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3. Coumarins-lipophilic cations conjugates: Efficient mitocans targeting carbonic anhydrases

Author

Fuentes-Aguilar, Alma, González-Bakker, Aday, Jovanović, Mirna, Stojanov, Sofija Jovanović, Puerta, Adrián, Gargano, Adriana, Dinić, Jelena, Vega-Báez, José L., Merino-Montiel, Penélope, Montiel-Smith, Sara, Alcaro, Stefano, Nocentini, Alessio, Pešić, Milica, Supuran, Claudiu T., Padrón, José M., Fernández-Bolaños, José G., and López, Óscar

Published
2024
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6. Exploring the Anticancer Potential of Phenolic nor -Triterpenes from Celastraceae Species.

Author

Reyes, Carolina P., Ardiles, Alejandro, Anaissi-Afonso, Laura, González-Bakker, Aday, Padrón, José M., Jiménez, Ignacio A., Machín, Félix, and Bazzocchi, Isabel L.

Subjects
CELL imaging, HELA cells, MOLECULES, MOLECULAR structure, CELL lines, LUNGS
Abstract

To explore new compounds with antitumour activity, fifteen phenolic nor-tripterpenes isolated from Celastraceae species, Maytenus jelskii, Maytenus cuzcoina, and Celastrus vulcanicola, have been studied. Their chemical structures were elucidated through spectroscopic and spectrometric techniques, resulting in the identification of three novel chemical compounds. Evaluation on human tumour cell lines (A549 and SW1573, non-small cell lung; HBL-100 and T-47D, breast; HeLa, cervix, and WiDr, colon) revealed that three compounds, named 6-oxo-pristimerol, demethyl-zeylasteral, and zeylasteral, exhibited significant activity (GI50 ranging from 0.45 to 8.6 µM) on at least five of the cell lines tested. Continuous live cell imaging identified apoptosis as the mode of action of selective cell killing in HeLa cells. Furthermore, their effect on a drug-sensitive Saccharomyces cerevisiae strain has been investigated to deepen on their mechanism of action. In dose-response growth curves, zeylasteral and 7α-hydroxy-blepharodol were markedly active. Additionally, halo assays were conducted to assess the involvement of oxidative stress and/or mitochondrial function in the anticancer profile, ruling out these modes of action for the active compounds. Finally, we also delve into the structure-activity relationship, providing insights into how the molecular structure of these compounds influences their biological activity. This comprehensive analysis enhances our understanding of the therapeutic potential of this triterpene type and underscores its relevance for further research in this field. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Early pharmacological profiling of isatin derivatives as potent and selective cytotoxic agents

Author

Puerta, Adrián, González-Bakker, Aday, Brandão, Pedro, Pineiro, Marta, Burke, Anthony J., Giovannetti, Elisa, Fernandes, Miguel Xavier, Padrón, José M., Puerta, Adrián, González-Bakker, Aday, Brandão, Pedro, Pineiro, Marta, Burke, Anthony J., Giovannetti, Elisa, Fernandes, Miguel Xavier, and Padrón, José M.

Abstract

Isatin derivatives have attracted a lot of interest for their potential in the development of new anticancer drugs. A library of 38 isatin derivatives, created through an Ugi four-component reaction, underwent an initial screening in a panel of six human solid tumor cell lines. The four most active derivatives were then selected for further testing. These compounds showed selectivity towards the non-small cell lung cancer (NSCLC) cell line SW1573, whilst NSCLC A549 cells were barely affected. The combination of phenotypic assays, including wound healing, clonogenic and continuous live cell imaging provided a deeper understanding of the compounds’ mode of action. In particular, the latter demonstrated that isatin derivatives were able to induce necroptosis in SW1573 cells. The kinetics of cell death showed that necroptosis appeared after 2.5 h of exposure, which could be delayed to 7 h when co-treated with necrostatin-1. Interaction between the isatin derivatives and the KRAS G12C protein variant was discarded after in silico studies. Further studies are warranted to identify the cellular target responsible for the observed selectivity among cell lines.

