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Stiff-Stilbene Ligands Target G-Quadruplex DNA and Exhibit Selective Anticancer and Antiparasitic Activity

preprint
submitted on 19.12.2019 and posted on 23.12.2019 by Michael O'Hagan, pablo Peñalver, Rosina S. L. Gibson, Juan Carlos Morales, M. Carmen Galan

G-quadruplex nucleic acid structures have long been studied as potential anticancer targets while their potential in antiparasitic therapy has only recently been recognized but barely explored. Herein we report the synthesis, biophysical characterization and in vitro screening of a series of stiff-stilbene G4 binding ligands featuring differing 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 whist remaining up to two orders of magnitude less toxic to non-tumoral mammalian cell line MRC5. Our study demonstrates that stiff-stilbenes show exciting potential as the basis of selective anticancer and antiparasitic therapies. In order to achieve the most efficient G4 recognition the scaffold must possess the optimal electronics and substitution pattern and correct molecular geometry.

Funding

EPSRC (EP/L015366/1)

Spanish Ministerio de Ciencia Innovación y Universidades (Grants CTQ2015-64275- P and RTI2018-099036-B-I00)

European Research Council (ERC-COG: 648239)

History

Email Address of Submitting Author

m.c.galan@bristol.ac.uk

Institution

School of Chemistry, University of Bristol

Country

United Kingdom

ORCID For Submitting Author

0000-0001-7307-2871

Declaration of Conflict of Interest

No conflict of interests

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