A comparison between pure active pharmaceutical ingredients and therapeutic deep eutectic solvents: solubility and permeability studies

THEDES, so called therapeutic deep eutectic solvents are here defined as a mixture of two components, which at a particular molar composition become liquid at room temperature and in which one of them is an active pharmaceutical ingredient (API). In this work, THEDES based on menthol complexed with three different APIs, ibuprofen (ibu), BA (BA) and phenylacetic acid (PA), were prepared. The interactions between the components that constitute the THEDES were studied by NMR, confirming that the eutectic system is formed by H-bonds between menthol and the API. The mobility of the THEDES components was studied by PFGSE NMR spectroscopy. It was determined that the self-diffusion of the species followed the same behavior as observed previously for ionic liquids, in which the components migrate via jumping between voids in the suprastructure created by punctual thermal fluctuations. The solubility and permeability of the systems in an isotonic solution was evaluated and a comparison with the pure APIs was established through diffusion and permeability studies carried out in a Franz cell. The solubility of the APIs when in the THEDES system can be improved up to 12 fold, namely for the system containing ibu. Furthermore, for this system the permeability was calculated to be 14 105 cm/s representing a 3 fold increase in comparison with the pure API. With the exception of the systems containing PA an increase in the solubility, coupled with an increase in permeability was observed. In this work, we hence demonstrate the efficiency of THEDES as a new formulation for the enhancement of the bioavailability of APIs by changing the physical state of the molecules from a solid dosage to a liquid system.he European Union’s Seventh Framework Programme (FP7/2007- 2013) under grant agreement nREGPOT-CT2012-316331- POLARIS and from Project ‘‘Novel smart and biomimetic materials for innovative regenerative medicine approaches (Ref.: RL1 - ABMR - NORTE-01-0124-FEDER-000016)” co-financed by North Portugal Regional Operational Programme (ON.2 – O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF). Funding was also provided by Fundação para a Ciência e a Tecnologia, through contracts LAQV-REQUIMTE: UID/QUI/50006/2013 and UCIBIOREQUIMTE: UID/Multi/04378/2013. This work was co-financed by the ERDF under the PT2020 Partnership Agreement (POCI-01- 0145-FEDER-007728).info:eu-repo/semantics/publishedVersio

Interaction of a potential antitumoral benzothieno[3,2-b]pyrrole with lipid membranes and salmon sperm DNA

This work was funded by FCT and FEDER through CQ-UM and CFUM, project POCI/QUI/59407/2004 and post-Doc grant (SFRH/BPD/24548/2005) of A.S.A

Fluorescence studies on potential antitumoral heteroaryl and heteroannulated indoles in solution and in lipid membranes

Fluorescence properties of three potential antitumoral compounds, a 3-(dibenzothien-4-yl)indole 1, a phenylbenzothienoindole 2 and a 3-(dibenzofur-4-yl)indole 3, were studied in solution and in lipid aggregates of dipalmitoyl phosphatidylcholine (DPPC), dioleoyl phosphatidylethanolamine (DOPE) and egg yolk phosphatidylcholine (Egg-PC). The 3-(dibenzofur-4-yl)indole 3 exhibits the higher fluorescence quantum yields in all solvents studied (0.32 ≤ ΦF ≤ 0.51). All the compounds present a solvent sensitive emission, with significant red shifts in alcohols. The results point to an ICT character of the excited state, more pronounced for compound 1. Fluorescence (steady-state) anisotropy measurements of the compounds incorporated in lipid aggregates of DPPC, DOPE and Egg-PC indicate that the three compounds are deeply located in the lipid bilayer, feeling the difference between the rigid gel phase and fluid phases.Fundação para a Ciência e a Tecnologia (FCT) - Projecto POCI/QUI/59407/2004, bolsa doutoramento SFRH/BPD/24548/2005Fundo Europeu de Desenvolvimento Regional (FEDER

Fluorescence studies of new potential antitumoral indole derivatives in lipid membranes

This work was funded by FCT and FEDER through CFUM and CQ-UM, project POCI/QUI/59407/2004 and post-Doc grant (SFRH/BPD/24548/2005) of A.S.

Toward Light-Controlled Supramolecular Peptide Dimerization

The selective photodeprotection of the NVoc-modified FGG tripeptide yields the transformation of its 1:1 receptor−ligand complex with cucurbit[8]uril into a homoternary FGG2@CB8 assembly. The resulting lightinduced dimerization of the model peptide provides a tool for the implementation of stimuli-responsive supramolecular chemistry in biologically relevant contexts.The work was supported by the Associate Laboratory for Green ChemistryLAQV (UIDB/50006/2020) and by the Applied Molecular Biosciences UnitUCIBIO (UIDB/ 04378/2020), both financed by FCT. FCT/MCTES is also acknowledged for supporting the National Portuguese NMR Network (ROTEIRO/0031/2013-PINFRA/22161/2016, cofinanced by FEDER through COMPETE 2020, POCI, PORL, and FCT through PIDDAC) and for the grants PTDC/QUICOL/32351/2017, PTDC/QUI-QFI/30951/2017, and CEECIND/00466/2017 (N.B.). U.P. thanks the Spanish Ministry of Science, Innovation, and Universities (CTQ2017-89832-P). We are grateful to Dr. J.P. Da Silva for the mass spectrometry data (equipment financed by CRESC Algarve 2020 and COMPETE 2020; project EMBRC.PT ALG-01-0145-FEDER022121). Funding for open access charge: Universidad de Huelva / CBU

Jatrophane and lathyrane diterpenoids from Euphorbia hyberna L

A new diterpene tetraester, from the jatrophane family, and two new diterpene triesters, with a lathyrane skeleton, have been isolated from the chloroform extract of the roots of Euphorbia hyberna L. The structures of these compounds have been established by spectroscopic methods, including 2D NMR experiments.info:eu-repo/semantics/publishedVersio

