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378 results on '"Unciti ‐ Broceta, Asier"'

51. Loss of Integrin-Linked Kinase Sensitizes Breast Cancer to SRC Inhibitors

Author

Beetham, Henry, primary, Griffith, Billie G.C., additional, Murina, Olga, additional, Loftus, Alexander E.P., additional, Parry, David A., additional, Temps, Carolin, additional, Culley, Jayne, additional, Muir, Morwenna, additional, Unciti-Broceta, Asier, additional, Sims, Andrew H., additional, Byron, Adam, additional, and Brunton, Valerie G., additional

Published
2021
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54. Novel purine chemotypes with activity against Plasmodium 2 falciparum and Trypanosoma cruzi

Author

Martinez-Peinado, Nieves, Lorente Macias, Alvaro, Garcia-Salbuero, Alejandro, Cortes-Serra, Nuria, Fenollar-Collado, Angel, Ros-Lucas, Albert, Gascon, Joaquim, Pinazo, Maria-Jesus, Molina, Ignacio J., Unciti-Broceta, Asier, Díaz-Mochón, Juan J., Villatoro, Maria J. Pineda de las Infantas y, Izquierdo, Luis, and Alonso-Padilla, Julio

Subjects
Plasmodium Falciparum, parasitic diseases, cytotoxity assays, Trypanosome cruzi, purine metabolism, purine derivatives, pyrimidine analogs, phenotypic assays
Abstract

Malaria and Chagas disease, caused by Plasmodium spp. and Trypanosoma cruzi parasites, 25 remain an important global health problem. Available treatments for those diseases present several 26 limitations such as lack of efficacy, toxic side effects and drug resistance. Thus, finding new drugs 27 is urgently needed. The discovery of new drugs may be benefited by considering significant bio-28 logical differences between host and parasites. One of the most striking differences is found in the 29 purine metabolism because most of the parasites are incapable of de novo purine biosynthesis. 30 Herein, we have analyzed the in vitro anti-P. falciparum and anti-T. cruzi activity of a collection of 81 31 purine derivatives and pyrimidine analogs. We firstly used a primary screening at three fixed 32 concentrations (100, 10 and 1 μM) and progressed to dose-response assays those compounds that 33 kept the growth of the parasites < 30% at 100 μM. Then, we performed two different cytotoxicity 34 assays on Vero cells and human HepG2 cells. Finally, compounds specifically active against T. cruzi 35 were tested against intracellular amastigote forms. Purines 33 (IC50 = 19.19 μM) and 76 (IC50 = 18.27 36 μM) were the most potent against P. falciparum. On the other hand, 6D (IC50 = 3.78 μM) and 34 (IC50 37 = 4.24 μM) were identified as hit purines against T. cruzi amastigotes. Moreover, an in silico docking 38 study revealed that P. falciparum and T. cruzi hypoxanthine guanine phosphoribosyltransferase 39 enzymes could be the potential targets of those compounds. Our study identified two novel pu-40 rine-based chemotypes that can be further optimized to generate potent and diversified an-41 ti-parasitic drugs against both parasites.

Published
2021
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55. A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability

Author

Temps, Carolin, primary, Lietha, Daniel, additional, Webb, Emily R., additional, Li, Xue-Feng, additional, Dawson, John C., additional, Muir, Morwenna, additional, Macleod, Kenneth G., additional, Valero, Teresa, additional, Munro, Alison F., additional, Contreras-Montoya, Rafael, additional, Luque-Ortega, Juan R., additional, Fraser, Craig, additional, Beetham, Henry, additional, Schoenherr, Christina, additional, Lopalco, Maria, additional, Arends, Mark J., additional, Frame, Margaret C., additional, Qian, Bin-Zhi, additional, Brunton, Valerie G., additional, Carragher, Neil O., additional, and Unciti-Broceta, Asier, additional

