Nuestros investigadores

Daniel Plano Amatriain

Departamento
Facultad de Farmacia y Nutrición. Universidad de Navarra
Líneas de investigación
Design, synthesis and development of novel organoselenium compounds as chemopreventive and/or chemotherapeutic agents in several cancer models
Índice H
16, (WoS, 28/02/2018)

Publicaciones científicas más recientes (desde 2010)

Autores: Fernandez-Rubio, C.; Larrea, Esther; Peña Guerrero, J.; et al.
Revista: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN 0066-4804  Vol. 63  Nº 2  2019  págs. e00904-18
Conventional chemotherapy against leishmaniasis includes agents exhibiting considerable toxicity. In addition, reports of drug resistance are not uncommon. Thus, safe and effective therapies are urgently needed. Isoselenocyanate compounds have recently been identified with potential antitumor activity. It is well known that some antitumor agents demonstrate effects against Leishmania In this study, the in vitro leishmanicidal activities of several organo-selenium and organo-sulfur compounds were tested against Leishmania major and Leishmania amazonensis parasites, using promastigotes and intracellular amastigote forms. The cytotoxicity of these agents was measured in murine peritoneal macrophages and their selectivity indexes were calculated. One of the tested compounds, the isoselenocyanate derivative NISC-6, showed selectivity indexes 2- and 10-fold higher than those of the reference drug amphotericin B when evaluated in L. amazonensis and L. major, respectively. The American strain (L. amazonensis) was less sensitive to NISC-6 than L. major, showing a trend similar to that observed previously for amphotericin B. In addition, we also observed that NISC-6 significantly reduced the number of amastigotes per infected macrophage. On the other hand, we showed that NISC-6 decreases expression levels of Leishmania genes involved in the cell cycle, such as topoisomerase-2 (TOP-2), PCNA, and MCM4, therefore contributing to its leishmanicidal activity. The effect of this compound on cell cycle progression was confirmed by flow cytometry. We observed a significant increase of cells in the G1 phase and a dramatic reduction of cells in the S phase compared to untreated cells. Altogether, our data suggest that the isoselenocyanate NISC-6 may be a promising candidate for new drug development against leishmaniasis.
Autores: Alcolea, Verónica; DNK; MKP; et al.
Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN 1422-0067  Vol. 20  Nº 3  2019  págs. 521
Autores: de Lucio, H. ; Moreno, Esther; et al.
Revista: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN 0066-4804  Vol. 63  Nº 5  2019  págs. e02200-18
A novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity, with 50% effective concentration (EC50) values lower than that for the reference drug miltefosine (EC50, 2.84 mu M). In addition, the derivatives 9, 11, 42, and 47, with EC50 between 1.1 and 1.95 mu M, also displayed excellent selectivity (selectivity index ranged from 12.4 to 22.7) and were tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes, with EC50 values similar to those observed for the standard drug edelfosine. Structure-activity relationship analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leish-manicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase. Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their activity comparable to that of the standards
Autores: Encio, I. ; Plano, Daniel; et al.
Revista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0223-5234  Vol. 175  2019  págs. 234 - 246
Selenocyanates and diselenides are potential antitumor agents. Here we report two series of selenium derivatives related to selenocyanates and diselenides containing carboxylic, amide and imide moieties. These compounds were screened for their potency and selectivity against seven tumor cell lines and two non-malignant cell lines. Results showed that MCF-7 cells were especially sensitive to the treatment, with seven compounds presenting GI(50) values below 10 mu M. Notably, the carboxylic selenocyanate 8b and the cyclic imide 10a also displayed high selectivity for tumor cells. Treatment of MCF-7 cells with these compounds resulted in cell cycle arrest at S phase, increased levels of pJNK and pAMPK and caspase independent cell death. Autophagy inhibitors wortmannin and chloroquine partially prevented 8b and 10a induced cell death. Consistent with autophagy, increased Beclinl and LC3-IIB and reduced SQSTM1/p62 levels were detected. Our results point to 8b and 10a as autophagic cell death inducers. Published by Elsevier Masson SAS.
Autores: N.; Plano, Daniel; Antolín, María del Carmen; et al.
Revista: ARCHIV FUER ACKER- UND PFLANZENBAU UND BODENKUNDE
ISSN 0365-0340  Vol. 65  Nº 10  2019  págs. 1341-1353
Autores: Uriz, A.; Sanmartín, María del Carmen; Plano, Daniel; et al.
Revista: COLLOIDS AND SURFACES B-BIOINTERFACES
ISSN 0927-7765  Vol. 170  2018  págs. 463 - 469
Selenium (Se) incorporated into organic frameworks has demonstrated anticancer activity against several cancer types. One of the drawbacks of most of these constructs is their poor solubility and bioavailability, which can be overcome with the use of suitable nanocarriers. We have synthesized a series of 5-substituted amide selenodiazoles, based on the parent structure of ebselen, an organoselenium drug with proven cytoprotective activity, and solubilized them in polymeric micelles of poloxamines, poly(ethylene oxide)-poly(propylene oxide) X-shaped tetrablock-copolymers. Scattering methods (SANS and DLS) were employed to characterize the micellar nanocarriers. MTT biological evaluation highlights the selectivity of the Se-compounds towards cancer cells, with MCF-7 standing as the most responsive line. The alkylation of the heterocycle with a 12-carbon hydrophobic tail displays the highest activity, showing a 100-fold increase with respect to ebselen. This compound also exhibits the greatest increase in solubility in poloxamine micelles, overall resulting in a one-fold increase in activity with respect to the non-formulated form, making it a hit compound for further optimization.
