Person: Martín Carmona, María Antonia
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First Name
María Antonia
Last Name
Martín Carmona
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Química en Ciencias Farmacéuticas
Area
Química Analítica
Identifiers
6 results
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Now showing 1 - 6 of 6
Item Eco-friendly liquid chromatographic separations based on the use of cyclodextrins as mobile phase additives(Green Chemistry, 2011) González Ruiz, Víctor; León Leal, Andrés Gerardo; Menéndez Ramos, José Carlos; Martín Carmona, María Antonia; Olives Barba, Ana IsabelAcetonitrile and methanol are the most popular solvents employed in analytical HPLC, but they suffer from a number of drawbacks from the environmental point of view. Alternative, greener mobile phases employing methanol or the less toxic solvent ethanol as the sole organic solvent are proposed in this paper, and applied to the problem of the separation of b-carbolines on C18-stationary phases. The use of b-cyclodextrin (b-CD) and (2-hydroxypropyl)-b-cyclodextrin (HPb-CD) as mobile phase additives allowed us to increase the proportion of water in the mobile phases without loss in the resolution or efficiency of the separations, leading initially to a considerable reduction of the proportion of methanol in the mobile phase (from 70% to 50%) and at a later stage, to the development of a mobile phase containing only 30% of ethanol. The b-carboline–cyclodextrin association constants were determined by HPLC, and the inclusion complexes were also characterized by 1 H-NMR, 13C-NMR and 2D-ROESY experiments, and these studies were used to explain the chromatographic behaviour. The new chromatographic methodology developed was validated and applied to the quantitation of b-carboline derivatives in spiked human serum samples. For the extraction of b-carboline alkaloids from serum samples, liquid–liquid extraction (LLE) and solid-phase extraction (SPE) procedures were compared. It was concluded that the combination of a pre-treatment procedure (ionic exchange SPE) with a water-enriched chromatographic separation leads to a promising, environmentally friendly new methodology.Item Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation(Antioxidants, 2021) Cores Esperón, Ángel; Abril Comesaña, Sheila; Michalska Dziama, Patrycja; Duarte, Pablo; Olives Barba, Ana Isabel; Martín Carmona, María Antonia; Villacampa Sanz, Mercedes; León Martínez, Rafael; Menéndez Ramos, José CarlosOxidative stress is crucial to the outbreak and advancement of neurodegenerative diseases and is a common factor to many of them. We describe the synthesis of a library of derivatives of the 4-arylmethylen-2-pyrrolin-5-one framework by sequential application of a three-component reaction of primary amines, β-dicarbonyl compounds, and α-haloketones and a Knoevenagel condensation. These compounds can be viewed as cyclic amides of caffeic and ferulic acids, and are also structurally related to the bisavenanthramide family of natural antioxidants. Most members of the library showed low cytotoxicity and good activity as inductors of Nrf2, a transcription factor that acts as the master regulator of the antioxidant response associated with activation of the antioxidant response element (ARE). Nrf2-dependent protein expression was also proved by the significant increase in the levels of the HMOX1 and NQO1 proteins. Some compounds exerted neuroprotective properties in oxidative stress situations, such as rotenone/oligomycin-induced toxicity, and also against protein hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. Compound 3i, which can be considered a good candidate for further hit-to-lead development against neurodegenerative diseases due to its well-balanced multitarget profile, was further characterized by proving its ability to reduce phosphorylated Tau levels.Item Bifunctional carbazole derivatives for simultaneous therapy and fluorescence imaging in prion disease murine cell models(European Journal of Medicinal Chemistry, 2022) Staderini, Matteo; Vanni, Silvia; Colini Baldeschi, Arianna; Zattoni, Marco; Celauro, Luigi; Ferracin, Chiara; Bistaffa, Edoardo; Moda, Fabio; Pérez, Daniel I.; Martínez, Ana; Martín Carmona, María Antonia; Martín Cámara, Olmo; Cores Esperón, Ángel; Bianchini, Giulia; Kammerer, Robert; Menéndez Ramos, José Carlos; Legname, Giuseppe; Bolognesi, Maria LauraPrion diseases are characterized by the self-assembly of pathogenic misfolded scrapie isoforms (PrPSc) of the cellular prion protein (PrPC). In an effort to achieve a theranostic profile, symmetrical bifunctional carbazole derivatives were designed as fluorescent rigid analogues of GN8, a pharmacological chaperone that stabilizes the native PrPC conformation and prevents its pathogenic conversion. A focused library was synthesized via a four- step route, and a representative member was confirmed to have native fluorescence, including a band in the near- infrared region. After a cytotoxicity study, compounds were tested on the RML-infected ScGT1 neuronal cell line, by monitoring the levels of protease-resistant PrPSc. Small dialkylamino groups at the ends of the molecule were found to be optimal in terms of therapeutic index, and the bis-(dimethylaminoacetamido)carbazole derivative 2b was selected for further characterization. It showed activity in two cellClines infected with the mouse-adapted RML strain (ScGT1 and ScN2a). Unlike GN8, 2b did not affect PrP levels, which represents a potential advantage in terms of toxicity. Amyloid Seeding Assay (ASA) experiments showed the capacity of 2b to delay the aggregation of recombinant mouse PrP. Its ability to interfere with the amplification of the scrapie RML strain by Protein Misfolding Cyclic Amplification (PMCA) was shown to be higher than that of GN8, although 2b did not inhibit the amplification of human vCJD prion. Fluorescent staining of PrPSc aggregates by 2b was confirmed in living cells. 