Published
2021
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56. In CelluloBioorthogonal Catalysis by Encapsulated AuPdNanoalloys: Overcoming Intracellular Deactivation

Author

Rubio-Ruiz, Belén, Pérez-López, Ana M., Uson, Laura, Ortega-Liebana, M. Carmen, Valero, Teresa, Arruebo, Manuel, Hueso, Jose L., Sebastian, Victor, Santamaria, Jesus, and Unciti-Broceta, Asier

Abstract

Bioorthogonal metallocatalysis has opened up a xenobiotic route to perform nonenzymatic catalytic transformations in living settings. Despite their promising features, most metals are deactivated inside cells by a myriad of reactive biomolecules, including biogenic thiols, thereby limiting the catalytic functioning of these abiotic reagents. Here we report the development of cytocompatible alloyed AuPdnanoparticles with the capacity to elicit bioorthogonal depropargylations with high efficiency in biological media. We also show that the intracellular catalytic performance of these nanoalloys is significantly enhanced by protecting them following two different encapsulation methods. Encapsulation in mesoporous silica nanorods resulted in augmented catalyst reactivity, whereas the use of a biodegradable PLGA matrix increased nanoalloy delivery across the cell membrane. The functional potential of encapsulated AuPdwas demonstrated by releasing the potent chemotherapy drug paclitaxel inside cancer cells. Nanoalloy encapsulation provides a novel methodology to develop nanoreactors capable of mediating new-to-life reactions in cells.

Published
2023
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57. Novel Purine Chemotypes with Activity against Plasmodium falciparum and Trypanosoma cruzi

Author

Martinez-Peinado, Nieves, primary, Lorente-Macías, Álvaro, additional, García-Salguero, Alejandro, additional, Cortes-Serra, Nuria, additional, Fenollar-Collado, Ángel, additional, Ros-Lucas, Albert, additional, Gascon, Joaquim, additional, Pinazo, Maria-Jesus, additional, Molina, Ignacio J., additional, Unciti-Broceta, Asier, additional, Díaz-Mochón, Juan J., additional, Pineda de las Infantas y Villatoro, María J., additional, Izquierdo, Luis, additional, and Alonso-Padilla, Julio, additional

Published
2021
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58. A minimally-masked inactive prodrug of panobinostat that is bioorthogonally activated by gold chemistry

Author

Engineering and Physical Sciences Research Council (UK), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Rubio‐Ruiz, Belén, Pérez‐López, Ana M., Sebastián, Víctor, Unciti-Broceta, Asier, Engineering and Physical Sciences Research Council (UK), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Rubio‐Ruiz, Belén, Pérez‐López, Ana M., Sebastián, Víctor, and Unciti-Broceta, Asier

Abstract

The recent incorporation of Au chemistry in the bioorthogonal toolbox has opened up new opportunities to deliver biologically independent reactions in living environments. Herein we report that the O-propargylation of the hydroxamate group of the potent HDAC inhibitor panobinostat leads to a vast reduction of its anticancer properties (>500-fold). We also show that this novel prodrug is converted back into panobinostat in the presence of Au catalysts in vitro and in cell culture.

Published
2021

59. Nondestructive production of exosomes loaded with ultrathin palladium nanosheets for targeted bio-orthogonal catalysis

Author

European Research Council, Engineering and Physical Sciences Research Council (UK), European Commission, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Gobierno de Aragón, Sebastián, Víctor, Sancho‐Albero, María, Arruebo, Manuel, Pérez‐López, Ana M., Rubio‐Ruiz, Belén, Martín-Duque, Pilar, Unciti-Broceta, Asier, Ricote, J., European Research Council, Engineering and Physical Sciences Research Council (UK), European Commission, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Gobierno de Aragón, Sebastián, Víctor, Sancho‐Albero, María, Arruebo, Manuel, Pérez‐López, Ana M., Rubio‐Ruiz, Belén, Martín-Duque, Pilar, Unciti-Broceta, Asier, and Ricote, J.