Autores: Gonzalez, R.; Plano, Daniel; et al.
Revista: JOURNAL OF CELLULAR AND MOLECULAR MEDICINE (ONLINE)
ISSN 1582-4934  Vol. 22  Nº 1  2018  págs. 289 - 301
Symmetric aromatic diselenides are potential anticancer agents with strong cytotoxic activity. In this study, the invitro anticancer activities of a novel series of diarylseleno derivatives from the diphenyldiselenide (DPDS) scaffold were evaluated. Most of the compounds exhibited high efficacy for inducing cytotoxicity against different human cancer cell lines. DPDS 2, the compound with the lowest mean GI(50) value, induced both caspase-dependent apoptosis and arrest at the G(0)/G(1) phase in acute lymphoblastic leucemia CCRF-CEM cells. Consistent with this, PARP cleavage; enhanced caspase-2, -3, -8 and -9 activity; reduced CDK4 expression and increased levels of p53 were detected in these cells upon DPDS 2 treatment. Mutated p53 expressed in CCRF-CEM cells retains its transactivating activity. Therefore, increased levels of p21(CIP1) and BAX proteins were also detected. On the other hand, DPDS 6, the compound with the highest selectivity index for cancer cells, resulted in G(2)/M cell cycle arrest and caspase-independent cell death in p53 deficient HTB-54 lung cancer cells. Autophagy inhibitors 3-methyladenine, wortmannin and chloroquine inhibited DPDS 6-induced cell death. Consistent with autophagy, increased LC3-II and decreased SQSTM1/p62 levels were detected in HTB-54 cells in response to DPDS 6. Induction of JNK phosphorylation and a reduction in phospho-p38 MAPK were also detected. Moreover, the JNK inhibitor SP600125-protected HTB-54 cells from DPDS 6-induced cell death indicating that JNK activation is involved in DPDS 6-induced autophagy. These results highlight the anticancer effects of these derivatives and warrant future studies examining their clinical potential.
Autores: Encio, I. ; Plano, Daniel; et al.
Revista: ACS MEDICINAL CHEMISTRY LETTERS
ISSN 1948-5875  Vol. 9  Nº 4  2018  págs. 306 - 311
A series of 16 new diselenide-acylselenourea conjugates have been designed following the fragment-based drug strategy. Compound in vitro cytotoxic potential was evaluated against six human cancer cell lines and two nonmalignant derived cell lines with the aim of determining their potency and selectivity. Nine derivatives exhibited GI(50) values under 10 mu M in at least four cancer cell lines. A clear gap situated phenyl substitution over heterocyclic moieties in terms of selectivity. Among carbocyclic compounds, derivatives 2 and 7 significantly inhibited cell growth of breast adenocarcinoma cells with GI50 values of 1.30 and 0.15 nM, respectively, with selectivity indexes 12 and 121 times higher than those obtained for doxorubicin. Preliminary mechanistic studies indicated that compounds 2 and 7 induce cell cycle arrest and autophagy-dependent cell death evidenced by the blockage of cell death with pretreatment with wortmannin or chloroquine and confirmed by the upregulation of the markers Bedinl and LC3B in MCF-7 cells.
Autores: Ruberte, Ana Carolina; Plano, Daniel; Encio, I.; et al.
Revista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0223-5234  Vol. 157  2018  págs. 14 - 27
Twenty-seven novel benzo[c][1,2,5]selenadiazole-5-carboxylic acid (BSCA) derivatives were designed and synthesized. Anti-proliferative activity of these structures was tested in vitro against a panel of five human cancer cell lines, including prostate (PC-3), colon (HT-29), leukemia (CCRF-CEM), lung (HTB-54) and breast (MCF-7). Four compounds (5, 6, 7 and 19) showed potent inhibitory activity with GI(50) values below 10 mu M in at least one of the cancer cell lines. The selectivity of these compounds was further examined in two non-malignant cell lines derived from breast (18465) and lung (BEAS-2B). Compound 7 exhibited promising anti-proliferative activity (GI(50) = 3.7 mu M) in MCF-7 cells, together with high selectivity index (SI> 27.1). The induction of cell death by compound 7 was independent of the apoptotic process and it did not affect cell cycle progression either. Likewise, radical scavenging properties of the new selenadiazole derivatives were confirmed by testing their ability to scavenge DPPH radicals. Four compounds (1, 2, 8 and 9) showed potent radical scavenging activity, compound 9 being the most effective. Overall, while compound 7 was identified as the most cell growth inhibitory agent and selectively toxic to cancer cells, compound 9 proved to be the most potent antioxidant among the selenadiazole derivatives synthesized. This series of compounds can serve as an excellent scaffold to achieve new and potent antioxidant compounds useful for several diseases, i.e. cancer, neurodegenerative, heart diseases and leishmaniasis, considering the high radical scavenging activity and low toxicity showed by most of the compounds. (C) 2018 Elsevier Masson SAS. All rights reserved.
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: Ruberte, Ana Carolina; Plano, Daniel; Encio, I.; et al.
Revista: CANCER RESEARCH
ISSN 0008-5472  Vol. 78  Nº 13  2018 
Autores: Plano, Daniel; Ramisetti, S.; Kim, S. Y.; et al.
Revista: CANCER RESEARCH
ISSN 0008-5472  Vol. 78  Nº 13  2018 
Autores: Sanmartín, María del Carmen; Ruberte, Ana Carolina; Ibáñez, Elena; et al.