Published
2024
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9. Coumarins-lipophilic cations conjugates: Efficient mitocans targeting carbonic anhydrases

Author

Universidad de Sevilla. Departamento de Química orgánica, Universidad de Sevilla. FQM134: Química Fina de Carbohidratos, Ministerio de Ciencia e Innovación (MICIN). España, Agencia Estatal de Investigación. España, Junta de Andalucía, República de Serbia, Fuentes Aguilar, Alma, González-Bakker, Aday, Jovanović, Mirna, Stojanov, Sofija Jovanović, Puerta, Adrián, Gargano, Adriana, Fernández-Bolaños Guzmán, José María, López López, Óscar, Universidad de Sevilla. Departamento de Química orgánica, Universidad de Sevilla. FQM134: Química Fina de Carbohidratos, Ministerio de Ciencia e Innovación (MICIN). España, Agencia Estatal de Investigación. España, Junta de Andalucía, República de Serbia, Fuentes Aguilar, Alma, González-Bakker, Aday, Jovanović, Mirna, Stojanov, Sofija Jovanović, Puerta, Adrián, Gargano, Adriana, Fernández-Bolaños Guzmán, José María, and López López, Óscar

Abstract

Being aware of the need to develop more efficient therapies against cancer, herein we disclose an innovative approach for the design of selective antiproliferative agents. We have accomplished the conjugation of a coumarin fragment with lipophilic cations (triphenylphosphonium salts, guanidinium) for providing mitochondriotropic agents that simultaneously target also carbonic anhydrases IX and XII, involved in the development and progression of cancer. The new compounds prepared herein turned out to be strong inhibitors of carbonic anhydrases IX and XII of human origin (low-to-mid nM range), also endowed with high selectivity, exhibiting negligible activity towards cytosolic CA isoforms. Key interactions with the enzyme were analysed using docking and molecular dynamics simulations. Regarding their in vitro antiproliferative activities, an increase of the tether length connecting both pharmacophores led to a clear improvement in potency, reaching the submicromolar range for the lead compounds, and an outstanding selectivity towards tumour cell lines (S.I. up to >357). Cytotoxic effects were also analysed on MDR cell lines under hypoxic and normoxic conditions. Chemoresistance exhibited by phosphonium salts, and not by guanidines, against MDR cells was based on the fact that the former were found to be substrates of P-glycoprotein (P-gp), the pump responsible for extruding foreign chemicals; this situation was reversed by administrating tariquidar, a third generation P-gp inhibitor. Moreover, phosphonium salts provoked a profound depolarization of mitochondria membranes from tumour cells, thus probably compromising their oxidative metabolism. To gain insight into the mode of action of title compounds, continuous live cell microscopy was employed; interestingly, this technique revealed two different antiproliferative mechanisms for both families of mitocans. Whereas phosphonium salts had a cytostatic effect, blocking cell division, guanidines led to cell death via apo

Published
2024

11. Fluoro-labelled sp2-iminoglycolipids with immunomodulatory properties

Author

Universidad de Sevilla. Departamento de Química orgánica, Ministerio de Ciencia e Innovación (MICIN). España, Agencia Estatal de Investigación. España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Universidad de Sevilla, Instituto de Salud Carlos III, Junta de Andalucía, Gobierno de Canarias. España, Padilla Pérez, María del Carmen, Sánchez Fernández, Elena Matilde, González-Bakker, Aday, Puerta, Adrián, Padrón, José M., Martín-Loro, Francisco, García Fernández, José Manuel, Ortiz Mellet, Carmen, Universidad de Sevilla. Departamento de Química orgánica, Ministerio de Ciencia e Innovación (MICIN). España, Agencia Estatal de Investigación. España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Universidad de Sevilla, Instituto de Salud Carlos III, Junta de Andalucía, Gobierno de Canarias. España, Padilla Pérez, María del Carmen, Sánchez Fernández, Elena Matilde, González-Bakker, Aday, Puerta, Adrián, Padrón, José M., Martín-Loro, Francisco, García Fernández, José Manuel, and Ortiz Mellet, Carmen

