Category Archives: Publicación

2017, BioImag, Publicación

Bosch et al. Dyes and Pigments. 2017;:135-146. Imidazopyridinium cations: A new family of azonia aromatic heterocycles with applications as DNA intercalators.

Publications > Bosch et al

Dyes Pigm. 2017, 138, 135

Imidazopyridinium cations: A new family of azonia aromatic heterocycles with applications as DNA intercalators.

Pedro Bosch1, Verónica García2, Başak S. Bilen3, David Sucunza1, Alberto Domingo2, Francisco Mendicuti3, Juan J Vaquero1

1. Departamento de Química Inorgánica y Química Orgánica, Química Física e Ingeniería Química, Universidad de Alcalá, 28871, Alcalá de Henares, Madrid, Spain.  2. Departamento de Biología de Sistemas, Química Física e Ingeniería Química, Universidad de Alcalá, 28871, Alcalá de Henares, Madrid, Spain.  3. Departamento de Química Analítica, Química Física e Ingeniería Química, Universidad de Alcalá, 28871, Alcalá de Henares, Madrid, Spain.

Abstract

Two novel imidazopyridinium cations formed by a hexacyclic azonia aromatic system have been synthesized. Spectrofluorimetric titrations, circular dichroism measurements, theoretical simulations and fluorescence-based thermal denaturation experiments on these materials have shown the interesting fluorescence properties and DNA-binding ability by intercalation, with a marked preference for AT-rich sequences. Compound 2 presents the highest fluorescence quantum yield (0.32 in 5% DMSO/water and 0.46 in MeOH) and affinity for DNA (binding constant of ∼4.5 × 105 M−1). Moreover, the potential of these compounds for cell staining has been investigated in living HeLa cells by confocal microscopy imaging. This analysis showed the remarkable capacity of both compounds for uptake and accumulation by living cells.

2017, BioImag, Publicación

Zacharioudakis et al. Biorg. Med. Chem. Lett.. 2017;:203-207. Quinolizinium as a new fluorescent lysosomotropic probe.

Publications > Zacharioudakis et al

Biorg. Med. Chem. Lett. 2017, 27, 203

Quinolizinium as a new fluorescent lysosomotropic probe.

Emmanouil Zacharioudakis1, Tatiana Cañeque2, Raúl Custodio3, Sebastian Müller1, Ana M. Cuadro2, Juan J Vaquero2, Raphaël Rodriguez1

1. Institut Curie, PSL Research University, Organic Synthesis and Cell Biology Group, 26 rue d’Ulm, 75248 Paris Cedex 05, France, CNRS UMR3666, 75005 Paris, France, INSERM U1143, 75005 Paris, France.  2. Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28871, Alcalá de Henares, Madrid, Spain.  3. Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain.

Abstract

We have synthesized a collection of quinolizinium fluorescent dyes for the purpose of cell imaging. Preliminary biological studies in human U2OS osteosarcoma cancer cells have shown that different functional groups appended to the cationic quinolizinium scaffold efficiently modulate photophysical properties but also cellular distribution. While quinolizinium probes are known nuclear staining reagents, we have identified a particular quinolizinium derivative salt that targets the lysosomal compartment. This finding raises the question of predictability of specific organelle targeting from structural features of small molecules.

2017, Publicación

Vasilev et al. Beilstein J Org Chem. 2017;13:2902-2914. Halogen-containing thiazole orange analogues – new fluorogenic DNA stains.

Publications > Vasilev et al

Beilstein J. Org. Chem. 2017, 13, 2902 PubMed 29564018

Halogen-containing thiazole orange analogues - new fluorogenic DNA stains.

Aleksey A Vasilev1, Meglena I Kandinska2, Stanimir S Stoyanov2, Stanislava B Yordanova2, David Sucunza3, Juan J Vaquero3, Obis D Castano3, Stanislav Baluschev4, Silvia E Angelova3

1. Department of Pharmaceutical and Applied Organic Chemistry, Faculty of Chemistry and Pharmacy, Sofia University "St. Kliment Ohridski", 1 James Bourchier Blvd., 1164 Sofia, Bulgaria.  2. Department of Organic Chemistry and Pharmacognosy, Faculty of Chemistry and Pharmacy, Sofia University "St. Kliment Ohridski", 1 James Bourchier Blvd., 1164 Sofia, Bulgaria.  3. Departments of Organic and Physical Chemistry, University of Alcala, 28871-Alcala de Henares, Madrid, Spain.  4. Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.