Revista: CURRENT ORGANIC SYNTHESIS
ISSN 1570-1794  Vol. 14  Nº 8  2017  págs. 1075 - 1081
Background: The incorporation of selenium (Se) atom onto organic scaffolds is a very promising approach to obtain more active and selective compounds against several types of cancer. During the last decade, a plethora of organoselenium compounds have been reported with very potent anticancer activity through diverse mechanisms of action, some of the most interesting being autophagy, angiogenesis, affectation of cancer stem cells and lethal mitosis. Several studies have related Se status and different selenoproteins with the development of Leishmania. Furthermore, one of the most used approaches for seeking new antitrypanosomal drugs is the drug repositioning. Considering both facts, our research group is developing organoselenium derivatives with dual activity against cancer and Leishmaniasis. Objective: The objective of this review is to gather, for the first time, every organic selenocompound with this dual activity. Thereby, the synthetic procedures will be discussed, along with their most important biological effects in both pathologies. Conclusion: To conclude, the reported results show that the introduction of Se atom onto organic molecules is a valid rational approach to obtain dual anticancer/leishmanicidal agents. Furthermore, the synthetic procedures needed are quite straightforward and occur with good yields. Thus, bisacylimidoselenocarbamates and diselenides are very good candidates to further develop as dual agents.
Autores: Martín-Montes, A.; Plano, Daniel; Martín-Escolano, R.; et al.
Revista: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN 0066-4804  Vol. 61  Nº 6  2017  págs. e02546-16
The in vitro leishmanicidal activities of a series of 48 recently synthesized selenium derivatives against Leishmania infantum and Leishmania braziliensis parasites were tested using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds for J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (compounds 8, 10, 11, 15, 45, and 48) showed selectivity indexes higher than those of the reference drug, meglumine antimonate (Glucantime), for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, data on infection rates and amastigote numbers per macrophage showed that compounds 8, 10, 11, 15, 45, and 48 were the most active against both Leishmania species studied. The observed changes in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe superoxide dismutase (Fe-SOD) in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials, and straightforward synthesis make these compounds appropriate molecules for the development of affordable antileishmanicidal agents.
Autores: Plano, Daniel; Alcolea, Verónica; Sanmartín, María del Carmen; et al.
Revista: EXPERT OPINION ON THERAPEUTIC PATENTS
ISSN 1354-3776  Vol. 27  Nº 5  2017 
Introduction: Colorectal cancer (CRC) is the fourth most common cancer worldwide. Targeted therapy drugs (TTDs) are a valid treatment, epithelial growth factor receptor (EGFR) inhibitors being one of the most commonly used for CRC patients. However, this treatment is only useful for patients with wild-type KRAS (wtKRAS) and is effective only on about 40 to 60% of this subset due to the high plasticity of ErbB network. Areas covered: The invention proposes the use of ErbB protein levels and ErbB receptor dimer formation as biomarkers for selecting, predicting and monitoring CRC patients showing sensitivity to the action of EGFR inhibitors to benefit from the combination therapy of EGFR and HER2 inhibitors. The in vitro data on Lim1215 cells suggest the over-activation of HER3 signaling pathway in response to the use of EGFR inhibitors on monotherapy; the use of HER2 or HER3 or MEK inhibitors in combination with EGFR inhibitors reversed this activation. Expert opinion: To assess the clinical applicability of this invention, further studies are needed since the conclusions are derived solely based on the data obtained from only one CRC cell line (Lim1215). Furthermore, other biofactors/mutations should be considered to assure the potential benefits of the combination therapies proposed.
Autores:  Encio, I.; Plano, Daniel; et al.
Revista: MOLECULES
ISSN 1420-3049  Vol. 22  Nº 8  2017  págs. 1288
Selenium (Se) compounds are potential therapeutic agents in cancer. Importantly, the biological effects of Se compounds are exerted by their metabolites, with methylselenol (CH3SeH) being one of the key executors. In this study, we developed a new series of methylselenoesters with different scaffolds aiming to modulate the release of CH3SeH. The fifteen compounds follow Lipinski's Rule of Five and with exception of compounds 1 and 14, present better drug-likeness values than the positive control methylseleninic acid. The compounds were evaluated to determine their radical scavenging activity. Compound 11 reduced both DPPH and ABTS radicals. The cytotoxicity of the compounds was evaluated in a panel of five cancer cell lines (prostate, colon and lung carcinoma, mammary adenocarcinoma and chronic myelogenous leukemia) and two non-malignant (lung and mammary epithelial) cell lines. Ten compounds had GI(50) values below 10 mu M at 72 h in four cancer cell lines. Compounds 5 and 15 were chosen for further characterization of their mechanism of action in the mammary adenocarcinoma cell line due to their similarity with methylseleninic acid. Both compounds induced G(2)/M arrest whereas cell death was partially executed by caspases. The reduction and metabolism were also investigated, and both compounds were shown to be substrates for redox active enzyme thioredoxin reductase.
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: 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: Alcolea, Verónica; Plano, Daniel; Karelia, D. N.; et al.