Published
2023

12. Biotinylated selenocyanates: Potent and selective cytostatic agents

Author

Universidad de Sevilla. Departamento de Química orgánica, Ministerio de Ciencia e Innovación (MICIN). España, Junta de Andalucía, Republic of Serbia Government, Roldán Peña, Jesús Miguel, Puerta, Adrián, Dinić, Jelena, Jovanović Stojanov, Sofija, González-Bakker, Aday, Hicke, Francisco J., Mishra, Atreyee, Piyasaengthong, Akkharadet, Maya Castilla, Inés, Walton, James W., Pešić, Milica, Padrón, José M., Fernández-Bolaños Guzmán, José María, López López, Óscar, Universidad de Sevilla. Departamento de Química orgánica, Ministerio de Ciencia e Innovación (MICIN). España, Junta de Andalucía, Republic of Serbia Government, Roldán Peña, Jesús Miguel, Puerta, Adrián, Dinić, Jelena, Jovanović Stojanov, Sofija, González-Bakker, Aday, Hicke, Francisco J., Mishra, Atreyee, Piyasaengthong, Akkharadet, Maya Castilla, Inés, Walton, James W., Pešić, Milica, Padrón, José M., Fernández-Bolaños Guzmán, José María, and López López, Óscar

Abstract

Most of the currently available cytotoxic agents for tackling cancer are devoid of selectivity, thus causing severe side-effects. This situation stimulated us to develop new antiproliferative agents with enhanced affinity towards tumour cells. We focused our attention on novel chalcogen-containing compounds (thiosemicarbazones, disulfides, selenoureas, thio- and selenocyanates), and particularly on selenium derivatives, as it has been documented that this kind of compounds might act as prodrugs releasing selenium-based reactive species on tumour cells. Particularly interesting in terms of potency and selectivity was a pharmacophore comprised by a selenocyanato-alkyl fragment connected to a p-phenylenediamine residue, where the nature of the second amino moiety (free, Boc-protected, enamine-protected) provided a wide variety of antiproliferative activities, ranging from the low micromolar to the nanomolar values. The optimized structure was in turn conjugated through a peptide linkage with biotin (vitamin B7), a cellular growth promoter, whose receptor is overexpressed in numerous cancer cells; the purpose was to develop a selective vector towards malignant cells. Such biotinylated derivative behaved as a very strong antiproliferative agent, achieving GI50 values in the low nM range for most of the tested cancer cells; moreover, it was featured with an outstanding selectivity, with GI50 > 100 µM against human fibroblasts. Mechanistic studies on the mode of inhibition of the biotinylated selenocyanate revealed (Annexin-V assay) a remarkable increase in the number of apoptotic cells compared to the control experiment; moreover, depolarization of the mitochondrial membrane was detected by flow cytometry analysis, and with fluorescent microscopy, what supports the apoptotic cell death. Prior to the apoptotic events, cytostatic effects were observed against SW1573 cells using label-free cell-living imaging; therefore, tumour cell division was prevented. Multidrug resistan

Published
2023

13. Fluoro-labelled sp2-iminoglycolipids with immunomodulatory properties

Author

Padilla Pérez, María del Carmen, Sánchez Fernández, Elena Matilde, González-Bakker, Aday, Puerta, Adrián, Padrón, José M., Martín-Loro, Francisco, García Fernández, José Manuel, Ortiz Mellet, Carmen, Universidad de Sevilla. Departamento de Química orgánica, Ministerio de Ciencia e Innovación (MICIN). España, Agencia Estatal de Investigación. España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Universidad de Sevilla, Instituto de Salud Carlos III, Junta de Andalucía, and Gobierno de Canarias. España

