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Biradical Formation by Deprotonation in Thiazole-Derivatives: The Hidden Nature of Dasatinib

preprint
submitted on 31.10.2019 and posted on 06.11.2019 by Carlos Heras, Daniel Reta, Rosendo Valero, Guillermo Albareda, Nicholas Chilton, Alistair Fielding, Iberio de P. R Moreira, Josep Maria Bofill, Francisco Lopez Calahorra
The formation of stable organic biradicals by a deprotonation process is reported for a series of conjugated heterocycles that share a Ph-N(H)-2-thiazole structural motif. We characterise the paramagnetic electronic ground state by means of continuous-wave and pulse EPR. We propose a simple valence bond mechanism for a deprotonation-induced formation of paramagnetic organic molecules, based on the interplay between the electronegativity of heteroatomic groups and the recovery of aromaticity to stabilise the biradical species. The Ph-N(H)-2-thiazole motif is found in a variety of biologically active molecules, exemplified here with the anticancer drug Dasatinib, and our results suggest a radical-based mechanism for the protein kinase inhibition activity of the drug. The existence of this structure-property relationship for an elementary chemical motif suggests that biradical species may be more prevalent than previously thought and have an important role in bioorganic chemistry.

Funding

FEDER CTQ2016-76423-P

Spanish Structures of Excellence María de Maeztu program (MDM-2017–0767

Generalitat de Catalunya (grant 2017SGR348)

EPSRC (EP/P002560/1

European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 752822

History

Email Address of Submitting Author

daniel.reta@manchester.ac.uk

Institution

University of Manchester

Country

United Kingdom

ORCID For Submitting Author

0000-0003-0000-9892

Declaration of Conflict of Interest

no conflict of interest

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