Abstract

The use of exosomes as selective delivery vehicles of therapeutic agents, such as drugs or hyperthermia-capable nanoparticles, is being intensely investigated on account of their preferential tropism toward their parental cells. However, the methods used to introduce a therapeutic load inside exosomes often involve disruption of their membrane, which may jeopardize their targeting capabilities, attributed to their surface integrins. On the other hand, in recent years bio-orthogonal catalysis has emerged as a new tool with a myriad of potential applications in medicine. These bio-orthogonal processes, often based on Pd-catalyzed chemistry, would benefit from systems capable of delivering the catalyst to target cells. It is therefore highly attractive to combine the targeting capabilities of exosomes and the bio-orthogonal potential of Pd nanoparticles to create new therapeutic vectors. In this protocol, we provide detailed information on an efficient procedure to achieve a high load of catalytically active Pd nanosheets inside exosomes, without disrupting their membranes. The protocol involves a multistage process in which exosomes are first harvested, subjected to impregnation with a Pd salt precursor followed by a mild reduction process using gas-phase CO, which acts as both a reducing and growth-directing agent to produce the desired nanosheets. The technology is scalable, and the protocol can be conducted by any researcher having basic biology and chemistry skills in ~3 d.

Published
2021

61. Discovery of pyrazolopyrimidines that selectively inhibit CSF-1R kinase by iterative design, synthesis and screening against glioblastoma cellsElectronic supplementary information (ESI) available: Methods, characterisation of intermediates and final compounds, NMR spectra of compounds B40–63, Table S1 and Fig. S1–S11. See DOI: https://doi.org/10.1039/d3md00454f

Author

Baillache, Daniel J., Valero, Teresa, Lorente-Macías, Álvaro, Bennett, David Jonathan, Elliott, Richard J. R., Carragher, Neil O., and Unciti-Broceta, Asier

Abstract

Glioblastoma multiforme (GBM) is the most aggressive type of brain cancer in adults, with an average life expectancy under treatment of approx. 15 months. GBM is characterised by a complex set of genetic alterations that results in significant disruption of receptor tyrosine kinase (RTK) signaling. We report here an exploration of the pyrazolo[3,4-d]pyrimidine scaffold in search for antiproliferative compounds directed to GBM treatment. Small compound libraries were synthesised and screened against GBM cells to build up structure–antiproliferative activity–relationships (SAARs) and inform further rounds of design, synthesis and screening. 76 novel compounds were generated through this iterative process that found low micromolar potencies against selected GBM lines, including patient-derived stem cells. Phenomics analysis demonstrated preferential activity against glioma cells of the mesenchymal subtype, whereas kinome screening identified colony stimulating factor-1 receptor (CSF-1R) as the lead's target, a RTK implicated in the tumourigenesis and progression of different cancers and the immunoregulation of the GBM microenvironment.

Published
2023
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67. Bioorthogonal catalysis goes chiral

Author

Ricote, J., Unciti-Broceta, Asier, Ricote, J., and Unciti-Broceta, Asier

Abstract

Bioorthogonal nanofactories have emerged in the last decade to provide xenobiotic pathways that generate nonbiological substances in living environments. In this issue of Chem, Qu and co-workers incorporate asymmetric catalytic properties and chemotactic capabilities into novel nanodevices to achieve the stereo- and site-selective synthesis of the active enantiomer of ibuprofen at inflammation sites.