Revista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0223-5234  Vol. 113  2016  págs. 134 - 144
A series of novel selenourea derivatives and corresponding thiourea analogs were synthesized and tested against a panel of six human cancer cell lines: melanoma (1205Lu), lung carcinoma (A549), prostatic carcinoma (DU145), colorectal carcinoma (HCT116), pancreatic epithelioid carcinoma (PANC-1) and pancreatic adenocarcinoma (BxPC3). In general, we found that the selenium-containing derivatives were more potent than their isosteric sulfur analogs. Four selenourea derivatives (1e, 1f, 1g and 1i) showed IC50 values below 10 mM in all of tested cell lines at 72 h. On the basis of its potent activity, compound 1g was selected for further biological evaluation in different colon cancer cell lines. Our results indicated that compound 1g induced apoptosis by caspase activation, along with inhibition of anti-apoptotic proteins.
Autores: Alcolea, Verónica; Plano, Daniel; Encío, I.; et al.
Revista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0223-5234  Vol. 123  2016  págs. 407 - 418
In this work, 27 novel hybrid derivatives containing diverse substituents with chalcogen atoms (selenium or sulfur) and several active heterocyclic scaffolds have been synthesized. Compounds were tested against two human cancer cells lines (MCF7 and PC-3) and a normal human mammary epithelial cell line (184B5) in order to determine their activity and selectivity against malignant cells. Ten compounds showed GI50 values below 10 mM in at least one of the cancer cell lines and six of them exhibited a selectivity index higher than 9. In general, selenium-containing compounds were more active than their corresponding sulfur analogs but we found some thiocyanate derivatives with comparable or higher activity and selectivity. Among the different substituents, the seleno- and thio-cyanate groups showed the most promising results. On the basis of their potent activity and high selectivity index, compounds 7e and 8f (containing a thiocyanate and a selenocyanate group, respectively) were selected for further biological evaluation. Both the compounds induced caspase-dependent cell death and cell cycle arrest in G2/M phase. In addition, these compounds do not violate any of the Lipinski's Rule of Five and thus possess good potential to become drugs, compound 7e being particularly promising.
Autores: Plano, Daniel; Karelia, D. N.; Pandey, M. K.; et al.
Revista: JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0022-2623  Vol. 59  Nº 5  2016  págs. 1946 - 1959
The synthesis and anticancer evaluation of novel selenium-nonsteroidal anti-inflammatory drug (Se-NSAID) hybrid molecules are reported. The Se-aspirin analogue 8 was identified as the most effective agent in reducing the viability of different cancer cell lines, particularly colorectal cancer (CRC) cells, was more selective toward cancer cells than normal cells, and was >10 times more potent than 5-FU, the current therapy for CRC. Compound 8 inhibits CRC growth via the inhibition of the cell cycle in G1 and G2/M phases and reduces the cell cycle markers like cyclin E1 and B1 in a dose dependent manner; the inhibition of the cell cycle may be dependent on the ability of 8 to induce p21 expression. Furthermore, 8 induces apoptosis by activating caspase 3/7 and PARP cleavage, and its longer exposure causes increase in intracellular ROS levels in CRC cells. Taken together, 8 has the potential to be developed further as a chemotherapeutic agent for CRC.
Autores: Karelia, D.; Pandey, M. K.; Plano, Daniel; et al.
Revista: CANCER RESEARCH
ISSN 0008-5472  Vol. 76  Nº Supl. 14   2016  págs. 3061
Patients with pancreatic cancer (PC) have a median survival of only 6 months and a five-year survival of less than 5%, hence making PC one of the deadliest cancer. Severity of PC is due to its identification at late stages, rapid local invasion, early metastases, and meager response to current chemotherapeutic agents. Current therapies result in minimal survival advantage and are linked with multiple adverse events and drug resistance. Hence, there is an urgent need for novel agents which are less toxic and offer greater benefits over conventional therapy. There is ample evidences in literature demonstrating that inflammation plays a critical role in PC growth and promotion. Nuclear factor ¿B (NF-¿B) pathway, one of the major inflammatory pathway, is well known for its inflammatory response, cell proliferation, and resistance to apoptosis. It has been demonstrated that activation of NF-¿B in PC is also responsible for resistance towards first line chemotherapeutic agent, gemcitabine, in PC. Through extensive structure-activity relationship studies, we have recently identified a novel small molecule, AS-10, which was lethal to PC cells. We sought to evaluate the mechanism of action of AS-10 responsible for inhibiting the growth of PC cells. In vitro, AS-10 reduced PC cell growth with an EC50, in the range of 2.5 to 5 ¿M. Growth arrest was confirmed by cell cycle studies, which showed that AS-10 induced G1 and G2 cell cycle arrest...
Autores: Fernández, Celia; Campbell, D.; et al.
Revista: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN 0066-4804  Vol. 59  Nº 9  2015  págs. 5705 - 5713
The generation of new antileishmanial drugs has become a priority. Selenium and its derivatives stand out as having promising leishmanicidal activity. In fact, some parasites express selenoproteins and metabolize selenium. Recently, selenium derivatives have shown the potential to reduce parasitemia, clinical manifestations, and mortality in parasite-infected mice. In this paper, after selecting four candidates according to drug similarity parameters, we observed that two of them, called compounds 2b [methyl-N,N¿-di(thien-2-ylcarbonyl)-imidoselenocarbamate] and 4b [methyl-N,N¿-di(5-nitrothien-3-ylcarbonyl)-imidoselenocarbamate], exhibit low 50% inhibitory concentrations (IC50s) (<3 ¿M) and good selectivity indexes (SIs) (>5) in Leishmania major promastigotes and lack toxicity on macrophages. In addition, in analysis of their therapeutic potential against L. major in vitro infection, both compounds display a dramatic reduction of amastigote burden (~80%) with sublethal concentrations. Furthermore, in macrophages, these selenocompounds induce nitric oxide production, which has been described to be critical for defense against intracellular pathogens. Compounds 2b and 4b were demonstrated to cause cell cycle arrest in G1 . Interestingly, evaluation of expression of genes related to proliferation (PCNA), treatment resistance (ABC transporter and alpha-tubulin), and virulence (quinonoid dihydropteridine reductase [QDPR]) showed several alterations in gene expression profiling. All these results prompt us to propose both compounds as candidates to treat leishmanial infections.