Subjects
Immunomodulation, Inflammation, Fluorinated glycomimetics, Selectfluor, p38α MAPK, Cancer
Abstract

The unique electronic properties of the fluorine atom make its strategic incorporation into a bioactive compound a very useful tool in the design of drugs with optimized pharmacological properties. In the field of the carbo- hydrates, its selective installation at C2 position has proven particularly interesting, some 2-deoxy-2-fluorosugar derivatives being currently in the market. We have now transferred this feature into immunoregulatory glyco- lipid mimetics that contain a sp2-iminosugar moiety, namely sp2-iminoglycolipids (sp2-IGLs). The synthesis of two epimeric series of 2-deoxy-2-fluoro-sp2-IGLs, structurally related to nojirimycin and mannonojirimycin, has been accomplished by sequential Selectfluor-mediated fluorination and thioglycosidation of sp2-iminoglycals. Exclusively the α-anomer is obtained regardless of the configurational profile of the sp2-IGL (D-gluco or D-manno), highlighting the overwhelming anomeric effect in these prototypes. Notably, the combination of a fluorine atom at C2 and an α-oriented sulfonyl dodecyl lipid moiety in compound 11 led to remarkable anti-proliferative properties, featuring similar GI50 values than the chemotherapy drug Cisplatin against several tumor cell lines and better selectivity. The biochemical data further evidence a strong reduction of the number of tumor cell colonies and apoptosis induction. Mechanistic investigations revealed that this fluoro-sp2-IGL induces the non- canonical activation mode of the mitogen-activated protein kinase signaling pathway, causing p38α autoacti- vation under an inflammatory context. VII Plan Propio de Investigación y Transferencia de la Universidad de Sevilla - VIIPPIT-2022-V.1 Junta de Andalucía y Fondos Europeos de Desarrollo Regional -P20_00166 Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación, de España y Fondos Europeos de Desarrollo Regional - PID2019-105858RB-I00, RTI2018-097609-B-C21, PID2021-124247OB-C21 y PID2021-123059OB-I00 Instituto de Salud Carlos III - PI22/01718 Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía - PI20-01331 Agencia Canaria de Investigación Innovación d Sociedad de la Información del Gobierno canario (ACIISI) - TESIS2020010055

Published
2023

16. Synthesis of Oxazole–Tetrahydropyran Hybrids and Study on Their Antiproliferative Activity Against Human Tumour Cells

Author

Alexander von Humboldt Foundation, Pedeciba (Uruguay), Gobierno de Canarias, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Quintana, Vanesa, González-Bakker, Aday, Padrón, Juan I., Martín, Víctor S., Padrón, José M., Davyt, Danilo, Valdomir, Guillermo, Alexander von Humboldt Foundation, Pedeciba (Uruguay), Gobierno de Canarias, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Quintana, Vanesa, González-Bakker, Aday, Padrón, Juan I., Martín, Víctor S., Padrón, José M., Davyt, Danilo, and Valdomir, Guillermo

Abstract

Based on a previously prepared lead compound, a new series of hybrid compounds was prepared and tested against six human tumour cell lines. These new triazole linked tetrahydropyran–oxazole hybrids were prepared evaluating the impact of the LogP for the proposed modifications. The compounds exhibited good antiproliferative results when compared with standards cisplatin and 5-fluorouracil. A series of triazole linked tetrahydropyran–oxazole hybrids was synthesized based on a previously reported lead compound with selective antiproliferative activity against human tumour cell lines. The series was prepared to evaluate the impact of LogP and different modifications in the activity, and the new compounds were assayed against A549, HBL-100, HeLa, SW1573, T-47D, and WiDr cell lines. Also, the potentiality to be P-gp substrate was tested. The compounds exhibited good antiproliferative results when compared with the standards cisplatin and 5-fluorouracil. In silico studies to evaluate pharmacokinetic properties using pkCSM software were also carried out.