Keywords: DFT calculations; cyanine dyes; green synthesis; nucleic acids; thiazole orange

Abstract

Novel asymmetric monomeric monomethine cyanine dyes 5a-d, which are analogues of the commercial dsDNA fluorescence binder thiazole orange (TO), have been synthesized. The synthesis was achieved by using a simple, efficient and environmetally benign synthetic procedure to obtain these cationic dyes in good to excellent yields. Interactions of the new derivatives of TO with dsDNA have been investigated by absorption and fluorescence spectroscopy. The longest wavelength absorption bands in the UV-vis spectra of the target compounds are in the range of 509-519 nm and these are characterized by high molar absorptivities (63000-91480 L.mol(-1).cm(-1)). All investigated dyes from the series are either not fluorescent or their fluorescence is quite low, but they become strongly fluorescent after binding to dsDNA. The influence of the substituents attached to the chromophores was investigated by combination of spectroscopic (UV-vis and fluorescence spectroscopy) and theoretical (DFT and TDDFT calculations) methods.

2016, Publicación

Sucunza et al. J Org Chem. 2016;81(21):10126-10135. Recent Advances in the Synthesis of Azonia Aromatic Heterocycles.

Publications > Sucunza et al

J Org Chem. 2016, 81, 10126 PubMed 27385555

Recent Advances in the Synthesis of Azonia Aromatic Heterocycles.

David Sucunza, Ana M Cuadro, Julio Alvarez-Builla, Juan J Vaquero

Department of Organic and Inorganic Chemistry, University of Alcala , 28871 Alcala de Henares, Madrid, Spain.

Abstract

Azonia aromatic heterocycles are an important subclass of aza-heterocyles as they are the structural motif of relevant cationic alkaloids, and they have a wide range of potential applications such as bioactive compounds and organic materials. In this Synopsis, recent and novel approaches to their synthesis are surveyed, with particular emphasis on ring-closing metathesis reactions and annulation reactions based on C-H activation.

2016, Publicación, TosMIC

Gutierrez et al. Org Lett. 2016;18(14):3378-81. Synthesis of 1-Substituted Isoquinolines by Heterocyclization of TosMIC Derivatives: Total Synthesis of Cassiarin A.

Publications > Gutierrez et al

Org Lett. 2016, 18, 3378 PubMed 27351205

Synthesis of 1-Substituted Isoquinolines by Heterocyclization of TosMIC Derivatives: Total Synthesis of Cassiarin A.

Sara Gutierrez, Anna Coppola, David Sucunza, Carolina Burgos, Juan J Vaquero

Departamento de Quimica Organica y Quimica Inorganica, Universidad de Alcala , Alcala de Henares 28871, Spain.

Abstract

A new method for the synthesis of 1-substituted isoquinolines by a heterocyclization that involves alpha-benzyl TosMIC derivatives and different electrophiles has been developed. This methodology has been successfully applied to a total synthesis of cassiarin A, an alkaloid with potent antiplasmodial activity against Plasmodium falciparum.

2015, BioImag, Publicación

Gutierrez et al. Chemistry. 2015;21(51):18758-63. Highly Fluorescent Green Fluorescent Protein Chromophore Analogues Made by Decorating the Imidazolone Ring.

Publications > Gutierrez et al

Chem. Eur. J. 2015, 21, 18758 PubMed 26525155

Highly Fluorescent Green Fluorescent Protein Chromophore Analogues Made by Decorating the Imidazolone Ring.

Sara Gutierrez1, David Martinez-Lopez2, Maria Moron1, David Sucunza1, a, Diego Sampedro2, a, Alberto Domingo3, Antonio Salgado4, Juan J Vaquero1, a

1. Departamento de Quimica Organica y Quimica Inorganica, Universidad de Alcala, Edificio de Farmacia, 28871, Alcala de Henares, Madrid (Spain).  2. Departamento de Quimica, Centro de Investigacion en Sintesis Quimica (CISQ), Universidad de La Rioja, Madre de Dios, 53, 26006, Logrono, La Rioja (Spain).  3. Departamento de Biologia de Sistemas, Universidad de Alcala, Edificio de Medicina, 28871, Alcala de Henares, Madrid (Spain).  4. Departamento de Quimica, Universidad Yachay Tech, Hacienda San Jose s/n, San Miguel de Urcuqui, 100119 (Ecuador).

