Molecular Mechanisms Involved in the Chemical Instability of ONC201 and Methods to Counter Its Degradation in...

Glioblastoma is one of the most common and aggressive forms of brain tumor, a rare disease for which there is a great need for innovative therapies. ONC201, a new drug substance, has been used in a compassionate treatment program where the choice of dosage form and regimen have yet to be justified. The prior knowledge needed to anticipate ONC201 stability problems has recently been partially addressed, by (i) showing that ONC201 is sensitive to light and oxidation and (ii) identifying the molecular structures of the main degradation products formed. The aim of the work presented here was to improve our understanding of the degradation pathways of ONC201 using data from ab initio calculations and experimental work to supplement the structural information we already published. The C-H bonds located αto the amine of the tetrahydropyridine group and those located alpha to the imine function of the dihydroimidazole group exhibit the lowest bond dissociation energies (BDEs) within the ONC201 molecule. Moreover, these values drop well below 90 kcal.mol^-1 when ONC201 is in an excited state (S1; T1). The structures of the photoproducts we had previously identified are consistent with these data, showing that they would have resulted from radical processes following the abstraction of alpha hydrogens. Concerning ONC201's sensitivity to oxidation, the structures of the oxidation products matched the critical points revealed through mapped electrostatic potential (MEP) and average local ionization energy (ALIE). The data obtained from ab initio calculations and experimental work showed that the reactivity of ONC201 to light and oxidation conditions is highly dependent on pH. While an acidic environment (pH < 6) contributes to making ONC201 quantitatively more stable in solution in the face of oxidation and photo-oxidation, it nevertheless seems that certain chemical groups in the molecule are more exposed to nucleophilic attacks, which explains the variation observed in the profile of degradation products formed in the presence of certain antioxidants tested. This information is crucial to better understand the stability results in the presence of antioxidant agents and to determine the right conditions for them to act.