Published
2020

69. Truly‐Biocompatible Gold Catalysis Enables Vivo‐Orthogonal Intra‐CNS Release of Anxiolytics.

Author

Ortega‐Liebana, M. Carmen, Porter, Nicola J., Adam, Catherine, Valero, Teresa, Hamilton, Lloyd, Sieger, Dirk, Becker, Catherina G., and Unciti‐Broceta, Asier

Subjects
TRANQUILIZING drugs, CATALYSIS, GOLD, CENTRAL nervous system, CENTRAL nervous system stimulants
Abstract

Being recognized as the best‐tolerated of all metals, the catalytic potential of gold (Au) has thus far been hindered by the ubiquitous presence of thiols in organisms. Herein we report the development of a truly‐catalytic Au‐polymer composite by assembling ultrasmall Au‐nanoparticles at the protein‐repelling outer layer of a co‐polymer scaffold via electrostatic loading. Illustrating the in vivo‐compatibility of the novel catalysts, we show their capacity to uncage the anxiolytic agent fluoxetine at the central nervous system (CNS) of developing zebrafish, influencing their swim pattern. This bioorthogonal strategy has enabled ‐for the first time‐ modification of cognitive activity by releasing a neuroactive agent directly in the brain of an animal. [ABSTRACT FROM AUTHOR]

Published
2022
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71. ALDH1 bio-activates nifuroxazide to eradicate ALDHHigh melanoma-initiating cells

Author

Sarvi, Sana, Crispin, Richard, Lu, Yuting, Zeng, Lifan, Hurley, Thomas D., Houston, Douglas R., von Kriegsheim, Alex, Chen, Che-Hong, Mochly-Rosen, Daria, Ranzani, Marco, Mathers, Marie E., Xu, Xiaowei, Xu, Wei, Adams, David J., Carragher, Neil O., Fujita, Mayumi, Schuchter, Lynn, Unciti-Broceta, Asier, Brunton, Valerie G., and Patton, E. Elizabeth

Subjects
BRAF inhibitor, cancer stem cells, nifuroxazide, pro-drugs, 5-nitrofurans, drug targets, melanoma, ALDH, drug mechanism of action, tumor-initiating cells
Abstract

5-Nitrofurans are antibiotic pro-drugs that have potential as cancer therapeutics. Here, we show that 5-nitrofurans can be bio-activated by aldehyde dehydrogenase (ALDH) 1A1/1A3 enzymes that are highly expressed in a subpopulation of cancer-initiating (stem) cells. We discover that the 5-nitrofuran, nifuroxazide, is selective for bio-activation by ALDH1 isoforms over ALDH2, whereby it both oxidizes ALDH1 and is converted to cytotoxic metabolites in a two-hit pro-drug mechanism. We show that ALDH1High melanoma cells are sensitive to nifuroxazide, while ALDH1A3 loss-of-function mutations confer drug resistance. In tumors, nifuroxazide targets ALDH1High melanoma subpopulations with the subsequent loss of melanoma-initiating cell potential. BRAF and MEK inhibitor therapy increases ALDH1 expression in patient melanomas, and effectively combines with nifuroxazide in melanoma cell models. The selective eradication of ALDH1High cells by nifuroxazide-ALDH1 activation goes beyond current strategies based on inhibiting ALDH1 and provides a rational basis for the nifuroxazide mechanism of action in cancer.

Published
2018
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72. Bioorthogonal Uncaging of the Active Metabolite of Irinotecan by Palladium-Functionalized Microdevices

Author

Adam, Catherine, Pérez-lópez, Ana M., Hamilton, Lloyd, Rubio-ruiz, Belén, Bray, Thomas L., Sieger, Dirk, Brennan, Paul M., and Unciti-broceta, Asier

Abstract

SN-38, the active metabolite of irinotecan, is released upon liver hydrolysis to mediate potent antitumor activity. Systemic exposure to SN-38, however, also leads to serious side effects. To reduce systemic toxicity by controlling where and when SN-38 is generated, a new prodrug was specifically designed to bemetabolically stable and undergo rapid Palladium-mediated activation. Blocking the phenolic OH of SN-38 with a 2,6-bis(propargyloxy)benzyl group led to significant reduction of cytotoxic activity (up to 44-fold). Anticancer properties were swiftly restored in the presence of heterogeneous Palladium (Pd) catalysts to kill colorectal cancer and glioma cells, proving the efficacy of this novel masking strategy for aromatic hydroxyls. Combination with a Pd-activated 5FU prodrug augmented the antiproliferative potency of the treatment, while displaying no activity in the absence of the Pd source, which illustrates the benefit of achieving controlled release of multiple approved therapeutics —sequentially or simultaneously— by the same bioorthogonal catalyst to increase anticancer activity.

