Nuestros investigadores

María Font Arellano

Departamento
Facultad de Farmacia y Nutrición. Universidad de Navarra
Facultad de Farmacia y Nutrición. Universidad de Navarra
Líneas de investigación
Síntesis de fármacos, diseño, modelización molecular, antitumorales, alzheimer, leihsmania, alcoholismo.

Publicaciones científicas más recientes (desde 2010)

Autores: Font, María , (Autor de correspondencia); González-Peñas, E.; et al.
Revista: METALLOMICS
ISSN 1756-5901  Vol. 10  Nº 8  2018  págs. 1128 - 1140
A molecular modeling study has been carried out on two previously reported series of methylselenocarbamate derivatives that show remarkable antiproliferative and cytotoxic in vitro activity, against a panel of human cancer cell lines. These derivatives can be considered as having been constructed by a selenomethyl fragment located over a carbon atom which is decorated with two carbamate moieties, both aliphatic and aromatic, one of them attached by a single bond to the central carbon atom, while the second is connected by a double bond. According to the data obtained, these derivatives can undergo a water-mediated nucleophilic attack on the carbons with marked electrophilic character, which leads to the rupture of C-Se and carbamate C-O bonds. The aliphatic derivatives, series 1, show an early release of methylselenol and a further release of hydroxyl derivatives (alcohols), whereas the aromatic carbamates, series 2, show an early release of phenols followed by the subsequent release of methylselenol. Thus, the activity of the compounds can be related to the progressive release of active fragments. The data that support this connection are related to the overall molecular topology, volume and surface area as well as to quantum parameters such as the relative electrophilic character of the target carbon atoms (measured in terms of positive charge values) or the bond order values, especially concerning the central C-SeCH3 bond and the carbamate ones. Moreover, the data obtained regarding the chromatographic behavior of some representative compounds confirm this proposal.
Autores: Lucio, David; Irache, Juan M.; Font, María ; et al.
Revista: INTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN 0378-5173  Vol. 519  Nº 1 - 2  2017  págs. 263 - 271
Glibenclamide is a sulfonylurea used for the oral treatment of type II diabetes mellitus. This drug shows low bioavailability as consequence of its low solubility. In order to solve this problem, the interaction with cyclodextrin has been proposed. This study tries to provide an explanation about the processes involved in the formation of GB-beta CDs complexes, which have been interpreted in different ways by several authors. Among native cyclodextrins, beta CD presents the most appropriate cavity to host glibenclamide molecules showing A(L) solubility diagrams (K-1:1 approximate to 1700 M-1). However, A(L)- solubility profiles were found for pa) derivatives, highlighting the coexistence of several phenomena involved in the drug solubility enhancement. At low CD concentration, the formation of inclusion complexes can be studied and the stability constants can be calculated (K-1:1 approximate to 1700 M-1) Whereas at high CD concentration, the enhancement of GB solubility would be mainly attributed to the formation of nanoaggregates of CD and GB-CD complexes (sizes between 100 and 300 nm). The inclusion mode into beta CD occurs through the cyclohexyl ring of GB, adopting a semi-folded conformation which maximizes the hydrogen bond network. As consequence of all these phenomena, a 150-fold enhancement of drug solubility has been achieved using beta-cyclodextrin derivatives. Thus, its use has proven to be an interesting tool to improve the oral administration of glibenclamide in accordance with dosage bulk and dose/solubility ratio requirements. (C) 2017 Elsevier B.V. All rights reserved.
Autores: Font, María ; Plano, Daniel; Sanmartín, María del Carmen; et al.
Revista: JOURNAL OF MOLECULAR GRAPHICS AND MODELLING
ISSN 1093-3263  Vol. 73  2017  págs. 62 - 73
A molecular modeling study has been carried out on a previously reported series of (diselanediyldibenzene-4,1-diylnide)biscarbamate derivatives that show cytotoxic and antiproliferative in vitro activity against MCF-7 human cell line; radical scavenging properties were also confirmed when these compounds were tested for their ability to scavenge DPPH and ABTS radicals. The data obtained allowed us to classify the compounds into two different groups: (a) aliphatic carbamates for which the activity could be related with a first nucleophilic attack (mediated by H2O, for example) on the selenium atoms of the central scaffold, followed by the release of the alkyl N-(4-selanylphenyl) and N-(4-selenenophenyl)carbamate moieties. Then, a second nucleophilic attack on the carbamate moiety, to yield 4-aminobenzeneselenol and 4-selenenoaniline respectively, which can ultimately be responsible for the activity of the compounds; (b) aromatic carbamates, for which we propose a preferred nucleophilic attack on the carbamate moiety, yielding 4-[(4-aminophenyl)diselanyl]aniline, the common structural fragment for this series, for which we have previously demonstrated its cytotoxic profile. Then, selenium atoms of the central fragment may later undergo a new nucleophilic attack, to yield 4-selenenoaniline and 4-aminobenzeneselenol. The phenolic moieties released in this process may also have a synergistic cytotoxic and redox activity.
