Development of a Library of Thiophene-Based Drug-Like Lego Molecules: Evaluation of Their Anion Binding, Transport Properties, and Cytotoxicity(Article)

Chemistry - A European Journal

Journal Article

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 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. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

P.a Vieira

M.Q.b Miranda

I.b Marques

L.-J.c Chen

E.N.W.c Howe

C.c Zhen

C.Y.c Leung

M.J.d Spooner

B.e Morgado

O.A.B.e da Cruz e Silva

C.a Moiteiro

P.A.c Gale

V.b Félix

Publication

Year of publication: 2020

Identifiers

ISSN: 09476539

Locators

DOI: 10.1002/chem.201904255

Alternative Titles