Published
2018
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73. Drug 'Clicking' on Cell-Penetrating Fluorescent Nanoparticles for In Cellulo Chemical Proteomics

Author

Valero, Teresa, Delgado-gonzález, Antonio, Unciti-broceta, Juan Diego, Cano-cortés, Victoria, Pérez-lópez, Ana, Unciti-broceta, Asier, and Sánchez-martín, Rosario

Subjects
Proteomics, Azides, Cell Membrane Permeability, Cycloaddition Reaction, Drug-polymer conjugate, Dasatinib, Baeyer test, Catalysis, target ID, cell-penetrating nanoparticles, Humans, Nanoparticles, Click Chemistry, CuAAC, Fluorescent Dyes
Abstract

Chemical proteomics approaches are widely used to identify molecular targets of existing or novel drugs. This manuscript describes the development of a straightforward approach to conjugate azide-labelled drugs via click chemistryto alkyne-tagged cell-penetrating fluorescent nanoparticles as a novel tool to study target engagement and/or identification inside living cells. A modification of the Baeyer test for alkynes allows monitoring the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, guaranteeing the presence of the drug on the solid support. As a proof of concept, the conjugation of the promiscuous kinase inhibitor dasatinib to Cy5-labelled nanoparticles is presented. Dasatinib-decorated fluorescent nanoparticles efficiently inhibited its protein target SRC in vitro, entered cancer cells and colocalized with SRC in cellulo.

Published
2018
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74. Development of potent inhibitors of receptor tyrosine kinases by ligand-based drug design and target-biased phenotypic screening

Author

Myers, Samuel, Temps, Carolin, Houston, Douglas, Brunton, Valerie G, and Unciti-Broceta, Asier

Abstract

Pyrazolopyrimidines with potent antiproliferative properties were developed by an adaptive strategy that applies ligand-based design and phenotypic screening iteratively, and is informed by biochemi-cal assays. To drive development towards specific onco-pathways, compounds were tested against cancer cells that overexpress, or not, AXL kinase. Identified phenotypic hits were found to inhibit oncotargets AXL, RET and FLT3. Subsequent optimization generated antiproliferative lead compounds with unique selectivity profiles, including selective AXL inhibitors and a highly-potent inhibitor of FLT3.

Published
2018
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76. Regioselective one-pot synthesis of 9-alkyl-6-chloropyrido[3,2-e][1,2,4]triazolo-[4,3-a]pyrazines. Reactivity of aliphatic and aromatic hydrazides

Author

Unciti-Broceta, Asier, Pineda-de-las-Infantas, Maria J., Diaz-Mochon, Juan J., Romagnoli, Romeo, Espinosa, Antonio, Baraldi, Pier G., and Gallo, Miguel A.

Subjects
Nucleophiles -- Research, Organic compounds -- Chemical properties, Pyridazine -- Chemical properties, Biological sciences, Chemistry
Abstract

A report on the one-pot synthesis of new 9-alkyl-6-chloropyrido[3,2-e]-[1,2,4] triazolo[4,3-a]pyrazines, which was obtained from 2,3-dichloropyrido[2,3-b]pyrazine in a single step, is presented. The key step was the regioselective nucleophilic aromatic substitution that gave rise to unique isomers before ring closure.