Autores: Stoedter, M.; Renko, K.; Ibáñez, Elena; et al.
Revista: METALLOMICS
ISSN 1756-5901  Vol. 7  Nº 2  2015  págs. 347 - 354
The biological activity of thyroid hormones (TH) is regulated by selenoenzymes of the iodothyronine deiodinase (DIO) family catalysing TH activating and inactivating reactions. Besides TH metabolism, several studies indicate an important role of DIO isoenzymes in tumorigenesis and cancer growth. It is therefore of therapeutic importance to identify modulators of DIO expression. We have synthesized and studied a series of selenocompounds containing a methyl- or benzyl-imidoselenocarbamate backbone. One of these novel compounds had chemotherapeutic activities in a murine xenograft tumour model by an unknown mechanism. Therefore, we tested their effects on DIO expression in vitro. In HepG2 hepatocarcinoma cells, DIO1 activity was strongly (up to 10-fold) increased by the methyl-but not by the corresponding benzyl-imidoselenocarbamates. Steady-state mRNA levels remained unaltered under these conditions indicating a post-transcriptional mode of action. The effects were further characterized in HEK293 cells stably expressing DIO1, DIO2 or DIO3. Even within the artificial genetic context of the expression vectors, all three DIO isoenzymes were up-regulated by the methyl-and to a lesser extent by the benzyl-imidoselenocarbamates. Consistent stimulating effects were observed with methyl-N, N'-di(quinolin-3-ylcarbonyl)-imidoselenocarbamate (EI201), a selenocompound known for its anti-tumour activity. DIO inducing effects were unrelated to the intracellular accumulation of selenium, yet the precise mode of action remains elusive. Collectively, our data highlight that these selenocompounds may constitute interesting pharmacological compounds for modifying DIO expression potentially affecting the balance between cell differentiation and proliferation.
Autores: Plano, Daniel; Encío, I.; et al.
Revista: BIOORGANIC AND MEDICINAL CHEMISTRY
ISSN 0968-0896  Vol. 23  Nº 8  2015  págs. 1716 - 1724
Novel selenocyanate and diselenide derivatives containing a carbamate moiety were synthesised and evaluated in vitro to determine their cytotoxic and radical scavenging properties. Cytotoxic activity was tested against a panel of human cell lines including CCRF-CEM (lymphoblastic leukaemia), HT-29 (colon carcinoma), HTB-54 (lung carcinoma), PC-3 (prostate carcinoma), MCF-7 (breast adenocarcinoma), 184B5 (non-malignant, mammary gland derived) and BEAS-2B (non-malignant, derived from bronchial epithelium). Most of the compounds displayed high antiproliferative activity with GI(50) values below 10 mu M in MCF-7, CCRF-CEM and PC-3 cells. Radical scavenging properties of the new selenocompounds were confirmed testing their ability to scavenge DPPH and ABTS radicals. Based on the activity of selenium-based glutathione peroxidases (GPxs), compounds 1a, 2e and 2h were further screened for their capacity to reduce hydrogen peroxide under thiol presence. Results suggest that compound 1a mimics GPxs activity. Cytotoxic parameters, radical scavenging activity and ADME profile point to 1a as promising drug candidate.
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: Karelia, D.; Pandey, M.; Plano, Daniel; et al.
Revista: CANCER RESEARCH
ISSN 0008-5472  Vol. 75  Nº Suppl. 15   2015  págs. 4502
In the US, colorectal cancer (CRC) remains the second leading cause of cancer-related death. The 5-year survival rate for patients with CRC is 64%, although for patients who present with distant metastases at diagnosis the 5 year survival is only 12%. Currently used standard care for CRC can only marginally extend the survival of patients and is associated with numerous adverse events. Hence, there remains an urgent need for more effective and less toxic treatments, which can increase CRC patient survival with better quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. Aspirin, Ibuprofen, Naproxen), which are widely used for their anti-inflammatory and analgesic effects, have also been shown to be effective in reducing colon cancer incidences and are proposed to be effective chemopreventive agents. However, these NSAIDs are not potent enough to be used as cancer therapeutics and also carry a liability of gastrointestinal bleeding mainly associated with COX inhibition. Through extensive structure activity relationship (SAR) studies based on newly synthesized NSAID-analogs, we have identified a novel aspirin analog, ASD-49, as the most effective small molecule that showed efficacy in different cancer cell lines, including CRC cells with an EC50 ranging between 1 to 2.5 ¿M at 48 h treatment in culture. This unique compound selectively killed cancer cells and is >50-times more potent than the current therapy for CRC and >100-times more potent...