Autores: Lucio, David; Irache, Juan M.; Font, María ; et al.
Revista: INTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN 0378-5173  Vol. 530  Nº 1 - 2  2017  págs. 377 - 386
Glibenclamide is an antidiabetic drug showing low bioavailability as consequence of its low solubility. To solve this drawback, the interaction with cyclodextrins has been proposed. The formation of GB-beta CDs inclusion complexes was carried out using different methods, beta CD derivatives and drug-to-cyclodextrin ratios. The structures of the corresponding complexes have been studied by molecular modelling, X-ray diffraction and differential thermal analysis. The dissolution behavior of inclusion complexes has been compared to that of pure GB. Dimeric inclusion complexes were obtained with different CD disposals, head-to-head for beta CD and head-to-tail for HP beta CD and RM beta CD. Amorphous inclusion complexes were obtained by employing methods of freeze-drying or coevaporation in ammonia-water. However, crystalline structures were formed by kneading and coevaporation in ethanol/water in the case of GB-beta CD complexes. The arrangement of these structures depended on the GB:beta CD ratio, yielding cage type structures for 1:3 and 1:5 ratios and channel-type structures for higher GB contents. The amount of GB released and its dissolution rate was considerably increased by the use of amorphous inclusion complexes; whereas, slower GB release rates were found from crystalline inclusion complexes formed by kneading or coevaporation in ethanol/water. In addition, it was found that the porous structure strongly conditioned the GB dissolution rate from crystalline products.
Autores: Baquedano, Ylenia; Alcolea, Verónica; Toro, M. Á.; et al.
Revista: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN 0066-4804  Vol. 60  Nº 6  2016  págs. 3802 - 3812
A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and their in vitro leishmanicidal activities against Leishmania infantum amastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED50) values ranging from 0.45 to 1.27 ¿M and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3'-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design.
Autores: Moreno, Esther; Larrea, Esther; et al.
Revista: NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE
ISSN 1549-9634  Vol. 11  Nº 8  2015  págs. 2003 - 2012
Patients affected by cutaneous leishmaniasis need a topical treatment which cures lesions without leaving scars. Lesions are produced not only by the parasite but also by an uncontrolled and persistent inflammatory immune response. In this study, we proposed the loading of ß-lapachone (ß-LP) in lecithin-chitosan nanoparticles (NP) for targeting the drug to the dermis, where infected macrophages reside, and promote wound healing. Although the loading of ß-LP in NP did not influence the drug antileishmanial activity it was critical to achieve important drug accumulation in the dermis and permeation through the skin. When topically applied in Leishmania major infected BALB/c mice, ß-LP NP achieved no parasite reduction but they stopped the lesion progression. Immuno-histopathological assays in CL lesions and quantitative mRNA studies in draining lymph nodes confirmed that ß-LP exhibited anti-inflammatory activity leading to the down-regulation of IL-1ß and COX-2 expression and a decrease of neutrophils infiltrate.
Autores: Font, María ; Baquedano, Ylenia; Plano, Daniel; et al.
Revista: JOURNAL OF MOLECULAR GRAPHICS AND MODELLING
ISSN 1093-3263  Vol. 60  2015  págs. 63 - 78
A molecular modeling study has been carried out on two previously reported series of symmetric diselenide derivatives that show remarkable antileishmanial in vitro activity against Leishmania infantum intracellular amastigotes and in infected macrophages (THP-1 cells), in addition to showing favorable selectivity indices. Series 1 consists of compounds that can be considered as central scaffold constructed with a diaryl/dialkylaryl diselenide central nucleus, decorated with different substituents located on the aryl rings. Series 2 consists of compounds constructed over a diaryl diselenide central nucleus, decorated in 4 and 4' positions with an aryl or heteroaryl sulfonamide fragment, thus forming the diselenosulfonamide derivatives. With regard to the diselenosulfonamide derivatives (2 series), the activity can be related, as a first approximation, with (a) the ability to release bis(4-aminophenyl) diselenide, the common fragment which can be ultimately responsible for the activity of the compounds. (b) the anti-parasitic activity achieved by the sulfonamide pharmacophore present in the analyzed derivatives. The data that support this connection include the topography of the molecules, the conformational behavior of the compounds, which influences the bond order, as well as the accessibility of the hydrolysis point, and possibly the hydrophobicity and polarizability of the compounds.