a. david.sucunza@uah.es  a. diego.sampedro@unirioja.es  a. juanjose.vaquero@uah.es

Keywords: TD-DFT calculations; cell staining; fluorescence; imidazolone derivatives; proteins

Abstract

The synthesis and photophysical behavior of an unexplored family of green fluorescent protein (GFP)-like chromophore analogues is reported. The compound (Z)-4-(4-hydroxybenzylidene)-1-propyl-2-(propylamino)-1H-imidazol-5(4 H)-one (p-HBDNI, 2 a) exhibits significantly enhanced fluorescence properties relative to the parent compound (Z)-5-(4-hydroxybenzylidene)-2,3-dimethyl-3,5-dihydro-4H-imidazol-4-one (p-HBDI, 1). p-HBDNI was considered as a model system and the photophysical properties of other novel 2-amino-3,5-dihydro-4H-imidazol-4-one derivatives were evaluated. Time-dependent DFT calculations were carried out to rationalize the results. The analogue AIDNI (2 c), in which the 4-hydroxybenzyl group of p-HBDNI was replaced by an azaindole group, showed improved photophysical properties and potential for cell staining. The uptake and intracellular distribution of 2 c in living cells was investigated by confocal microscopy imaging.

2015, Publicación

Vasilev et al. Australian Journal of Chemistry. 2015;:1399-1408. Assembly of New Merocyanine Chromophores with a 1,8-Naphthalimide Core by a New Method for the Synthesis of the Methine Function.

Publications > Vasilev et al

Aust. J. Chem. 2015, 68, 1399

Assembly of New Merocyanine Chromophores with a 1,8-Naphthalimide Core by a New Method for the Synthesis of the Methine Function.

Aleksey A. Vasilev1, Stanislav Baluschev2, Diana Cheshmedzhieva1, Sonia Ilieva1, Obis D. Castaño3, Juan J Vaquero4, Silvia E. Angelova3, Katharina Landfester2

1. Department of Pharmaceutical and Applied Organic Chemistry, Faculty of Chemistry and Pharmacy, University of Sofia, James Bourchier 1, 1164 Sofia, Bulgaria.  2. Max Planck Institute for Polymer Research, PO Box 3148 - D-55021 Mainz, Germany.  3. Departamento de Química Analítica, Química Física e Ingeniería Química, Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain.  4. Departamento de Química Orgánica, Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain.

Abstract

A new method for the synthesis of the monomethine group using nitro as a leaving group in an SN-Ar reaction is described. A series of novel merocyanine dyes has been synthesised and their photophysical properties have been elucidated. The longest wavelength absorption occurs in the range 519–619 nm and the molar absorptivities vary with the substituents and are in the range 1000–47700 L mol–1 cm–1. The dyes show high chemical and photostability. One example from the series has the ability to distinguish methanol from ethanol. The introduction of a quinoid fragment into the structure leads to a pronounced intramolecular charge transfer and hence a noticeable positive solvatochromism. The structures and electronic properties of the compounds have been studied by density functional theory (DFT) and time-dependent DFT.

2015, BioImag, Publicación

Marcelo et al. The Journal of Physical Chemistry A. 2015;:2351-2362. Nonlinear Emission of Quinolizinium Based Dyes With Application in Fluorescence Lifetime Imaging.

Publications > Marcelo et al

J. Phys. Chem. A 2015, 119, 11, 2351

Nonlinear Emission of Quinolizinium Based Dyes With Application in Fluorescence Lifetime Imaging.

Gema Marcelo1, Sandra Pinto1, Tatiana Cañeque2, Inês F. A. Mariz1, Ana M. Cuadro2, Juan J Vaquero2, José M. G. Martinho1, Ermelinda M. S. Maçôas1

1. Centro de Química-Física Molecular (CQFM) and Institute of Nanoscience and Nanotechnology (IN), Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1, 1049-001 Lisboa, Portugal.  2. Departamento de Química Orgánica y Química Inorganica, Universidad de Alcalá, 28871, Alcalá de Henares, Madrid, Spain.

