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Development of a Library of Thiophene‐Based Drug‐Like Lego Molecules: Evaluation of Their Anion Binding, Transport Properties, and Cytotoxicity
Author(s) -
Vieira Paulo,
Miranda Margarida Q.,
Marques Igor,
Carvalho Sílvia,
Chen LiJun,
Howe Ethan N. W.,
Zhen Carl,
Leung Claudia Y.,
Spooner Michael J.,
Morgado Bárbara,
Cruz e Silva Odete A. B.,
Moiteiro Cristina,
Gale Philip A.,
Félix Vítor
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201904255
Subject(s) - cytotoxicity , thiophene , chemistry , combinatorial chemistry , molecule , drug , small molecule , nanotechnology , organic chemistry , materials science , biochemistry , in vitro , pharmacology , medicine
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 α‐ or β‐thiophene or α‐, β‐, or γ‐benzo[ b ]thiophene moieties to an ortho ‐phenylenediamine central core, yielding six subsets of positional isomers. Through 1 H 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.