Autores: Plano, Daniel; Font, María ; et al.
Revista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0223-5234  Vol. 73  2014  págs. 153 - 166
A series of 31 new selenoesters were synthesized and their cytotoxic activity was evaluated against a prostate cancer cell line (PC-3). The most active compounds were also tested against three tumoural cell lines (MCF-7, A-549 and HT-29) and one non-tumour prostate cell line (RWPE-1). Thirteen compounds showed significant activity towards all tumour cells investigated, and some of them were even more potent than etoposide and cisplatin, which were used as reference drugs. Because of their pronounced potency and/or selectivity, four analogues (5, 21, 28 and 30), were selected in order to assess their redox properties related to a possible redox modulating activity. The glutathione peroxidase (GPx) assay showed slight activity for compound 30 and the 2,2-diphenyl-1-picrylhydrazyl-(DPPH) assay showed a weak activity for compounds 5 and 28. The present results revealed that analogues 5, 21, 28 and 30 might serve as a useful starting point for the design of improved anti-tumour agents.
Autores: Moreno, Esther; Doughty-Shenton, D.; Plano, Daniel; et al.
Revista: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
ISSN 0928-0987  Vol. 63  2014  págs. 87 - 95
The PI3K/Akt/mTOR/S6 ribosomal protein signalling pathway is a key potential target in breast cancer therapy, playing a central role in proliferation and cell survival. In this study, we found that the seleno-compound 2,4-dihydroselenoquinazoline (3a) generally inhibited this signalling axis in MCF-7 breast cancer cells and caused downregulation of S6 ribosomal protein phosphorylation in a dose- and time-dependent manner. Furthermore, 3a caused a dose- and time-dependent decrease in MCF-7 cell viability as well as cell cycle arrest in G2/M. Interestingly 3a also induced apoptosis, as evidenced by cleavage of PARP and caspase-7, and inhibited autophagy, as demonstrated by accumulation of LC3-II and p62/SQSTM1. Given that induction of autophagy has been previously described as a mechanism by which some breast cancer cells counteract proapoptotic signalling and develop resistance to anti-hormone therapy, this suggests that this derivative, which both triggers apoptosis and inhibits autophagy, may be beneficial in preventing and overcoming resistance in breast cancer cells. The data also show the complexity of this signalling axis which is far from being understood.
Autores: Baquedano, Ylenia; Moreno, Esther; Espuelas, S; et al.
Revista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0223-5234  Vol. 74  2014  págs. 116-123
Diselenide and sulfonamide derivatives have recently attracted considerable interest as leishmanicidal agents in drug discovery. In this study, a novel series of sixteen hybrid selenosulfonamides has been synthesized and screened for their in vitro activity against Leishmania infantum intracellular amastigotes and THP-1 cells. These assays revealed that most of the compounds exhibited antileishmanial activity in the low micromolar range and led us to identify three lead compounds (derivatives 2, 7 and 14) with IC50 values ranging from 0.83 to 1.47 ¿M and selectivity indexes (SI) over 17, much higher than those observed for the reference drugs miltefosine and edelfosine. When evaluated against intracellular amastigotes, hybrid compound 7 emerged as the most active compound (IC50 = 2.8 ¿M), showing higher activity and much less toxicity against THP-1 cells than edelfosine. These compounds could potentially serve as templates for future drug-optimization and drug-development efforts for their use as therapeutic agents in developing countries.
Autores: Font, María ; Lizarraga, Elena; Ibáñez, Elena; et al.