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: 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: Plano, Daniel; Amin, S.; Sharma, A. K.;
Revista: JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0022-2623  Vol. 57  Nº 13  2014  págs. 5509 - 5524
Sphingosine kinase (SphK) is an oncogenic lipid kinase that regulates the sphingolipid metabolic pathway that has been shown to play a role in numerous hyperproliferative/inflammatory diseases. The SphK isoforms (SphK1 and SphK2) catalyze the conversion of the pro-apoptotic substrate D-erythrosphingosine to the pro-mitogenic/migratory product sphingosine-1-phosphate (S1P). Accumulation of S1P has been linked to the development/progression of cancer and various other diseases including, but not limited to, asthma, inflammatory bowel disease, rheumatoid arthritis and diabetic nephropathy. SphK therefore represents a potential new target for developing novel therapeutics for cancer and other diseases. This finding has stimulated the development and evaluation of numerous SphK inhibitors over the past decade or so. In this Perspective, we highlight the recent advancement in the field of SphK inhibitors including SphK1 and SphK2 specific inhibitors. Both sphingolipid based and nolipidic small molecule inhibitors, as well as their importance in treatment of cancer and other diseases are discussed.
Autores: Palop, Juan Antonio; Plano, Daniel; Moreno, Esther; et al.
Revista: ARKIVOC
ISSN 1551-7004  Vol. 2014  Nº 2  2014  págs. 187 - 206
A series of 22 quinazolines, pyrido[2,3-d]pyrimidines and their hydroselenite salts were synthesized with the aim of evaluating in vitro their cytotoxicity against PC-3 cell line and their antioxidant properties related to DPPH (1,1-diphenyl-2-picrylhydrazylradical) activity, showing some of them better profile than the respective controls. Three of these derivatives (5d, 6d and 7f) were selected in order to gain preliminary insights to establish the mechanism of action. Caspase-3 activity and cell cycle regulation studies revealed that compound 6d provoked an increase in caspase-3 level accompanied by cell cycle perturbation in a time-dependent manner.
Autores: Karelia, D.; Pandey, M.; Plano, Daniel; et al.
Revista: CANCER RESEARCH
ISSN 0008-5472  Vol. 74  Nº Suppl. 19   2014  págs. 814
Inflammation plays an important role in tumor growth promotion and has been linked to several human cancers. Evidences have demonstrated that inflammation has a high correlation with pancreatic cancer (PC) growth and promotion. An important mediator of inflammatory process is Cyclooxygenase 2 (COX-2) protein, which has been shown to be over-expressed in PC. Another major pathway which is crucial for inflammatory responses, cell proliferation, and resistance to apoptosis is the nuclear factor ¿B (NF-¿B) pathway. It has been demonstrated that NF-¿B pathway is responsible for drug resistance in PC. Aspirin, a well-known non-steroidal anti-inflammatory drug (NSAID), has been shown to have anti-cancer effects against PC. The mechanism of action of aspirin against PC is partially dependent on COX inhibition, as well as COX independent mechanism. Through extensive structure-activity relationship studies on Se-NSAID compounds, we have recently identified two Se-Aspirin compounds, ASD-43 and ASD-49, designed by incorporating selenium (Se) into salicylic acid structure, rendering it lethal to cancer cells. Previously, we had reported that Se-aspirin hybrid compounds were effective in different cancers, including PC. In this study we sought to evaluate the mechanism of action of these compounds in inhibiting the growth of PC. Since aspirin induces its effect partially by inhibiting COX, we hypothesized that these agents (ASD-43 and ASD-49) showed their anti-cancer activity...
Autores: Plano, Daniel; Aliaga, C.; Pandey, M.; et al.
Revista: CANCER RESEARCH
ISSN 0008-5472  Vol. 74  Nº 19 Supplement  2014  págs. 2139 - 2139
Despite the identification of several preventive agents and strategies, prevention of lung cancer, especially in smokers who are at high risk, is still largely unattained. 1,4-Phenylenebis(methylene)selenocyanate (p-XSC) has been shown to inhibit tobacco carcinogen NNK induced lung cancer development in several animal models. It metabolizes through the formation of active bis-selenol (p-XSeH) along with the release of poisonous hydrogen cyanide (HCN). Nevertheless, the HCN released upon metabolism of p-XSC to form active metabolite p-XSeH, pose a serious challenge its clinical use in a chemopreventive set up where a continuous intake is required for healthy individuals over a longer period of time. Recently, we developed a hybrid agent, p-XS-Asp, linking p-XSe- to commonly used non-steroidal anti-inflammatory drug, aspirin (Asp), which has been shown to be preventive of lung, and colorectal cancer. We hypothesized that p-XS-Asp would cleave in vivo to release the active p-XSeH, not releasing undesired HCN but the aspirin, thus making the compound less toxic and more potent than p-XSC or aspirin alone. Our studies have shown p-XS-Asp to be orally bioavailable and a highly effective lung cancer chemopreventive agent both in vitro and in animal studies. Elemental selenium (Se) analysis of plasma, lung, and liver tissue in orally fed mice showed that the level of Se significantly higher for p-XS-Asp than p-XSC, denoting a better bioavailability profile for p-XS-Asp...
Autores: Plano, Daniel; Palop, Juan Antonio; et al.
