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Stiff‐Stilbene Ligands Target G‐Quadruplex DNA and Exhibit Selective Anticancer and Antiparasitic Activity
Author(s) -
O'Hagan Michael P.,
Peñalver Pablo,
Gibson Rosina S. L.,
Morales Juan C.,
Galan M. Carmen
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.201905753
Subject(s) - antiparasitic , hela , chemistry , dna , nucleic acid , stereochemistry , in vitro , antiparasitic agent , combinatorial chemistry , biochemistry , biology , pharmacology , medicine , pathology
G‐quadruplex nucleic acid structures have long been studied as anticancer targets whilst their potential in antiparasitic therapy has only recently been recognized and barely explored. Herein, we report the synthesis, biophysical characterization, and in vitro screening of a series of stiff‐stilbene G4 binding ligands featuring different electronics, side‐chain chemistries, and molecular geometries. The ligands display selectivity for G4 DNA over duplex DNA and exhibit nanomolar toxicity against Trypasanoma brucei and HeLa cancer cells whilst remaining up to two orders of magnitude less toxic to non‐tumoral mammalian cell line MRC‐5. Our study demonstrates that stiff‐stilbenes show exciting potential as the basis of selective anticancer and antiparasitic therapies. To achieve the most efficient G4 recognition the scaffold must possess the optimal electronics, substitution pattern and correct molecular configuration.