Revista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0223-5234  Vol. 66  2013  págs. 489 - 498
A molecular modelling study has been carried out on a previously reported series of symmetrically substituted bisacylimidoselenocarbamate (BSeC) derivatives that show remarkable antitumour activity in vitro against a panel of human tumour cell lines. These derivatives can be considered as a central scaffold constructed around a methyl carbamimidoselenoate nucleus in which two heteroarylacyl fragments are located on the scaffold nitrogen atoms, thus forming the different BSeCs. The results reveal that the nature of the selected heteroaryl ring has a marked influence on the antiproliferative activity of the compounds and this can be related, as a first approximation, to the ability to release methylselenol (MeSeH), a compound that, according to our initial hypothesis, is ultimately responsible for the antitumour activity of the compounds under investigation. The release of MeSeH from the active BSeCs has been confirmed by means of Head Space Gas Chromatography Mass Spectrometry techniques. The data that support this connection include the topography of the molecules, the conformational behaviour of the compounds, which influences the accessibility of the hydrolysis point, the interaction map obtained for an O2H type probe, and the location and energy of the HOMO/LUMO orbitals.
Autores: Lamberto, I.; Plano, Daniel; Moreno, Esther; et al.
Revista: CURRENT MEDICINAL CHEMISTRY
ISSN 0929-8673  Vol. 20  Nº 12  2013  págs. 1609 - 1619
Bisacylimidoselenocarbamate derivatives (BSC) are potent anticancer agents with a strong cytotoxic activity against different types of tumour cells. Based in phosphatidylserine exposure on the cell membranes we show that BSC treatment resulted in enhanced cell death in leukaemia CCRF-CEM cells. DNA fragmentation detection in breast adenocarcinoma MCF-7 cells showed that BSC triggered cell death is concentration and time dependent. We also show that two of these compounds, BSC 3g and 3n, cause cell-cycle arrest in the late G2/M in MCF-7 cells. Consistent with this, a reduction in CDK1 and CDK2 expression with no change in cyclin A an B1 was observed in this cell line. Activation of caspase-2 was also detected. However, the involvement of the caspase-dependent pathway in the process of cell death induced by either BSC 3g or 3n is discarded since cell death could not be prevented by pretreatment with the pancaspase inhibitor z-VAD-fmk. Moreover, since reduced levels of p21(CIP1) and Chk2 proteins but no change in p53 levels could be detected in MCF-7 cells after BSC 3g or 3n treatment our results suggest that BSC treated cells die from lethal mitosis.
Autores: Espuelas, S; Plano, Daniel; Nguewa, Paul; et al.
Revista: CURRENT MEDICINAL CHEMISTRY
ISSN 0929-8673  Vol. 19  Nº 25  2012  págs. 4259 - 4288
The protozoan diseases leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease (CD) are responsible for substantial global morbidity and mortality in tropical and subtropical regions. Environmental changes, drug resistance and immunosuppression are contributing to the emergence and spread of these diseases. In the absence of safe and efficient vaccines, chemotherapy, together with vector control, remains the most important measure to control kinetoplastid diseases. Nevertheless, the current chemotherapeutic treatments are clearly inadequate because of their toxic effects, generation of resistances as well as route and schedules of administration not adapted to the field-conditions. This review overlooks the strategies that can be addressed to meet immediately the patient needs such as the reconsideration of current regimens of administration and the rational combination of drugs in use. In the medium-long term, due to new methodologies of medicinal-chemistry, the screening from natural products and the identification of new therapeutic targets, new lead compounds have great chance to advance through the drug development pipeline to clinic. Modern pharmaceutical formulation strategies and nanomedicines also merit a place in view of the benefits of a single dose of liposomal Amphotericin B ( AmBisome (R)) against visceral leishmaniasis. BBB-targeted nanodevices could be suited for selective delivery of drugs against HAT encephalitic phase. Bioadhesive nanoparticles can be proposed to enhance the bioavailability of drugs after oral administration by reason of improving the drug solubility, and permeability across the intestinal epithelia.
Autores: Moreno, Esther; Plano, Daniel; Lamberto, I.; et al.
Revista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0223-5234  Vol. 47  Nº 1  2012  págs. 283 - 298
The synthesis, cytotoxic activities and selectivities of 35 derivatives related to quinazoline and pyrido [2,3-d]pyrimidine are described. The synthesized compounds were screened in vitro against four tumoral cell lines leukemia (CCRF-CEM), colon (HT-29), lung (HTB-54) and breast (MCF-7) - and two cell lines derived from non-malignant cell lines, one mammary (18485) and one from bronchial epithelium (BEAS-2B). MCF-7 and HTB-54 were the most sensitive cell lines with GI(50) values below 10 mu M for eleven and ten compounds. respectively. Two compounds (2o and 3a) were identified that evoked a marked cytotoxic effect in all cell lines tested and one compound, 7h, was potent and selective against MCF-7. A preliminary study into the mechanism of the potent derivatives 2o, 3a and 7h indicated that the cytotoxic activities of these compounds might be mediated by inducing cell death without affecting cell cycle phases.
