivity, and steric hindrance. The results established a set of rules governing the siRNA-mediated silencing, indicating that the thermodynamic stability of the 5'-end is a crucial determinant for antisense-mediated silencing but is not sufficient to avoid sense-mediated silencing. Both theoretical and experimental approaches consistently evidence the existence of a direct connection between the PAZ/3'-overhang binding affinity and siRNA's potency and specificity. An overall description of the systems is thus achieved by atomistic simulations and free energy calculations that allow us to propose a robust and self-contained procedure for studying the factors implied in PAZ/3'-overhang siRNA interactions. A higher RNAi activity is associated with a moderate-to-strong PAZ/3'-overhang binding. Contrarily, lower binding energies compromise siRNA potency, increase specificity, and favor siRNA downregulation by Ago2-independent mechanisms. This work provides in-depth details for the design of powerful and safe synthetic nucleotide analogues for substitution at the 3'-overhang, enabling some of the intrinsic siRNA disadvantages to be overcome.
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http://dx.doi.org/10.1039/c8sc00010gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896489PMC
February 2018

Critical Role of the Spacer Length of Gemini Surfactants on the Formation of Ionic Liquid Crystals and Thermotropic Behavior.

J Phys Chem B 2017 11 9;121(46):10583-10592. Epub 2017 Nov 9.

CIQUP, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto , Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal.

Numerous reports have shown that the self-assembling properties of 12-s-12 bis(quaternary ammonium) gemini surfactants in aqueous solution are significantly influenced by s, the number of methylene groups in the covalent spacer. However, the role played by s on the phase behavior of the single compounds has not been investigated in a similarly systematic way. Here, we report on the thermotropic phase behavior of the anhydrous compounds with s = 2-6, 8, 10, and 12, resorting to differential scanning calorimetry (DSC), polarized light microscopy (PLM), and X-ray diffraction (XRD). All of the compounds show a stepwise melting behavior, decomposing at 200 °C. As the spacer length increases, nonmonotonic trends are observed for the thermodynamic parameters of the thermotropic phase transitions, mesophase formation, and solid-state d spacings. In particular, the number and type of mesophases (ordered smectic phases and/or fluid smectic liquid crystals) depend critically on s. Further, upon heating molecules with s < 8 decompose before the liquid phase, while those with long spacers, s = 8-12, reach the isotropization (clearing) temperature, hence forming both ionic liquid crystals and ionic liquid phases. We demonstrate that the melting behavior and type of ionic mesophases formed by gemini molecules can be usefully manipulated by a simple structural parameter like the length of the covalent linker.
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http://dx.doi.org/10.1021/acs.jpcb.7b08618DOI Listing
November 2017

Reconstructing the historical synthesis of mauveine from Perkin and Caro: procedure and details.

Sci Rep 2017 07 28;7(1):6806. Epub 2017 Jul 28.

Coimbra Chemistry Centre, Department of Chemistry, University of Coimbra, P3004-535, Coimbra, Portugal.

Mauveine, an iconic dye, first synthesised in 1856 still has secrets to unveil. If nowadays one wanted to prepare the original Perkin's mauveine, what would be the procedure? It will be described in this work and lies on the use of a 1:2:1 (mole) ratio of aniline, p-toluidine and o-toluidine. This was found from a comparison of a series of products synthesized from different proportions of these starting materials, with a set of historical samples of mauveine and further analysed with two unsupervised chemometrics methods.
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http://dx.doi.org/10.1038/s41598-017-07239-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533699PMC
July 2017

Structural Characterization of Bubbles Formed in DNA Melting: A Monte Carlo Simulation Study.

ACS Omega 2017 May 9;2(5):1915-1921. Epub 2017 May 9.

Theoretical Chemistry, Lund University, POB 124, SE-221 00 Lund, Sweden.

Bubbles in DNA are involved in many important biological processes. In this work, a coarse-grained model is used for characterizing bubbles formed in DNA melting. The model resorts only to electrostatic interactions at the Debye-Hückel level, in combination with a short-ranged attractive interaction within a base pair. In spite of also omitting atomistic details, the model is able to capture experimentally established trends in persistence length and radius of gyration. By applying it on different systems, it is possible to conclude that there is a minimum size for stable bubbles, in the interval between 12 and 20 bp, which agrees well with previously published experimental findings. Simulated scattering data distinguishes between different bubbles and detects conformational changes in the melting process. Therefore, SAXS is regarded as useful for bubble formation studies, while simulations provide a molecular understanding.
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http://dx.doi.org/10.1021/acsomega.7b00323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044833PMC
May 2017

Free-energy patterns in inclusion complexes: the relevance of non-included moieties in the stability constants.