Published
2022

17. Early pharmacological profilling of bioactive natural products and their analogues

Author

González Bakker, Aday, Padrón Carrillo, José Manuel, "null", and Máster Universitario en Biomedicina Por la Universidad de la Laguna

Abstract

Bioprospection has a very important role in the discovery of compounds with antitumor activity. A large number of the actual anticancer drugs has a natural origin. Due to the high biodiversity around the world, which leads to new chemical structures (with new targets) and the general multi-faceted mechanisms, makes necessary the use of phenotypic profiling to discover and define the target of these compounds. Phenotypic drug discovery requires the use of different assays to narrow down the possible mechanism of action such as the evaluation of cell migration and phenotypic changes in the cell. In this study, we carried out an optimization of in vitro wound healing assay and tested a panel of natural extracts of Hypericum genus to evaluate cell migration. We determined that in lung cancer cells A549, a serum concentration of 1% is suitable to evaluate cell migration. We observed differential effect of the extracts on migration with a considerable inhibition in cell migration by the hydroalcoholic extract of H. grandifolium. In addition, we designed a preliminary model based on Fourier’s Transform to use Nanolive’s CX-A imaging and analysis system for target prediction. The designed model was able to preliminary cluster microtubule affecting drugs with similar mechanism of action to those of vinblastine and colchicine. La bioprospección juega un papel muy importante en el descubrimiento de compuestos con actividad antitumoral. Muchos de los compuestos quimioterápicos actuales están relacionados con productos naturales. Debido a la alta biodiversidad alrededor del mundo que supone la aparición de nuevas estructuras químicas (con nuevas dianas) y a la general actividad multifacética de los compuestos naturales, es necesario el estudio del perfil fenotípico de fármacos para descubrir estos compuestos y definir su diana. El descubrimiento fenotípico de fármacos requiere del uso de diferentes ensayos para acotar el posible mecanismo de acción, por ejemplo, la evaluación de la migración celular o cambios fenotípicos en la célula. En este trabajo realizamos la optimización del ensayo de herida in vitro y evaluamos el efecto de diferentes extractos vegetales del género Hypericum. Determinamos que la línea celular A549 con 1% de suero es el modelo óptimo para evaluar la migración. Observamos efectos diferenciales de los extractos sobre la migración con una inhibición considerable por el extracto hidroalcohólico de H. grandifolium. Además, diseñamos un modelo preliminar basado en la transformada de Fourier para usar el sistema de imagen y análisis CX-A de Nanolive para predecir dianas. El modelo bioinformático diseñado fue capaz de agrupar compuestos con mecanismo de acción similar contra los microtúbulos (vinblastina y colchicina)

Published
2022

19. Early pharmacological profiling of small molecules

Author

González Bakker, Aday, Padrón Carrillo, José Manuel, Puerta Arocha, Adrián, and Grado En Biología

