Gale P.A.,University of Southampton |
Perez-Tomas R.,University of Barcelona |
Quesada R.,University of Burgos
Accounts of Chemical Research | Year: 2013
In this Account, we discuss the development of new lipid bilayer aniontransporters based on the structure of anionophoric natural products (the prodigiosins) and purely synthetic supramolecular systems. We have studied the interaction of these compounds with human cancer cell lines, and, in general, the most active anion transporter compounds possess the greatest anti-cancer properties.Initially, we describe the anion transport properties of synthetic mol-ecules that are based on the structure of the family of natural products known as the prodiginines. Obatoclax, for example, is a prodiginine derivative with an indole ring that is currently in clinical trials for use as an anti-cancer drug. The anion transport properties of the compounds were correlated with their toxicity toward small cell human lung cancer GLC4 cells. We studied related compounds with enamine moieties, tambjamines, that serve as active transporters. These molecules and others in this series could depolarize acidic compartments within GLC4 cells and trigger apoptosis. In a study of the variation of lipophilicity of a series of these compounds, we observed that, as log P increases, the anion transport efficiency reaches a peak and then decreases.In addition, we discuss the anion transport properties of series of synthetic supramolecular anion receptor species. We synthesized trisureas and thioureas based on the tren backbone, and found that the thiourea compounds effectively transport anions. Fluorination of the pendant phenyl groups in this series of compounds greatly enhances the transport properties. Similar to our earlier results, the most active anion transporters reduced the viability of human cancer cell lines by depolarizing acidic compartments in GLC4 cells and triggering apoptosis.In an attempt to produce simpler transporters that obey Lipinski's Rule of Five, we synthesized simpler systems containing a single urea or thiourea group. Once again the thiourea systems, and in particular a thiourea with a pendant indole group, transported anions efficiently. A series of related compounds containing a pendant trifluoromethyl group showed enhanced transport and significant anticancer properties.Researchers still need to determine of the exact mechanism of how these compounds depolarize acidic organelles within cancer cells. However, this work shows that these transporters based upon both natural products and purely synthetic supramolecular systems transport anions, depolarize acidic compartments within cancer cells and trigger apoptosis. © 2013 American Chemical Society.
Verbeeten W.M.H.,University of Burgos
Journal of Rheology | Year: 2010
The experimental linear viscoelastic and steady-state shear data over a broad concentration range of several aqueous semi-flexible polysaccharide solutions can be quantitatively predicted by the multimode Phan-Thien Tanner, Giesekus, and extended Pom-Pom non-linear viscoelastic models using a single set of parameters. Experimental data from an aqueous solution of the polysaccharide guar galactomannan (Mw =1.12× 106 g/mol), aqueous phosphopolysaccharide "viilian" solution excreted by Lactococcus lactis subspecies cremoris SBT 0495 (Mw =2× 106 g/mol), and aqueous Propionibacterium acidi-propionici polysaccharide solution (Mw ≈ 106 g/mol) are taken from literature. A master curve can be constructed by shifting data from different concentrations over the horizontal and vertical axes. A simple model to describe the concentration dependence of the relaxation time and plateau modulus over the entire concentration range is presented. Transient shear viscosity data are quantitatively and first normal stress coefficient are qualitatively predicted for the guar galactomannan solution. Due to their proven performance in finite element simulations, these non-linear viscoelastic constitutive equations could help us to improve predictive modeling of time-dependent complex flow problems for polysaccharide solutions with variations in concentration and temperature in the spatial domain using only a single set of parameters. However, as a previous step, the performance of additional rheological experiments in simple flows, i.e., transient and steady-state extensional measurements, is recommended. © 2010 The Society of Rheology.
Alfonso I.,CSIC - Institute of Advanced Chemistry of Catalonia |
Quesada R.,University of Burgos
Chemical Science | Year: 2013
The control of ion transport and homeostasis is a critical function of living organisms. In this perspective, an overview of different synthetic systems capable of facilitating the transmembrane transport of ions along with the biological activity exerted by these compounds is presented. Examples of both cation selective and anion selective transporters are highlighted. The potential future applications of these systems in the treatment of conditions derived from the dysregulation of natural ion transport mechanisms and the development of new antimicrobials and anticancer drugs are discussed. © 2013 The Royal Society of Chemistry.
Davis J.T.,University of Maryland University College |
Okunola O.,University of Maryland University College |
Quesada R.,University of Burgos
Chemical Society Reviews | Year: 2010
Anions cannot diffuse passively through biological membranes and membrane-bound proteins mainly govern the transmembrane movement of these charged species. The use of synthetic compounds that are able to facilitate the transmembrane transport of anions is a fascinating and burgeoning topic. The study of facilitated anion transport across lipid bilayers is an emerging field in supramolecular and bioorganic chemistry. In this critical review we describe the recent research progress in this area, focusing on literature published during the years 2007-2009. An overview of the assays that are used in the transmembrane transport of anions is also included (158 references). © 2010 The Royal Society of Chemistry.
Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-14-2015 | Award Amount: 4.59M | Year: 2016
This project will develop an innovative therapeutic approach for the treatment of Cystic Fibrosis (CF). This condition originates from the defective function of the CFTR protein, a chloride and bicarbonate permeable transmembrane channel. This project will evaluate small molecules capable of facilitating the transmembrane transport of anions such as chloride and bicarbonate and will thus enable CF treatment by replacing the missing CFTR anion permeation activity. This represents an unexplored path in the treatment of CF and a paradigm shift with respect to current strategies searching for a cure for CF. Instead of focusing on the development of mutation-specific treatments, we plan to develop a therapy applicable to CF patients, regardless of the type of mutation they harbor. Thus, this therapeutic approach overcomes the limitation of current mutation-specific treatments and is applicable to CF patients in general. To achieve this goal we have set up a comprehensive program to validate a research concept and complete the preclinical development of a new lead compound, making it ready for early clinical development. A rmultidisciplinary team of qualified researchers have been assembled to bring to conclusion a truly translational project from the synthesis of new compounds to validation on animal models. Cystic Fibrosis affects more people than any other rare disease. Therefore, it could be said, at least in quantitative terms, that CF qualifies as the main target of the topic. This project aims to complete the preclinical development of novel, innovative drugs based on a radically new concept in Cystic Fibrosis therapies. This result fully addresses the expected impact set out in the work programme of advancing the development of new therapeutic options for patients living with rare diseases as well as contributing to reach the IRDiRC objective to deliver 200 new therapies for rare diseases by 2020.