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Biradical Formation by Deprotonation in Thiazole-Derivatives: The Hidden Nature of Dasatinib
preprintsubmitted on 31.10.2019, 12:04 and posted on 06.11.2019, 21:17 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.