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Soriano A.,University of Barcelona | Vendrell M.,University of Barcelona | Vendrell M.,Laboratory of Bioimaging Probe Development | Gonzalez S.,University of Barcelona | And 12 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2010

The indoloquinolizidine-peptide 28 [(3S,12bR)-N-((S)-1-((S)-1-((S)-2- carbamoylpyrrolidin-1-yl)-3-(4-fluorophenyl)-1-oxopropan-2-ylamino) -4-cyclohexyl-1-oxobutan-2-yl)-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a] quinolizine-3-carboxamide], a transindoloquinolizidine-peptide hybrid obtained by a combinatorial approach, behaved as an orthosteric ligand of all dopamine D2-like receptors (D2, D3, and D4) and dopamine D5 receptors, but as a negative allosteric modulator of agonist and antagonist binding to striatal dopamine D1 receptors. Indoloquinolizidine-peptide 28 induced a concentration-dependent hyperbolic increase in the antagonist apparent equilibrium dissociation constant values and altered the dissociation kinetics of dopamine D1 receptor antagonists. The negative allosteric modulation was also found when agonist binding to D1 receptors was assayed. Indoloquinolizidine-peptide 28 was a weak ago-allosteric modulator but markedly led to a decreased potency without decreasing the maximum partial/full agonist-mediated effect on cAMP levels. Compounds able to decrease the potency while preserving the efficacy of D1 receptor agonists are promising for exploration in psychotic pathologies. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics. Source

Jung J.,University of Ulsan | Jung J.,Duksung Womens University | Park S.-J.,University of Ulsan | Park S.-J.,Laboratory of Bioimaging Probe Development | And 9 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: To reduce the side effects and improve the efficacy of chemoradiation therapy, taxanes were incorporated into polymeric nanoparticles (PNP), and their synergic effect on radiation therapy in non-small cell lung cancer was evaluated. Methods and Materials: The properties of PNP-taxanes were characterized by transmission electron microscopy and dynamic light scattering. The chemoradiotherapeutic efficacy of PNP-taxanes was determined by clonogenic assay, cellular morphology, and flow cytometry in A549 cells. In mice bearing A549-derived tumors, the tumor growth delay was examined after the treatment of PNP-taxanes and/or ionizing radiation (IR). Results: The PNP-taxanes were found to be approximately 45 nm in average diameter and to have high solubility in water. They showed the properties of active internalization into cells and preserved the anticancer effect of free taxanes. The survival fraction of A549 cells by clonogenic assay was significantly reduced in the group receiving combined treatment of PNP-taxanes and IR. In addition, in vivo radiotherapeutic efficacy was markedly enhanced by the intravenous injection of PNP-taxanes into the xenograft mice. Conclusions: We have demonstrated the feasibility of PNP-taxanes to enhance the efficacy of chemoradiation therapy. These results suggest PNP-taxanes can hold an invaluable and promising position in treating human cancers as a novel and effective chemoradiation therapy agent. © 2012 Elsevier Inc. All rights reserved. Source

Vendrell M.,University of Barcelona | Vendrell M.,Laboratory of Bioimaging Probe Development | Molero A.,University of Barcelona | Molero A.,CIBER ISCIII | And 10 more authors.
Journal of Medicinal Chemistry | Year: 2011

The incorporation of chemical modifications into the structure of bioactive compounds is often difficult because the biological properties of the new molecules must be retained with respect to the native ligand. Ergopeptides, with their high affinities at D1 and D2 dopamine receptors, are particularly complex examples. Here, we report the systematic derivatization of two ergopeptides with different peptide-based spacers and their evaluation by radioligand binding assays. Selected spacer-containing ergopeptides with minimal biological alteration and a proper anchoring point were further derivatized with a biotin reporter. Detailed characterization studies identified 13 as a biotin ergopeptide maintaining high affinity and agonist behavior at dopamine receptors, being a useful tool for the study of heteromers involving D1R, D2R, or D3R. © 2011 American Chemical Society. Source

Cervantes S.,University of California at Riverside | Stout P.E.,Georgia Institute of Technology | Prudhomme J.,University of California at Riverside | Engel S.,Georgia Institute of Technology | And 9 more authors.
BMC Infectious Diseases | Year: 2012

Background: The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum.Methods: A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope.Results: Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts.Conclusion: Collectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials. © 2011 Cervantes et al; licensee BioMed Central Ltd. Source

Zhai D.,National University of Singapore | Xu W.,National University of Singapore | Zhang L.,National University of Singapore | Zhang L.,CAS Hefei Institutes of Physical Science | And 2 more authors.
Chemical Society Reviews | Year: 2014

"Aggregation-caused signal change" is a well-established mechanism by now and has been widely used as the basis for optical probe and sensor development. Compared to aggregation, its reverse process, disaggregation, has received much less attention and is not properly discussed in the literature so far. With the less established paradigm or mechanism, although some of the reported sensors and probes seem to work through disaggregation phenomena, the proper interpretation of the results and applying the concept to novel probe development is seriously hampered. The process from aggregation to disaggregation generally causes a recovery or enhancement of fluorescence signals, and thus provides an interesting new path to design "turn-on" probes. This tutorial review will provide the balanced comparison between aggregation and disaggregation mechanism, and focuses on the less explored advantages of "disaggregation" as a novel sensing mechanism and its recent applications in probe development. This journal is © the Partner Organisations 2014. Source

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