2b emerges as an initial hit compound for further medicinal chemistry optimization towards strain- independent anti-prion compounds.Item Fluorescence properties of the anti-tumour alkaloid luotonin A and new synthetic analogues: pH modulation as an approach to their fluorimetric quantitation in biological samples(Journal of Luminescence, 2012) González Ruiz, Víctor; González-Cuevas, Yamisley; Arunachalam, Sankaralingam; Martín Carmona, María Antonia; Olives Barba, Ana Isabel; Ribelles, Pascual; Ramos García, María Teresa; Menéndez Ramos, José CarlosLuotonin A is an alkaloid structurally related to the natural anti-tumour agent camptothecin. The fluorescence behaviour of luotonin A and a series of six analogues is described in the present work. The influence of solvent polarity and pH on the native fluorescence properties of these alkaloids was studied, finding that in organic solvents or in aqueous solutions (pH 5.5–7.2) the neutral form of the luotonin derivatives emit in the region of 410–450 nm but, in both media, acidification to pH values below 3.0 causes a new emission band to appear at about 500 nm. An ESPT reaction occurs due to the protonation of the basic nitrogen atoms of the pentacyclic ring. Acid-base titrations of luotonin A and its derivatives in aqueous and acetonitrile media were carried out in order to determine their pKa n values which were around 2, showing these compounds to be very weak bases. In aqueous media, the absence of an iso-emissive point in the emission spectra suggests the existence of more than two species in the proton transfer equilibria. The basicity of the luotonin A derivatives is increased in organic media, and a good correlation between the pKa n values and the chemical structure was found. The protonation of luotonin A was also studied by 1 H-NMR and 13C-NMR experiments, which proved the protonation of the nitrogen atoms at the positions 5 and 6 of the pentacyclic ring. The fluorescence quantum yields were determined in ethanol and in aqueous solutions under neutral and acidic conditions. The fluorescence quantum yields were higher in water for the case of the more polar compounds, and the opposite result was obtained for the more hydrophobic ones. The remarkable and interesting fluorescence properties of luotonin A prompted the development of its fluorimetric analytical quantitation, obtaining very good analytical featuresItem A fluorescent styrylquinoline with combined therapeutic and diagnostic activities against alzheimer’s and prion diseases(ACS Medicinal Chemistry Letters, 2013) Staderini, Matteo; Aulić, Suzana; Bartolini, Manuela; Tran, Hoang Ngoc Ai; González-Ruiz, Víctor; Pérez, Daniel I.; Martínez Gil, Ana; Andrisano, Vincenza; Legname, Giuseppe; Menéndez Ramos, José Carlos; Bolognesi, Maria Laura; Cabezas Baudot, Nieves; Martín Carmona, María Antonia(E)-6-Methyl-4′-amino-2-styrylquinoline (3) is a small molecule with the proper features to potentially diagnose, deliver therapy and monitor response to therapy in protein misfolding diseases. These features include compound fluorescent emission in the NIR region and its ability to interact with both Aβ and prion fibrils, staining them with high selectivity. Styrylquinoline 3 also inhibits Aβ self-aggregation in vitro and prion replication in the submicromolar range in a cellular context. Furthermore, it is not toxic and is able to cross the blood brain barrier in vitro (PAMPA test).Item Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin Complexation(Pharmaceutics, 2021) González Ruiz, Víctor; Cores Esperón, Ángel; Martín Cámara, Olmo; Serrano Orellana, Karen; Michalska Dziama, Patrycja; Cervera Carrascón, Víctor Enrique; León Martínez, Rafael; Olives Barba, Ana Isabel; Martín Carmona, María Antonia; Menéndez Ramos, José CarlosThe use of cyclodextrins as drug nano-carrier systems for drug delivery is gaining importance in the pharmaceutical industry due to the interesting pharmacokinetic properties of the resulting inclusion complexes. In the present work, complexes of the anti-cancer alkaloids camptothecin and luotonin A have been prepared with β-cyclodextrin and hydroxypropyl-β-cyclodextrin. These cyclodextrin complexes were characterized by nuclear magnetic resonance spectroscopy (NMR). The variations in the 1H-NMR and 13C-NMR chemical shifts allowed to establish the inclusion modes of the compounds into the cyclodextrin cavities, which were supported by docking and molecular dynamics studies. The efficiency of the complexation was quantified by UV-Vis spectrophotometry and spectrofluorimetry, which showed that the protonation equilibria of camptothecin and luotonin A were drastically hampered upon formation of the inclusion complexes. The stabilization of camptothecin towards hydrolysis inside the cyclodextrin cavity was verified by the quantitation of the active lactone form by reverse phase liquid chromatography fluorimetric detection, both in basic conditions and in the presence of serum albumin. The antitumor activity of luotonin A and camptothecin complexes were studied in several cancer cell lines (breast, lung, hepatic carcinoma, ovarian carcinoma and human neuroblastoma) and an enhanced activity was found compared to the free alkaloids, particularly in the case of hydroxypropyl-β-cyclodextrin derivatives. This result shows that the cyclodextrin inclusion strategy has much potential towards reaching the goal of employing luotonin A or its analogues as stable analogues of camptothecin.