Autores: Plano, Daniel; et al.
Revista: CHEMICAL RESEARCH IN TOXICOLOGY
ISSN 0893-228X  Vol. 25  Nº 11  2012  págs. 2479-2489
In the search for new molecules with potential antiangiogenic activity, we found that several imidoselenocarbamate derivatives effectively suppressed the expression of vascular endothelial growth factor (VEGF) induced by hypoxia in NCI-H157 tumor cells. Mechanistic studies indicated that these compounds inhibited STAT3 phosphorylation triggered by hypoxia, suggesting that inhibition of STAT3 function may play a role in VEGF inhibition. Moreover, these molecules showed interesting proapoptotic and antiproliferative effects. Both the presence of selenium, but not sulfur, and the nature of the radical substituents were important for activity. Interestingly, under hypoxic conditions, several methyl imidoselenocarbamate derivatives released methylselenol, a highly reactive and cytotoxic gas, which was responsible for their biological activities. The kinetics of the release of methylselenol by these molecules was highly dependent on the nature of the substituent radicals and correlated with their early proapoptotic activity. Our results support the notion that pharmacological activities reported for methyl imidoselenocarbamate derivatives are dependent on the release of methylselenol. Given the well-known antitumor activities of this compound, imidoselenocarbamate derivatives represent a promising approach to develop new drugs that release methylselenol in a controlled way.
Autores: Font, María ; et al.
Revista: Bioorganic & Medicinal Chemistry
ISSN 0968-0896  Vol. 20  Nº 17  2012  págs. 5110 - 5116
In the search for molecules with potential antiangiogenic activity we found that several imidoselenocarbamate derivatives, which have pro-apoptotic and antiproliferative activities, under hypoxic conditions release methylselenol, a volatile and highly reactive gas that was considered to be responsible for the observed biological activity. The kinetic for the liberation of methylselenol is highly dependent on the nature of the overall structure and correlate with their proven pro-apoptotic activity in lung cancer cell line H157. The preliminary structure-activity relationships allow us to select as the basic structural element a scaffold constructed with an imidoselenocarbamate fragment decorated with a methyl residue on the Se central atom and two heteroaromatic lateral rings. These imidoselenocarbamate derivatives may be of interest both for their antitumoral activities and because they have a structure that can be considered as a template for the design of new derivatives with apoptotic activity. This activity is related to the controlled delivery of methylselenol and makes this an interesting approach to develop new antitumoral agents.
Autores: Sanmartín, María del Carmen; Plano, Daniel; Font, María ; et al.
Revista: Current Cancer Drug Targets
ISSN 1568-0096  Vol. 11  Nº 4  2011  págs. 496 - 523
Kinases are enzymes that are involved in a wide-range of cellular targets such as cell proliferation, metabolism, survival and apoptosis. Aberrations in the activity of the kinases have been linked to many human diseases such as diabetes, inflammation and cancer. The discovery of more than 518 kinases encoded by the human genome has spurred the development of rapid screening techniques for potential drugs against these enzymes and these have been identified as interesting targets for medicinal chemistry programs, especially in cancer therapy. On the other hand, sulfur and selenium have been increasingly recognized as essential elements in biology and medicine. Converging data from epidemiological and clinical studies have highlighted these elements as effective chemopreventive agents, particularly against various types of cancer (prostate, lung, breast, leukemia, colon, skin, lymphome, thyroid, pancreas, liver). These elements act through a wide range of potential mechanisms where one identified signal pathway event is kinase modulation, which is common for the two elements and emerges as a valid target. The kinases modulated by sulfur and selenium derivatives include MAP, ERK, JNK, Akt, Cdc2, Cyclin B1 and Cdc25c amongst others. Although both of the elements in question are in the same group in the periodic table and have similar biochemistries, there are relevant differences related to redox potentials, stabilities, oxidation states and anticancer activity. Literature data suggest that the replacement of sulfur by selenium in established cancer chemopreventive agents results in more effective chemopreventive analogs. In view of the multi-target kinase mechanisms in preventing cellular transformation, as well as the differences and similarities between them, in this review we focus on the development of new structures that contain selenium and/or sulfur and discuss our understanding of the regulation of antitumoral effects with emphasis on kinase modulation activity and its implications in cancer.