Revista: JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY
ISSN 1388-6150  Vol. 111  Nº 1  2013  págs. 605-610
Differential scanning calorimetry (DSC) and thermogravimetry (TG) are analytical and quantitative methods capable of providing reliable, fast and reproducible results. These data allow establishing the thermal stability, purity degree and the polymorphic behavior of organic compounds. Thermal analysis of fusion and degradation processes was carried out on organonitrogen, organosulfur and organoselenium phthalazine derivatives to establish thermal stability criteria. Decomposition and fusion temperatures of 27 biological active compounds, synthesized by our research group were determined using TG and DSC. Analysis of the thermal data indicated that: (a) in general, nitrogen compounds are more stable than sulfur and selenium compounds; (b) thioderivatives possess degradation temperatures higher than selenium compounds; (c) the presence of selenium atoms in molecular structure has associated a minor thermal stability; (d) sulfide derivatives decomposition process have higher T-onset values than disulfide compounds; (e) there are differences in the stability due to groups selenol, methylseleno, and cyanoseleno; (f) the nature of the substituent located on the benzyl ring has no effects on selenophthalazines thermal stability.
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: Plano, Daniel; Karelia, D.; Pandey, M.; et al.
Revista: CANCER RESEARCH
ISSN 0008-5472  Vol. 73  Nº 8 Suppl. 1  2013  págs. 5553
Several non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective chemopreventive agents in both pre-clinical and clinical studies on various cancer types. Here in, we developed several selenium (Se)-NSAID hybrid molecules and evaluated their efficacy as cancer therapeutics. The rationale for introducing Se into the NSAIDs is that this redox-active trace element is an essential micronutrient and a normal component of diets with chemopreventive and anticancer properties. Our recent studies have also shown that appropriately designed organoselenium compounds exhibited promising anti-tumor properties in various preclinical cancer models. We hypothesized that the rational incorporation of Se into NSAIDs should enhance their anti-cancer properties and therefore, we synthesized 16 novel Se-NSAID hybrid agents designed by incorporating Se moieties into the structures of aspirin, ibuprofen, and naproxen. In the first phase, a selenocyanate moiety was incorporated to these NSAIDs and screened for their cytotoxicity in various cancer cell lines. The cell viability results at 24 and 48 h showed that the introduction of this Se functionality on aspirin scaffold achieved a dramatic increase in the activity as compared to aspirin, as well as other NSAIDs or their Se hybrids. Thus, we continued optimization of aspirin with a variety of Se moieties, such as selenides and selenomethyl functionalities. Most of these compounds reduced cell viability in a dose dependent...
Autores: Bapat, P.; Goswami, D.; Shastri, A.; et al.
Revista: FREE RADICAL BIOLOGY AND MEDICINE
ISSN 0891-5849  Vol. 65   Nº Supl. 2  2013  págs. S15
Autores: Sanmartín, María del Carmen; Plano, Daniel; Sharma, A.K.; et al.
Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN 1422-0067  Vol. 13  Nº 8  2012  págs. 9649 - 9672
Selenium (Se) is an essential trace element involved in different physiological functions of the human body and plays a role in cancer prevention and treatment. Induction of apoptosis is considered an important cellular event that can account for the cancer preventive effects of Se. The mechanisms of Se-induced apoptosis are associated with the chemical forms of Se and their metabolism as well as the type of cancer studied. So, some selenocompounds, such as SeO2 involve the activation of caspase-3 while sodium selenite induces apoptosis in the absence of the activation of caspases. Modulation of mitochondrial functions has been reported to play a key role in the regulation of apoptosis and also to be one of the targets of Se compounds. Other mechanisms for apoptosis induction are the modulation of glutathione and reactive oxygen species levels, which may function as intracellular messengers to regulate signaling pathways, or the regulation of kinase, among others. Emerging evidence indicates the overlaps between the apoptosis and other types of cell death such as autophagy. In this review we report different processes of cell death induced by Se compounds in cancer treatment and prevention.
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: Ibáñez, Elena; Prior, Celia; Nguewa, Paul; et al.
Revista: CURRENT MEDICINAL CHEMISTRY
ISSN 0929-8673  Vol. 19  Nº 18  2012  págs. 3031 - 3043
Methylimidoselenocarbamates have previously proven to display potent antitumor activities. In the present study we show that these compounds act as multikinase inhibitors. We found that the most effective compound, quinoline imidoselenocarbamate EI201, inhibits the PI3K/AKT/mTOR pathway, which is persistently activated and contributes to malignant progression in various cancers. EI201 blocked the phosphorylation of AKT, mTOR and several of its downstream regulators (p70(S6K) and 4E-BP1) and ERK1/2 in PC-3, HT-29 and MCF-7 cells in vitro, inducing both autophagy and apoptosis. EI201 also contributes to the loss of maintenance of the self-renewal and tumorigenic capacity of cancer stem cells (CSCs). 0.1 mu mol/L EI201 triggered a reduction in size and number of tumorspheres in PC-3, HT-29 and MCF-7 cells and 4 mu mol/L induced the elimination of almost all the tumorspheres in the three studied cell lines. In addition, EI201 suppressed almost 80% prostate tumor growth in vivo (p < 0.01) compared to controls at a relatively low dose (10 mg/kg) in a mouse xenograft model. There was a significant decrease in the subcutaneous primary tumor [18F]-FDG uptake (76.5% reduction, p < 0.05) and in the total tumor burden (76.8% reduction, p < 0.05) after EI201 treatment compared to vehicle control, without causing toxicity in mice. Taken together, our results support further development of EI201 as a novel multi-kinase inhibitor that may be useful against cancers with aberrant upregulation of PI3K/AKT and MAPK signaling pathways.
Autores: Ibáñez, Elena; Stoedter, M.; Hofmann, P.J.; et al.