Chemical constituents of Euphorbia hyberna L. (Euphorbiaceae)

Chemical investigation of the aerial part and the roots of Euphorbia hyberna L. subs. hyberna. resulted in the isolation and identification of four triterpenoids (3�-O-octadecanoyllupeol (1), glut-5-en-3�-ol (2), 24-methylenecicloartan-3�-ol (3) and cicloart-23-ene-3�,25-diol (6)) along with the phenolic compounds ellagic acid (4) and 3,30 -di-O-methylellagic acid (7). Although these are all known compounds, this is the first report of their isolation from this plant. Their structures were elucidated on the basis of spectral methods, including 2D NMR experiences, and confirmed by comparing with the literature data.info:eu-repo/semantics/publishedVersio

Increased extracellular polymeric substances production contributes for the robustness of aerobic granular sludge during long-term intermittent exposure to 2-fluorophenol in saline wastewater

Industrial effluents often contain organic pollutants and variable salinity levels, making their treatment challenging. The high content of extracellular polymeric substances (EPS) in the aerobic granular sludge (AGS) is thought to protect the microbial communities from stressful conditions. Ammonium and phosphate removal, EPS production, and granular morphology were assessed in a lab-scale AGS reactor operated during 138 days at continuous low or moderate salinity levels (1.41â6.46 g/L of NaCl) and intermittent short-term loadings of a fluoroorganic pollutant, 2-fluorophenol (2-FP, 20 mg/L). 2-FP was not degraded throughout operation. Ammonium removal efficiency was drastically affected whenever 2-FP stressor was present, decreasing from 99 % to non-detectable conversion levels, but completely recovering after 2-FP feeding ceased. Phosphate removal, initially disturbed by exposure to stress conditions, recovered with time, even when stressors were still present. Complete phosphate removal did not occur in periods when nitrite temporarily accumulated after nitrification started to recover. EPS composition and concentration in AGS varied during operation, initially decreasing from 133 to 34 mg/g VSS of AGS, during the stress phases but recovering thereafter to 176 mg/gVSS of AGS. Breakage of granules into smaller ones occurred at two different operational moments due to stressors presence. The presence of 2-FP and moderate salinity levels in wastewater had more immediate detrimental effects on nutrients removal than on EPS production. The AGS system capacity to recover the nutrient removal performance and EPS production, after the withdrawal of 2-FP from the inlet stream reinforced its robustness to deal with industrial wastewaters.The authors wish to thank the company Aguas ´ do Tejo Atlantico, S.A. for supplying the granules. This work was financed by Fundação para a Ciência e Tecnologia (FCT, Portugal) under the project AGeNT - PTDC/ BTA-BTA/31264/2017 (POCI-01-0145-FEDER-031264). We would like to thank the scientific collaboration of CBQF under the FCT project UID/Multi/50016/2019 and NORTE-08-5369-FSE-000007 and CEB under the FCT project UID/BIO/044697/2019 and BioTecNorte operation (NORTE-01-0145-FEDER-000004).info:eu-repo/semantics/publishedVersio

New tetracyclic heteroaromatic compounds based on dehydroamino acids : photophysical and electrochemical studies of interaction with DNA

A benzothienoindole (BTIN) and a benzofuroindole (BFIN) were synthesized in high yields, as potential new target DNA compounds, using a metal-assisted intramolecular C-N cyclization, developed by us, of the methyl esters of N-(t-butoxycarbonyl)-b,b-bis(dibenzothien-4-yl or dibenzofuro-4-yl)dehydroalanines. The latter were obtained by a bis-Suzuki coupling of a b,b-dibromodehydroalanine with the corresponding heteroarylboronic acids. The absorption and fluorescence properties of the novel tetracyclic heteroaromatic compounds were studied in different solvents and in the presence of natural double-stranded (ds) salmon sperm DNA. The results in several solvents show that either BTIN or BFIN can be used as fluorescence solvent sensitive probes. Spectroscopic studies of the interaction of both compounds with dsDNA allowed to determine binding constant (Ki) values and binding site sizes (n). Fluorescence quenching experiments using iodide ion allowed the determination of the accessibilities to the quencher, showing that intercalation is the preferred mode of binding of these molecules to DNA. From the results obtained BTIN is the more intercalative compound and has a higher affinity to DNA. The interaction of this more promising compound with DNA was also studied electrochemically, by using differential pulse voltammetry (DPV) in connection with disposable pencil graphite electrode (PGE). These studies are based on the differences in the BTIN and adenine oxidation signals. After the interaction of BTIN with DNA, the oxidation signals of BTIN and adenine strongly decreased. The latter was attributed to the binding of the BTIN to DNA and the former points to a possible damage of the oxidizable groups of the compound after intercalation into DNA. Several concentrations of BTIN were tested and 50 μg/mL was found to be the optimum concentration in order to detect its interaction with DNA. In addition, the detection limit and the reproducibility were determined by using a disposable electrochemical transducer. The results of spectroscopic and electrochemical detection of BTIN interaction with DNA are in good agreement.Academy of Pharmacists and Turkish Pharmacists Association (TEB)Turkish Academy of Sciences - Young Scientist Award Program (KAE/TUBA-GEBIP/2001-2-8)FEDERFundação para a Ciência e a Tecnologia (FCT) - Projecto POCI/QUI/59407/2004. A.S.A. acknowledges a post-doc. grant SFRH/BPD/24548/2005, Bolsa SFRH/BPD/24548/2005.Scientific and Technical Research Council of Turkey (TUBITAK)