Identification of a potent Nrf2 displacement activator among aspirin-containing prodrugs

Gaisina, I.N.; Hushpulian, D.M.; Gaisin, A.M.; Kazakov, E.H.; Kaidery, N.A.; Ahuja, M.; Poloznikov, A.A.; Gazaryan, I.G.; Thatcher Gregory, R.J.; Thomas, B.

Авторы: Gaisina Irina N., Hushpulian Dmitry M., Gaisin Arsen M., Kazakov Eliot H., Kaidery Navneet Ammal, Ahuja Manuj, Poloznikov Andrey A., Gazaryan Irina G., Thatcher Gregory R.J., Thomas Bobby
Журнал: Neurochemistry International
Том: 149
Год издания: 2021
Издательство: Elsevier BV
Местоположение издательства: Netherlands
Первая страница: 105148
Номер статьи: 105148
DOI: 10.1016/j.neuint.2021.105148
Аннотация: Aspirin is a desired leaving group in prodrugs aimed at treatment of neurodegeneration and other conditions. A library of aspirin derivatives of various scaffolds potentially activating Nrf2 has been tested in Neh2-luc reporter assay which screens for direct Nrf2 protein stabilizers working via disruption of Nrf2-Keap1 interaction. Most aspirin prodrugs had a pro-alkylating or pro-oxidant motif in the structure and, therefore, were toxic at high concentrations. However, among the active compounds, we identified a molecule resembling a well-known Nrf2 displacement activator, bis-1,4-(4-methoxybenzenesulfonamidyl) naphthalene (NMBSA). The direct comparison of the newly identified compound with NMBSA and its improved analog in the reporter assay showed no quenching with N-acetyl cysteine, thus pointing to Nrf2 stabilization mechanism without cysteine alkylation. The potency of the newly identified compound in the reporter assay was much stronger than NMBSA, despite its inhibitory action in the commercial fluorescence polarization assay was observed only in the millimolar range. Molecular docking predicted that mono-deacetylation of the novel prodrug should generate a potent displacement activator. The time-course of reporter activation with the novel prodrug had a pronounced lag-period pointing to a plausible intracellular transformation leading to an active product. Treatment of the novel prodrug with blood plasma or cell lysate demonstrated stepwise deacetylation as judge by liquid chromatography-mass spectrometry (LC-MS). Hence, the esterase-catalyzed hydrolysis of the prodrug liberates only acetyl groups from aspirin moiety and generates a potent Nrf2 activator. The discovered mechanism of prodrug activation makes the newly identified compound a promising lead for future optimization studies.
Добавил в систему: Газарян Ирина Георгиевна

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