Autores: Sanmartín, María del Carmen; Plano, Daniel; Font, María ; et al.
Revista: CURRENT MEDICINAL CHEMISTRY
ISSN 0929-8673  Vol. 18  Nº 30  2011  págs. 4635 - 4650
The understanding of the essential role of selenium (Se) in human health has increased substantially in recent decades. Micronutrient deficiencies are very common in the general population and may be even more common in patients with different pathologies due to genetic or environmental causes and prescription drug use. Selenium is used by people in the prevention and/or treatment of different disorders including cardiovascular disease, osteoarthritis, rheumatoid arthritis, hypothyroidism, stroke, atherosclerosis, cancer susceptibility and treatment, HIV, AIDS, neuronal diseases such as Alzheimer or amyotrophic lateral sclerosis, pancreatitis, depression, and diabetes amongst others. Several mechanisms have been suggested to mediate the biological effects of Se and these include antioxidant defence systems, synthesis and stability of metabolites that act as intermediates implicated in diverse selenoproteins expression pathways oxidative metabolism, immune system modulation, DNA intercalators, kinase regulation, enzymatic cofactor, and gene expression. A number of clinical trials in recent years have provided convincing evidence of the central role of this element, either alone or in combination with other micronutrients or antioxidants, in the prevention and treatment of multiple diseases. Based on these studies this review focuses on the advances made so far in the study of mechanisms and applications of selenium compounds that could be suitable for chronic diseases.
Autores: Font, María ; González, A.; Palop, Juan Antonio; et al.
Revista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0223-5234  Vol. 46  Nº 9  2011  págs. 3887 - 3899
As a continuation of our work on new anti-tumoral derivatives with selective pro-apoptotic activity in cancer cells, we describe the synthesis and the preliminary evaluation of the cytotoxic and pro-apoptotic activities of a series of pyrimidin-2,4-diamine derivatives that are structurally related to quinazolin-2,4-diamine and pyrido[2,3-d]pyrimidin-2,4-diamine derivatives. We also describe the structure-activity relationship studies carried out on four series' of quinazolin-2,4-diamine, 2-(alkylsulfanyl)-N-alkyl- and 2-(alkylsulfanyl)-N-alkylarylpyrido[2,3-d]pyrimidine and pyrimidin-2,4-diamine derivatives. The proposed preliminary pharmacophore consists of a flat heterocyclic ring, preferably a pyrido[2,3-d]pyrimidine, with two equivalent alkylarylamine chains, preferably N-benzyl- or N-ethylphenylamine, located in positions 2 and 4 of the ring, and with a preferred ALogP in the range 4.5-5.5. The nitrogen present in the central ring can act as hydrogen bond acceptors (HBA) whereas the amino group in the 4-position can act as a donor (HBD) or an HBA and the amino group in the 2-position can act as an HBD. On the basis of the analyzed structural profiles, different mechanisms of action can be suggested for the quinazolin-2,4-diamine, the 2-(alkylsulfanyl)-N-alkylpyrido[2,3-d]pyrimidin-4-amine and the pyrido [2,3-d]pyrimidin-2,4-diamine derivatives.
Autores: Ibáñez, Elena; Plano, Daniel; Font, María ; et al.
Revista: European Journal of Medicinal Chemistry
ISSN 0223-5234  Vol. 46  Nº 1  2011  págs. 265 - 274
Autores: Plano, Daniel; Baquedano, Ylenia; Moreno, David; et al.
Revista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0223-5234  Vol. 46  Nº 8  2011  págs. 3315 - 3323
Thirty five selenocyanate and diselenide compounds were subjected to in vitro screening against Leishmania infantum promastigotes and the most active ones were also tested in an axenic amastigote model. In order to establish the selectivity indexes (SI) the cytotoxic effect of each compound was also assayed against Jurkat and THP-1 cell lines. Thirteen derivatives exhibit better IC(50) values than miltefosine and edelfosine. Bis(4-aminophenyl)diselenide exhibits the best activity when assayed in infected macrophages and one of the lowest cytotoxic activities against the human cell lines tested, with SI values of 32 and 24 against Jurkat and THP-1 cells, respectively. This compound thus represents a new lead for further studies aimed at establishing its mechanism of action.