Phys Chem Chem Phys 2017 Feb;19(7):5209-5221

Coimbra Chemistry Centre, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.

Inclusion complexes play a definite role in a variety of applications, ranging from drug solubilization to smart materials. This work presents a series of studies based on molecular dynamics, including potential of mean force calculations, and aiming at understanding the factors that govern inclusion. Naphthalene and its derivatives are used as guests for a common host, β-cyclodextrin. It is observed that the substitution of naphthalene promotes an increase in the complexation constant (up to 100-fold), irrespective of the nature of the substituent, the latter comprising small hydrophobic and hydrophilic (including charged) groups. It is also seen that entropy does not favor inclusion, the order of magnitude of the binding free energy being given by the enthalpic component, with a dominating guest-host interaction contribution. Desolvation penalizes the inclusion process, and is not observed in the vicinity of the hydrophilic and charged groups, which remain exposed to the solvent. Results suggest that substantial modulation of the inclusion complexes can be achieved imposing different substituents, with direct transposition for the modulation of properties in supramolecular structures based on these complexes.
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http://dx.doi.org/10.1039/c6cp08081bDOI Listing
February 2017

Pulmonary pharmacokinetics of levofloxacin in rats after aerosolization of immediate-release chitosan or sustained-release PLGA microspheres.

Eur J Pharm Sci 2016 Oct 13;93:184-91. Epub 2016 Aug 13.

INSERM, U 1070, Pôle Biologie Santé, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9, France; Université de Poitiers, Faculté de Médecine et Pharmacie, 6 rue de la Milétrie, TSA 51115, 86073 Poitiers Cedex 9, France; CHU Poitiers, 2 rue de la Milétrie, 86000 Poitiers, France.

A comparative pharmacokinetic study was conducted in rats after intratracheal aerosolization of levofloxacin, as a solution, as immediate-release chitosan microspheres or as sustained-release PLGA microspheres. A pharmacokinetic model was constructed to model levofloxacin concentrations both in plasma and in the lung epithelial lining fluid (ELF). The plasma and ELF experimental concentration profiles versus time were similar for the intravenous and intratracheal levofloxacin solutions and for the intratracheal levofloxacin-loaded chitosan microsphere dry powder, indicating that levofloxacin diffused almost instantaneously through the broncho-alveolar barrier and that the chitosan microspheres released levofloxacin very rapidly, as anticipated from in vitro release studies. The bioavailability for the intratracheal levofloxacin solution and intratracheal chitosan microspheres was estimated to be 98% and 71%, respectively, both with a direct release into the ELF compartment. The ELF-to-unbound plasma AUC ratios were slightly above 2 and may result from an efflux transport. For the intratracheal PLGA microspheres, a high ELF-to-unbound plasma AUC concentration ratio (311) was observed and high levofloxacin concentrations were maintained in ELF for at least 72h in consistency with the in vitro release studies. The bioavailability was 92%, with 19% of the dose released immediately (burst release) into the ELF and 73% released slowly into the ELF from a depot compartment, i.e. the PLGA microspheres, according to a Weibull model. These results highlight the benefit of using sustained-release microspheres administered as aerosols to provide and to maintain high pulmonary concentrations of an antibiotic characterized with a high permeability profile through the broncho-alveolar barrier. The sustained-release microsphere dry powder aerosol may therefore provide advantages over solutions or pure drug dry powders for inhalation in terms of treatment efficiency, ease of use and frequency of administration.
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http://dx.doi.org/10.1016/j.ejps.2016.08.024DOI Listing
October 2016

Cyanobacteria and microalgae: a renewable source of bioactive compounds and other chemicals.

Sci Prog 2015 ;98(Pt 2):145-68

Microalgae and cyanobacteria are rich sources of many valuable compounds, including important bioactive and biotechnologically relevant chemicals. Their enormous biodiversity, and the consequent variability in the respective biochemical composition, make microalgae cultivations a promising resource for many novel chemically and biologically active molecules and compounds of high commercial value such as lipids and dyes. The nature of the chemicals produced can be manipulated by changing the cultivation media and conditions. Algae are extremely versatile because they can be adapted to a variety of cell culture conditions. They do not require arable land, can be cultivated on saline water and wastewaters, and require much less water than plants. They possess an extremely high growth rate making these microorganisms very attractive for use in biofuel production--some species of algae can achieve around 100 times more oil than oil seeds. In addition, microalgae and cyanobacteria can accumulate various biotoxins and can contribute to mitigate greenhouse gases since they produce biomass through carbon dioxide fixation. In this review, we provide an overview of the application of microalgae in the production of bioactive and other chemicals.
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http://dx.doi.org/10.3184/003685015X14298590596266DOI Listing
September 2015

Synthesis of chiral hexacyclic steroids via [8π + 2π] cycloaddition of diazafulvenium methides.