Published
2005

77. A 5-FU Precursor Designed to Evade Anabolic and Catabolic Drug Pathways and Activated by Pd Chemistry In Vitroand In Vivo

Author

Adam, Catherine, Bray, Thomas L., Pérez-López, Ana M., Tan, Ee Hong, Rubio-Ruiz, Belén, Baillache, Daniel J., Houston, Douglas R., Salji, Mark J., Leung, Hing Y., and Unciti-Broceta, Asier

Abstract

5-Fluorouracil (5-FU) is an antineoplastic antimetabolite that is widely administered to cancer patients by bolus injection, especially to those suffering from colorectal and pancreatic cancer. Because of its suboptimal route of administration and dose-limiting toxicities, diverse 5-FU prodrugs have been developed to confer oral bioavailability and increase the safety profile of 5-FU chemotherapy regimens. Our contribution to this goal is presented herein with the development of a novel palladium-activated prodrug designed to evade the metabolic machinery responsible for 5-FU anabolic activation and catabolic processing. The new prodrug is completely innocuous to cells and highly resistant to metabolization by primary hepatocytes and liver S9 fractions (the main metabolic route for 5-FU degradation), whereas it is rapidly converted into 5-FU in the presence of a palladium (Pd) source. In vivopharmokinetic analysis shows the prodrug is rapidly and completely absorbed after oral administration and exhibits a longer half-life than 5-FU. In vivoefficacy studies in a xenograft colon cancer model served to prove, for the first time, that orally administered prodrugs can be locally converted to active drugs by intratumorally inserted Pd implants.

Published
2022
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80. ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells

Author

Sarvi, Sana, primary, Crispin, Richard, additional, Lu, Yuting, additional, Zeng, Lifan, additional, Hurley, Thomas D., additional, Houston, Douglas R., additional, von Kriegsheim, Alex, additional, Chen, Che-Hong, additional, Mochly-Rosen, Daria, additional, Ranzani, Marco, additional, Mathers, Marie E., additional, Xu, Xiaowei, additional, Xu, Wei, additional, Adams, David J., additional, Carragher, Neil O., additional, Fujita, Mayumi, additional, Schuchter, Lynn, additional, Unciti-Broceta, Asier, additional, Brunton, Valerie G., additional, and Patton, E. Elizabeth, additional

Published
2018
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86. Purine derivatives as dapk1 inhibitors

Author

Molina Pineda Infantas, Ignacio Jesús, Torres Rusillo, Sara, Fernández Rubio, Pablo, Pineda de las Infantas y Villatoro, María J., Díaz Mochón, Juan José, and Unciti-Broceta, Asier

Subjects
C07D 473/34, C07D 473/30, Inhibidores, Purinas, A61K 31/52, Dapk1, Posesión 6
Abstract

Número de publicación: ES2548927 B1. Número de solicitud: 201400229., Derivados de purina como inhibidores de Dapk-1. La presente invención describe una nueva familia de derivados de purina que actúan como inhibidores selectivos de Dapk1. Se describe también el proceso para la obtención de los compuestos farmacéuticos y su uso como medicamento para el tratamiento o la profilaxis de enfermedades que precisan la inhibición de Dapk1, especialmente para el tratamiento del cáncer., Universidad de Granada

Published
2016

87. Next Generation Phenotypic Screening

Author

Warchal, Scott, Unciti-Broceta, Asier, and Carragher, Neil

Subjects
mechanism-of-action, Target-deconvolution, Phenotypic, Pathway profiling, Screening, image-informatics, High-content, Transcriptomics
Abstract

Phenotypic drug discovery (PDD) strategies are defined by screening and selection of hit or lead compounds based on quantifiable phenotypic endpoints without prior knowledge of the drug target. We outline the challenges associated with traditional phenotypic screening strategies and propose solutions and new opportunities to be gained by adopting modern PDD technologies. We highlight both historical and recent examples of approved drugs and new drug candidates discovered by modern phenotypic screening. Finally we offer a prospective view of a new era of PDD underpinned by a wealth of technology advances in the areas of in vitro model development, high content imaging and image-informatics, mechanism-of-action profiling and target deconvolution

Published
2016
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89. Metallofluorescent Nanoparticles for Multimodal Applications

