Development of a Library of Thiophene-Based Drug-Like Lego Molecules: Evaluation of Their Anion Binding,Transport Properties,and Cytotoxicity |
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Authors: | Paulo Vieira Margarida Q Miranda Dr Igor Marques Dr Sílvia Carvalho Dr Li-Jun Chen Dr Ethan N W Howe Carl Zhen Claudia Y Leung Dr Michael J Spooner Bárbara Morgado Prof Odete A B da Cruz e Silva Prof Cristina Moiteiro Prof Philip A Gale Prof Vítor Félix |
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Institution: | 1. Centro de Química e Bioquímica, Centro de Química Estrutural, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal;2. Department of Chemistry, CICECO – Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal;3. School of Chemistry (F11), The University of Sydney, Sydney, NSW, 2006 Australia;4. Chemistry, University of Southampton, Southampton, SO17 1BJ UK;5. Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, 3810-193 Aveiro, Portugal |
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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 α- or β-thiophene or α-, β-, or γ-benzob]thiophene moieties to an ortho-phenylenediamine central core, yielding six subsets of positional isomers. Through 1H 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. |
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Keywords: | anion transport cytotoxicity efflux studies molecular modelling thiophene-based molecules |
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