Org Biomol Chem 2015 Sep 30;13(34):9127-39. Epub 2015 Jul 30.

Centro de Química de Coimbra, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.

First examples of [8π + 2π] cycloaddition of 16-dehydropregnenolone (16-DPA) acetate with diazafulvenium methides leading to chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused steroids are reported. These hexacyclic steroids were obtained exclusively or selectively with the approach of the 1,7-dipole by the less hindered α-face of 16-DPA. Quantum chemical calculations at the DFT level were carried out, using the cycloaddition of 1-methyl- and 1-benzyl-diazafulvenium methides with N-phenylmaleimide as model reactions, in order to rationalize the stereochemistry outcome. The results indicate that endo cycloadditions of the more stable dipole conformation, having the 1-substituent pointing outward, are significantly more favorable than the alternative exo cycloaddition.
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http://dx.doi.org/10.1039/c5ob01110hDOI Listing
September 2015

Optimization of levofloxacin-loaded crosslinked chitosan microspheres for inhaled aerosol therapy.

Eur J Pharm Biopharm 2015 Oct 17;96:65-75. Epub 2015 Jul 17.

INSERM, U 1070, Pôle Biologie Santé, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9, France; University of Poitiers, Faculty of Medicine and Pharmacy, 6 rue de la Milétrie, TSA 51115, 86073 Poitiers Cedex 9, France.

The aim of this work was the development of innovative levofloxacin-loaded swellable microspheres (MS) for the dry aerosol therapy of pulmonary chronicPseudomonas aeruginosainfections in Cystic Fibrosis patients. In a first step, a factorial design was applied to optimize formulations of chitosan-based MS with glutaraldehyde as crosslinker. After optimization, other crosslinkers (genipin, glutaric acid and glyceraldehyde) were tested. Analyses of MS included aerodynamic and swelling properties, morphology, drug loading, thermal and chemical characteristics,in vitroantibacterial activity and drug release studies. The prepared MS presented a drug content ranging from 39.8% to 50.8% of levofloxacin in an amorphous or dispersed state, antibacterial activity and fast release profiles. The highest degree of swelling was obtained for MS crosslinked with glutaric acid and genipin. These formulations also presented satisfactory aerodynamic properties, making them a promising alternative, in dry-powder inhalers, to levofloxacin solution for inhalation.
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http://dx.doi.org/10.1016/j.ejpb.2015.07.010DOI Listing
October 2015

Confined polyelectrolytes: The complexity of a simple system.

J Comput Chem 2015 Aug 12;36(21):1579-86. Epub 2015 Jun 12.

CQC, Department of Chemistry, University of Coimbra, Rua Larga, 3004-535, Coimbra, Portugal.

The interaction between polyelectrolytes and counterions in confined situations and the mutual relationship between chain conformation and ion condensation is an important issue in several areas. In the biological field, it assumes particular relevance in the understanding of the packaging of nucleic acids, which is crucial in the design of gene delivery systems. In this work, a simple coarse-grained model is used to assess the cooperativity between conformational change and ion condensation in spherically confined backbones, with capsides permeable to the counterions. It is seen that the variation on the degree of condensation depends on counterion valence. For monovalent counterions, the degree of condensation passes through a minimum before increasing as the confining space diminishes. In contrast, for trivalent ions, the overall tendency is to decrease the degree of condensation as the confinement space also decreases. Most of the particles reside close to the spherical wall, even for systems in which the density is higher closer to the cavity center. This effect is more pronounced, when monovalent counterions are present. Additionally, there are clear variations in the charge along the concentric layers that cannot be totally ascribed to polyelectrolyte behavior, as shown by decoupling the chain into monomers. If both chain and counterions are confined, the formation of a counterion rich region immediately before the wall is observed. Spool and doughnut-like structures are formed for stiff chains, within a nontrivial evolution with increasing confinement.
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http://dx.doi.org/10.1002/jcc.23969DOI Listing
August 2015

Novel serine-based gemini surfactants as chemical permeation enhancers of local anesthetics: A comprehensive study on structure-activity relationships, molecular dynamics and dermal delivery.

Eur J Pharm Biopharm 2015 Jun 6;93:205-13. Epub 2015 Mar 6.