Author

Delgado-Gonzalez, Antonio, primary, Garcia-Fernandez, Emilio, additional, Valero, Teresa, additional, Cano-Cortes, M. Victoria, additional, Ruedas-Rama, Maria J., additional, Unciti-Broceta, Asier, additional, Sanchez-Martin, Rosario M., additional, Diaz-Mochon, Juan J., additional, and Orte, Angel, additional

Published
2018
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91. Bright insights into palladium-triggered local chemotherapy

Author

Bray, Thomas L., primary, Salji, Mark, additional, Brombin, Alessandro, additional, Pérez-López, Ana M., additional, Rubio-Ruiz, Belén, additional, Galbraith, Laura C. A., additional, Patton, E. Elizabeth, additional, Leung, Hing Y., additional, and Unciti-Broceta, Asier, additional

Published
2018
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93. Inside Back Cover: Gold‐Triggered Uncaging Chemistry in Living Systems (Angew. Chem. Int. Ed. 41/2017)

Author

Pérez‐López, Ana M., primary, Rubio‐Ruiz, Belén, additional, Sebastián, Víctor, additional, Hamilton, Lloyd, additional, Adam, Catherine, additional, Bray, Thomas L., additional, Irusta, Silvia, additional, Brennan, Paul M., additional, Lloyd‐Jones, Guy C., additional, Sieger, Dirk, additional, Santamaría, Jesús, additional, and Unciti‐Broceta, Asier, additional

Published
2017
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94. Innenrücktitelbild: Gold‐Triggered Uncaging Chemistry in Living Systems (Angew. Chem. 41/2017)

Author

Pérez‐López, Ana M., primary, Rubio‐Ruiz, Belén, additional, Sebastián, Víctor, additional, Hamilton, Lloyd, additional, Adam, Catherine, additional, Bray, Thomas L., additional, Irusta, Silvia, additional, Brennan, Paul M., additional, Lloyd‐Jones, Guy C., additional, Sieger, Dirk, additional, Santamaría, Jesús, additional, and Unciti‐Broceta, Asier, additional

Published
2017
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95. Gold‐Triggered Uncaging Chemistry in Living Systems

Author

Pérez‐López, Ana M., primary, Rubio‐Ruiz, Belén, additional, Sebastián, Víctor, additional, Hamilton, Lloyd, additional, Adam, Catherine, additional, Bray, Thomas L., additional, Irusta, Silvia, additional, Brennan, Paul M., additional, Lloyd‐Jones, Guy C., additional, Sieger, Dirk, additional, Santamaría, Jesús, additional, and Unciti‐Broceta, Asier, additional

Published
2017
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96. Palladium-mediated dealkylation of N-propargyl-floxuridine as a bioorthogonal oxygen-independent prodrug strategy

Author

Weiss, Jason T, Carragher, Neil O, and Unciti-Broceta, Asier

Subjects
inorganic chemicals
Abstract

Herein we report the development and biological screening of a bioorthogonal palladium-labile prodrug of the nucleoside analogue floxuridine, a potent antineoplastic drug used in the clinic to treat advanced cancers. N-propargylation of the N3 position of its uracil ring resulted in a vast reduction of its biological activity (~6,250-fold). Cytotoxic properties were bioorthogonally rescued in cancer cell culture by heterogeneous palladium chemistry both in normoxia and hypoxia. Within the same environment, the reported chemo-reversible prodrug exhibited up to 1,450-fold difference of cytotoxicity whether it was in the absence or presence of the extracellular palladium source, underlining the precise modulation of bioactivity enabled by this bioorthogonally-activated prodrug strategy.

Published
2015
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97. SYNFORM ISSUE 2014/07

Author

Unciti-Broceta, Asier, Carragher, Neil, Weiss, Jason T, Dawson, John, Macleod, Kenneth, Fraser, Craig, Patton, Elizabeth, Bradley, Mark, and Zanda, Matteo

Published
2014
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