Revista: METALLOMICS
ISSN 1756-5901  Vol. 4  Nº 12  2012  págs. 1297 - 1307
The essential micronutrient selenium (Se) exerts its biological effects mainly through selenoproteins thereby affecting a number of physiological pathways including intracellular redox control, stress response and cancer cell proliferation. Besides affecting selenoprotein expression, some selenocompounds have been synthesized and analyzed in order to serve as chemotherapeutic substances preferentially targeting cancer cells. This promising chemotherapeutic potential has recently been verified for a particular imidoselenocarbamate in a mouse tumor model. In the present study we tested the effects of this and a number of related Se-methyl-and Se-benzyl-imidoselenocarbamates on selenoprotein expression in nontransformed and hepatic carcinoma cells in culture. Most of the Se-benzyl-imidoselenocarbamates strongly stimulated selenoprotein P (SePP) secretion while the Se-methyl-imidoselenocarbamates elicited less pronounced effects in hepatocarcinoma HepG2 cells. However, most of the Se-methyl-imidoselenocarbamates increased glutathione peroxidase (GPx) activity and decreased thioredoxin reductase (TXNRD) activity in parallel, while the majority of the Se-benzyl-imidoselenocarbamates were without a respective effect in HepG2 cells. Performing inhibitor assays in vitro, GPx activity was unaffected by the imidoselenocarbamates. In contrast, most of the Se-methyl-imidoselenocarbamates inhibited TXNRD activity in vitro in line with the results in HepG2 cells. Both classes of imidoselenocarbamates strongly induced selenoprotein S (SELS) expression without a respective increase in ER stress or unfolded protein response which are known inducers of SELS biosynthesis. Notably, many of these effects were cancer cell-specific, and not observed in nontransformed AML12 hepatocytes. Our results indicate that these novel selenocompounds affect expression and activity of crucial selenoenzymes in a compound-and cell-specific way in hepatocytes. Especially the Se-methyl-imidoselenocarbamates elicit a unique spectrum of activities by stimulating GPx activity, SELS expression and SePP secretion while inhibiting TXNRD activity in hepatocarcinoma cells. These effects represent a promising finding with respect to the identification of therapeutic selenocompounds, as cancer-cell specificity is combined with desired effects on selenoprotein expression and activity.
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: Plano, Daniel; Ibáñez, Elena; Calvo, Alfonso; et al.
Revista: Molecules
ISSN 1420-3049  Vol. 16  Nº 8  2011  págs. 6349 - 6364
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; Ibáñez, Elena; Palop, Juan Antonio; et al.
Revista: STRUCTURAL CHEMISTRY
ISSN 1040-0400  Vol. 22  Nº 6  2011  págs. 1233 - 1240
Organoselenium compounds have already been reported to be good anticarcinogenic candidates. A new selenoquinazoline derivative, 2,4-bis(selenomethyl) quinazoline (compound 1), has been synthesized, spectroscopically characterized and its crystal structure has been studied. An intermolecular coupling between C(2) and H(5)' in the Heteronuclear Multiple Bond Correlation (HMBC) experiment has been observed. Assuming that the head-to-tail overlap of parallel molecules (as identified by X-ray diffraction) remains in solution to give bimolecular entities, the p-p interaction enables heteronuclear coupling between the former atoms with a three-bond distance [C(2)center dot center dot center dot(pi-pi)center dot center dot center dot C(5)'-H(5)']. The crystal structure of compound 1 has been solved by X-ray diffraction. It crystallizes in triclinic system, space group P-1. Unit cell parameters are a = 7.4969(7) angstrom, b = 8.7008(8) angstrom, c = 10.1666(9) angstrom, a = 110.215(2)degrees, beta = 90.354(2)degrees, gamma = 115.017(1)degrees. Linear chains in crystals of compound 1 are generated by C-H center dot center dot center dot Se and Se center dot center dot center dot Se bonds between molecules. Furthermore, head-to-tail overlap of parallel molecules, in which p-p interactions can occur, is observed. Compound 1 exhibited a cytotoxic effect in all of the evaluated tumoral cell lines and showed a higher cytotoxic effect in colon and breast cancer cell lines than etoposide, which was used as a reference compound.
Autores: Plano, Daniel; Lizarraga, Elena; Palop, Juan Antonio; et al.
Revista: JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY
ISSN 1388-6150  Vol. 105  Nº 3  2011  págs. 1007 - 1013
The thermal behavior of a series of organosulfur and organoselenium compounds has been studied by means of differential scanning calorimetry, X-ray diffraction, and thermomicroscopy in order to investigate their polymorphism. In this study, the polymorphism of some of the products has been established. The results of the experiments show that there are four types of thermal behavior for compounds studied. The physicochemical characterization of sulfur and selenium compounds showed differences in structural parameters and fusion temperatures among polymorphic forms.
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; Baquedano, Ylenia; Ibáñez, Elena; et al.
Revista: Molecules
ISSN 1420-3049  Vol. 15  Nº 10  2010  págs. 7292 - 7312
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: Moreno, David; Plano, Daniel; Baquedano, Ylenia; et al.
Revista: PARASITOLOGY RESEARCH
ISSN 0932-0113  Vol. 108  Nº 1  2010  págs. 233 - 239
Autores: Plano, Daniel; Palop, Juan Antonio; Sanmartín, María del Carmen;
Libro:  Applications of calorimetry in a wide context - Differential scanning calorimetry, isothermal titration calorimetry and microcalorimetry
2013  págs. 365 - 384
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: Sanmartín, María del Carmen; Palop, Juan Antonio; et al.
Libro:  Prostate cancer-Original scientific reports and case studies
2011  págs. 153 - 170