Stiff-Stilbene Ligands Target G-Quadruplex DNA and Exhibit Selective Anticancer and Antiparasitic Activity.
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.
["O'Hagan|Michael P|MP|http://orcid.org/0000-0003-4180-3144", 'Peñalver|Pablo|P|', 'Gibson|Rosina S L|RSL|http://orcid.org/0000-0002-9621-565X', 'Morales|Juan C|JC|http://orcid.org/0000-0003-2400-405X', 'Galan|M Carmen|MC|http://orcid.org/0000-0001-7307-2871']
D000970:Antineoplastic Agents D000977:Antiparasitic Agents D001665:Binding Sites D002942:Circular Dichroism D004247:DNA D015195:Drug Design D054856:G-Quadruplexes D006801:Humans D009369:Neoplasms D013267:Stilbenes D013329:Structure-Activity Relationship D016615:Telomere
G-quadruplexes DNA antiparasitic agents antitumor agents molecular recognition