Abstract

Charged molecules based on the quinolizinum cation have potential applications as labels in fluorescence imaging in biological media under nonlinear excitation. A systematic study of the linear and nonlinear photophysics of derivatives of the quinolizinum cation substituted by either dimethylaniline or methoxyphenyl electron donors is performed. The effects of donor strength, conjugation length, and symmetry in the two-photon emission efficiency are analyzed in detail. The best performing nonlinear fluorophore, with two-photon absorption cross sections of 1140 GM and an emission quantum yield of 0.22, is characterized by a symmetric D-π-A%@2B-π-D architecture based on the methoxyphenyl substituent. Application of this molecule as a fluorescent marker in optical microscopy of living cells revealed that, under favorable conditions, the fluorophore can be localized in the cytoplasmatic compartment of the cell, staining vesicular shape organelles. At higher dye concentrations and longer staining times, the fluorophore can also penetrate into the nucleus. The nonlinearly excited fluorescence lifetime imaging shows that the fluorophore lifetime is sensitive to its location in the different cell compartments. Using fluorescence lifetime microscopy, a multicolor map of the cell is drafted with a single dye.

2015, Publicación

Abengozar et al. Eur J Org Chem. 2015;6(24):4214-4223. Azonia Aromatic Cations by Ring-Closing Metathesis: Synthesis ofAzaquinolizinium Cations.

Publications > Abengozar et al

Eur J Org Chem. 2015, 6, 4214

Azonia Aromatic Cations by Ring-Closing Metathesis: Synthesis ofAzaquinolizinium Cations.

Alberto Abengozar, Beatriz Abarca, Ana M. Cuadro, David Sucunza, Julio Álvarez‐Builla, Juan J Vaquero

Departamento de Quimica Organica y Quimica Inorganica, Universidad de Alcala , 28805 Alcala de Henares , Spain.

Abstract

A new approach for the synthesis of the 1‐azaquinolizinium (pyrimido[1,2‐a]pyrimidin‐5‐ium) heterocycle and some simple derivatives is described. This strategy, based on an unprecedented ring‐closing metathesis (RCM) reaction to construct the pyrimidinium ring, was also applied to the first reported synthesis for the benzo‐1‐azaquinolizinium (pyrimido[2,1‐a]isoquinolinium) cation.

2015, Publicación

Rodríguez-Sanz et al. Eur. J. Med. Chem.. 2015;:83-92. Synthesis and biological evaluation of pyridazino%@5B1′,6′:1,2%@5Dpyrido%@5B3,4-b%@5Dindolinium and pyridazino%@5B1,6-a%@5Dbenzimidazolium salts as anti-inflammatory agents.

Publications > Rodríguez-Sanz et al

Eur. J. Med. Chem. 2015, 93, 83

Synthesis and biological evaluation of pyridazino%@5B1′,6′:1,2%@5Dpyrido%@5B3,4-b%@5Dindolinium and pyridazino%@5B1,6-a%@5Dbenzimidazolium salts as anti-inflammatory agents.

Aranzazu Rodríguez-Sanz1, Patricia Sánchez-Alonso2, Teresa Bellón1, Ramón Alajarín2, Virginia Martínez-Cabeza1, Rafael Selgas3, Juan J. Vaquero2, Julio Álvarez-Builla2

1. Instituto de Salud Hospital Universitario La Paz – IdiPAZ, Madrid, Spain.  2. Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Madrid, Spain.  3. Hospital Universitario La Paz, Servicio de Nefrología, IdiPAZ, IRSIN, Madrid, Spain.

Abstract

Condensed polycyclic heteroaromatic cations bearing a bridgehead nitrogen with pyridazino%@5B1′,6′:1,2%@5Dpyrido%@5B3,4-b%@5Dindolinium and pyridazino%@5B1,6-a%@5Dbenzimidazolium structures were assayed as inhibitors of LPS-induced TNF-α production by THP-1 cells. The hit compound 1e, which had the best IC50 value (4.49 μM) and low toxicity, was further assayed on human PMBCs (IC50 3.91 μM) and monocytes (IC50 1.82 μM). This compound also inhibited TNF-α production following poly I:C stimulation of human monocytes and monocyte-derived dendritic cells; in the latter case, inhibition of IL-12 production was also observed. Compound 1e was also able to inhibit TNF-α expression at the transcriptional level and proved to be effective in vivo. Compound 1e is an interesting potential therapeutic agent in IMIDs.