Abstract

La resistencia a fármacos antitumorales es un problema creciente para tratamientos de cáncer. Uno de los fármacos afectados es el paclitaxel (PTX), un alcaloide citotóxico empleado en el tratamiento de diferentes tipos de tumores. Este se une a la β-tubulina e induce la estabilización de microtúbulos alterando su dinámica durante la mitosis lo que finalmente lleva a la muerte celular. Uno de los mecanismos asociados a la resistencia a fármacos son cambios en su diana. En el caso del PTX cambios en la dinámica de microtúbulos o en la βtubulina podrían ser el mecanismo que otorga resistencia. En este estudio llevamos a cabo una comparación fenotípica entre la línea celular HeLa y su variante resistente a PTX en aspectos que involucran microtúbulos. Los resultados no mostraron diferencias significativas entre ambos tipos celulares en cuanto a la dinámica de migración, tampoco en la expresión ni localización de la β-tubulina. Especulamos que otro tipo de mecanismo que no involucra los microtúbulos es el responsable de esta resistencia al PTX. Sin embargo, más estudios en esta línea son necesarios para determinar el mecanismo de resistencia. Resistance to antitumor drugs is a major issue in cancer treatment. One of the drugs affected by this phenomenon is paclitaxel (PTX), a cytotoxic alkaloid used against multiple types of tumours. PTX binds to β-tubulin inducing microtubule stabilization altering normal microtubule dynamics during mitosis which ends in cell death. One of the different mechanisms associated to drug resistance is the alteration of β-tubulin. In the case of PTX, changes in microtubule dynamics or β-tubulin could lead to resistant cell types. In this study, we carried out a phenotypic comparison between HeLa cells (sensitive to PTX) and a PTXresistant variant. The results did not show significant differences in migration dynamics between these cell types, neither in β-tubulin expression and localization. We speculate that another type of mechanism that does not involve microtubules could be responsible for the resistance to PTX, but further experiments will be needed to conclude this.

Published
2021

20. Palladium nanoparticles for the synthesis of phenanthridinones and benzo[ c ]chromenes via C-H activation reaction.

Author

Díaz-Vázquez ED, Cuellar MA, Heredia MD, Barolo SM, González-Bakker A, Padrón JM, Budén ME, Martín SE, and Uberman PM

Abstract

In the present work, derivatives of phenanthridine-6(5 H )-ones and benzo[ c ]chromenes were efficiently prepared through an intramolecular C-H bond functionalization reaction catalyzed by photochemically synthesized Pd-PVP nanoparticles. The heterocycles were obtained via intramolecular arylation of the corresponding N -methyl- N -aryl-2-halobenzamide or aryl-(2-halo)benzyl ethers using K 2 CO 3 as base in a mixture of H 2 O : DMA as solvent without additives or ligands. High yields of the heterocyclic compounds were achieved (up to 95%) using a moderately low catalyst loading (1-5 mol%) under an air atmosphere at 100 °C. The reaction exhibited very good tolerance to diverse functional groups (OMe, Me, t Bu, Ph, OCF 3 , CF 3 , F, Cl, -CN, Naph), and both bromine and iodine substrates showed great reactivity. Finally, the in vitro antiproliferative activity of phenanthridine-6(5 H )-ones and benzo[ c ]chromenes was evaluated against six human solid tumor cell lines. The more active compounds exhibit activity in the low micromolar range. 1-Isopropyl-4-methyl-6 H -benzo[ c ]chromene was identified as the best compound with promising values of activity (GI 50 range 3.9-8.6 μM). Thus, the benzochromene core was highlighted as a novel organic building block to prepare potential antitumor agents., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Published
2024
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21. Microwave-assisted multicomponent synthesis of antiproliferative 2,4-dimethoxy-tetrahydropyrimido[4,5- b ]quinolin-6(7 H )-ones.

Author

Patel SG, González-Bakker A, Vala RM, Patel PJ, Puerta A, Malik A, Sharma RK, Padrón JM, and Patel HM

Abstract

In this study, we demonstrate a simple, highly efficient, rapid and convenient series of 2,4-dimethoxy-tetrahydropyrimido[4,5- b ]quinolin-6(7 H )-ones 4a-v. Microwave irradiation facilitates the one-pot multicomponent reaction of different aromatic aldehydes, 6-amino-2,4-dimethoxypyrimidine and dimedone using glacial acetic acid. Metal-free multicomponent synthesis, shorter reaction time, higher product yield, easy product purification without column chromatography and outstanding green credential parameters are the key features of this protocol. We analysed 4a-v against six human tumour cell lines for antiproliferative activity. 4h, 4o, 4q and 4v show good antiproliferative activity with a good in silico ADMET profile. Furthermore, 4h, 4o, 4q and 4v also show drug-likeness properties by obeying drug-like filters., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Published
2022
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