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

Chemistry. 2020 Jan 16;26(4):888-899. doi: 10.1002/chem.201904255. Epub 2019 Dec 27.

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-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.

Keywords: anion transport; cytotoxicity; efflux studies; molecular modelling; thiophene-based molecules.

MeSH terms

  • Anions / chemistry*
  • Biological Transport
  • Cell Line, Tumor
  • Chlorides / chemistry*
  • Crystallography, X-Ray
  • Humans
  • Ion Transport
  • Magnetic Resonance Spectroscopy
  • Thiophenes / chemistry*
  • Urea / chemistry*

Substances

  • Anions
  • Chlorides
  • Thiophenes
  • Urea