Autores: Plano, Daniel; Moreno, Esther; Font, María ; et al.
Revista: CHEM INFORM
ISSN 0931-7597  Vol. 42  Nº 13  2011 
2 Selenadiazoles of type (II), (IV), or (V) and 3 of type (VII) are prepared and tested for their anticancer activities
Autores: Plano, Daniel; Moreno, Esther; Font, María ; et al.
Revista: ARCHIV DER PHARMAZIE
ISSN 0365-6233  Vol. 343  Nº 11 - 12  2010  págs. 680 - 691
A novel series of fourteen substituted selenadiazoles has been synthesized and the compounds tested for their in vitro antiproliferative and cytotoxic activities. The tests were carried out against leukemia (CCRF-CEM), colon (HT-29), lung (HTB-54), and breast (MCF-7) cancer cells. In order to assess the selectivity of the compounds under investigation the assays were also carried out on two non-tumoral lines - one mammary (184B5) and one bronchial epithelium (BEAS-2B) cell line. Assay-based antiproliferative activity studies revealed that seven derivatives (2a, 2c, 2e, 2f, 2g, 3a, and 3b) exhibited good activity against MCF-7 cells: for instance, 2c and 2f inhibited cell growth with nanomolar GI¿¿ values. Compound 2f had a better antitumoral profile than vinorelbine and paclitaxel, two drugs that are used as first-line treatments in advanced, recurrent, and/or metastatic cancer. In the other cell lines the compounds showed moderate activity or were inactive - with the exception of 2a, which was also found to have antiproliferative activity. Modulation of the cell cycle and apoptotic effects of active compounds were further evaluated in MCF-7 cells. Of these, 6-bromo[1,2,5]selenadiazolo[3,4-b]pyridine (2a) was the most active, with an apoptogenic effect 3.9 times higher than that of camptothecin, which was used as a positive control. Compound 2a also provoked cell cycle arrest with a significant decrease in the G¿/G¿ phase cell population and an increase in S and G¿/M cells, thus suggesting mitotic arrest prior to metaphase.
Autores: Plano, Daniel; Font, María ; Palop, Juan Antonio; et al.
Libro:  Selenium sources, functions and health effects
2012  págs. 163 - 179
According to World Health Organization, neglected tropical diseases encompass all diseases that occur solely, or principally, in the tropics. In practice, the term is often taken to refer to infectious diseases that thrive in hot, humid conditions. Clinical and epidemiological studies suggest that selenium (Se) play an important role in tropical diseases, such as tuberculosis, leishmaniasis, filariasis and chagas, acting as preventive agent or in diagnosis and prognosis. Recent studies have evinced the importance of selenium in oxidative status and antioxidant defense capabilities during the course of infection and progression of the illness in human patients and experimental models. For this reason, one of the most relevant mechanism of action proposed involve selenoproteins, i.e. glutathione peroxidase (GPx), an enzyme that protects against oxidative stress and modulates the redox processes. In addition, it was observed that low Se levels were positively correlated with an increased susceptibility to infections. Besides, Se supplementation is proposed as an adjuvant therapy for treatment of these chronic diseases. However, there is a lack in the literature references related to synthesis and biological evaluation of novel derivatives containing selenium moiety against these diseases. During the last years our research group is interested in the design and synthesis of organoselenium compounds as new class of agents for treatment of neglected tropical diseases. In the present year we have reported two general structures with leishmanicidal activity, corresponding both of them to symmetrical compounds. The firsts are alkyl imidoselenocarbamates (alkyl isoselenourea) which possessed a moderate effect in vitro and the second ones are selenocyanates and diselenides. It is remarkable that some of them showed stronger in vitro antileishmanial activity than edelfosine and miltefosine, used as reference drugs, and combined high potency and low cytotoxicity against Jurkat and THP-1 cells. Selenium and Tropical Diseases (PDF Download Available). Available from: https://www.researchgate.net/publication/235745925_Selenium_and_Tropical_Diseases [accessed Jun 21, 2017].
Autores: López, Natalia María; Font, María ;
2015 
Autores: López, Natalia María; Font, María ;
2015 
Autores: López, Natalia María; Font, María ;
2014