Pharmaceutical Technology Department, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal. Electronic address:

This work aims at studying the efficacy of a series of novel biocompatible, serine-based surfactants as chemical permeation enhancers for two different local anesthetics, tetracaine and ropivacaine, combining an experimental and computational approach. The surfactants consist of gemini molecules structurally related, but with variations in headgroup charge (nonionic vs. cationic) and in the hydrocarbon chain lengths (main and spacer chains). In vitro permeation and molecular dynamics studies combined with cytotoxicity profiles were performed to investigate the permeation of both drugs, probe skin integrity, and rationalize the interactions at molecular level. Results show that these enhancers do not have significant deleterious effects on the skin structure and do not cause relevant changes on cell viability. Permeation across the skin is clearly improved using some of the selected serine-based gemini surfactants, namely the cationic ones with long alkyl chains and shorter spacer. This is noteworthy in the case of ropivacaine hydrochloride, which is not easily administered through the stratum corneum. Molecular dynamics results provide a mechanistic view of the surfactant action on lipid membranes that essentially corroborate the experimental observations. Overall, this study suggests the viability of these serine-based surfactants as suitable and promising delivery agents in pharmaceutical formulations.
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http://dx.doi.org/10.1016/j.ejpb.2015.02.024DOI Listing
June 2015

Combining polyethylenimine and Fe(III) for mediating pDNA transfection.

Biochim Biophys Acta 2015 Jun 19;1850(6):1325-35. Epub 2015 Feb 19.

Department of Chemistry, University of Coimbra, Rua Larga, Coimbra 3004-535, Portugal.

Background: The potential use of Fe(III) ions in biomedical applications may predict the interest of its combination with pDNA-PEI polyplexes. The present work aims at assessing the impact of this metal on pDNA complex properties.

Methods: Variations in the formation of complexes were imposed by using two types of biological buffers at different salt conditions. The incorporation of pDNA in complexes was characterised by gel electrophoresis and dynamic light scattering. Transfection efficiency and cytotoxicity were evaluated in HeLa and HUH-7 cell lines, supported by flow cytometry assays.

Results: Fe(III) enhances pDNA incorporation in the complex, irrespective of the buffer used. Transfection studies reveal that the addition of Fe(III) to complexes at low ionic strength reduces gene transfection, while those prepared under high salt content do not affect or, in a specific case, increase gene transfection up to 5 times. This increase may be a consequence of a favoured interaction of polyplexes with cell membrane and uptake. At low salt conditions, results attained with chloroquine indicate that the metal may inhibit polyplex endosomal escape. A reduction on the amount of PEI (N/P 5) formed at intermediary ionic strength, complemented by Fe(III), reduces the size of complexes while maintaining a transfection efficiency similar to that obtained to N/P 6.

Conclusions: Fe(III) emerges as a good supporting condensing agent to modulate pDNA-PEI properties, including condensation, size and cytotoxicity, without a large penalty on gene transfection.

General Significance: This study highlights important aspects that govern pDNA transfection and elucidates the benefits of incorporating the versatile Fe(III) in a gene delivery system.
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http://dx.doi.org/10.1016/j.bbagen.2015.02.007DOI Listing
June 2015

Reactions of nitrosoalkenes with dipyrromethanes and pyrroles: insight into the mechanistic pathway.

J Org Chem 2014 Nov 21;79(21):10456-65. Epub 2014 Oct 21.

Department of Chemistry, University of Coimbra , 3004-535 Coimbra, Portugal.

The reactivity of nitrosoalkenes toward dipyrromethanes, pyrrole, and 2,5-dimethylpyrrole is described. 1-(p-Bromophenyl)nitrosoethylene shows a different chemical behavior with these heterocycles than the previously reported reactions of ethyl nitrosoacrylate, which proceeds via a Diels-Alder reaction. 1-(p-Bromophenyl)nitrosoethylene reacts with dipyrromethanes and pyrrole to afford two isomeric oximes via conjugate addition followed by rearomatization of the pyrrole unit. On the other hand, this nitrosoalkene reacts with 2,5-dimethylpyrrole through an initial conjugate addition followed by intramolecular O- and N-nucleophilic addition with the formation of the corresponding bicyclic oxazine and five-membered cyclic nitrone, respectively. Quantum chemical calculations, at the DFT level of theory, indicate that the barriers associated with the Diels-Alder reactions of ethyl nitrosoacrylate are over 30 kJ/mol lower than those that would be required for the cycloadditions of 1-(p-bromophenyl)nitrosoethylene. Thus, calculations predict that the Diels-Alder reaction is privileged in the case of ethyl nitrosoacrylate and point to a different reaction pathway for 1-(p-bromophenyl)nitrosoethylene, corroborating the experimental findings.
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http://dx.doi.org/10.1021/jo502095kDOI Listing
November 2014
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