Development of a Library of Thiophene-Based Drug-Like Lego Molecules: Evaluation of Their Anion Binding, Transport Properties, and Cytotoxicity
authors Vieira, P; Miranda, MQ; Marques, I; Carvalho, S; Chen, LJ; Howe, ENW; Zhen, C; Leung, CY; Spooner, MJ; Morgado, B; Silva, OABDE; Moiteiro, C; Gale, PA; Felix, V
nationality International
journal CHEMISTRY-A EUROPEAN JOURNAL
author keywords anion transport; cytotoxicity; efflux studies; molecular modelling; thiophene-based molecules
keywords CELL; PRODIGIOSIN; AUTOPHAGY; INSIGHTS
abstract The anion-binding and transport properties of an extensive library of thiophene-based molecules are reported. Seventeen bis-urea positional isomers, with different binding conformations and lipophilicities, have been synthesized by appending alpha- or beta-thiophene or alpha-, beta-, or gamma-benzo[b]thiophene moieties to an ortho-phenylenediamine central core, yielding six subsets of positional isomers. Through H-1 NMR, X-ray crystallography, molecular modelling, and anion efflux studies, it is demonstrated that the most active transporters adopt a pre-organized binding conformation capable of promoting the recognition of chloride, using urea and C-H binding groups in a cooperative fashion. Additional large unilamellar vesicle-based assays, carried out under electroneutral and electrogenic conditions, together with N-methyl-d-glucamine chloride assays, have indicated that anion efflux occurs mainly through an H+/Cl- symport mechanism. On the other hand, the most efficient anion transporter displays cytotoxicity against tumor cell lines, while having no effects on a cystic fibrosis cell line.
publisher WILEY-V C H VERLAG GMBH
issn 0947-6539
isbn 1521-3765
year published 2020
volume 26
issue 4
beginning page 888
ending page 899
digital object identifier (doi) 10.1002/chem.201904255
web of science category Chemistry, Multidisciplinary
subject category Chemistry
unique article identifier WOS:000504508600001
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journal impact factor 4.857
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