Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis

Gibadullina, Elmira; Neganova, Margarita; Aleksandrova, Yulia; Nguyen, Hoang Bao Tran; Voloshina, Alexandra; Khrizanforov, Mikhail; Nguyen, Thi Thu; Vinyukova, Ekaterina; Volcho, Konstantin; Tsypyshev, Dmitry; Lyubina, Anna; Amerhanova, Syumbelya; Strelnik, Anna; Voronina, Julia; Islamov, Daut; Zhapparbergenov, Rakhmetulla; Appazov, Nurbol; Chabuka, Beauty; Christopher, Kimberley; Burilov, Alexander; Salakhutdinov, Nariman; Sinyashin, Oleg; Alabugin, Igor

doi:10.3390/ijms241612637

Open AccessArticle

Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis

by

Elmira Gibadullina

^1,*,

Margarita Neganova

^1,2

,

Yulia Aleksandrova

^1,2

,

Hoang Bao Tran Nguyen

³,

Alexandra Voloshina

¹,

Mikhail Khrizanforov

¹,

Thi Thu Nguyen

³

,

Ekaterina Vinyukova

²,

Konstantin Volcho

⁴

,

Dmitry Tsypyshev

⁴,

Anna Lyubina

¹,

Syumbelya Amerhanova

¹,

Anna Strelnik

¹,

Julia Voronina

⁵

,

Daut Islamov

⁶,

Rakhmetulla Zhapparbergenov

^7,*,

Nurbol Appazov

⁷

,

Beauty Chabuka

⁸

,

Kimberley Christopher

⁸,

Alexander Burilov

¹,

Nariman Salakhutdinov

⁴,

Oleg Sinyashin

¹ and

Igor Alabugin

^1,8

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¹

Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Akad. Arbuzov St. 8, Kazan 420088, Russia

²

Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Severnij Pr. 1, Chernogolovka 142432, Russia

³

The Department of General Organic and Petrochemical Synthesis Technology, The Kazan National Research Technological University, Karl Marx St. 68, Kazan 420015, Russia

⁴

Department of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Lavrentiev Av. 9, Novosibirsk 630090, Russia

⁵

Kurnakov Institute of General and Inorganic Chemistry of the Russian Academy of Sciences, Leninskii Prospekt, 31, Moscow 119071, Russia

⁶

Laboratory for Structural Analysis of Biomacromolecules, Kazan Scientific Center of Russian Academy of Science, 31, Kremlevskaya, Kazan 420008, Russia

⁷

Laboratory of Engineering Profile, Department of Engineering Technology, Korkyt Ata Kyzylorda University, 29A, Aiteke Bi Street, Kyzylorda 120014, Kazakhstan

⁸

Department of Chemistry and Biochemistry, Florida State University, 95 Chieftan Way, Tallahassee, FL 32306-3290, USA

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2023, 24(16), 12637; https://doi.org/10.3390/ijms241612637

Submission received: 15 July 2023 / Revised: 3 August 2023 / Accepted: 7 August 2023 / Published: 10 August 2023

(This article belongs to the Special Issue Recent Advances in Novel Compositions for Electrochemical Applications)

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Abstract

The utility of sterically hindered phenols (SHPs) in drug design is based on their chameleonic ability to switch from an antioxidant that can protect healthy tissues to highly cytotoxic species that can target tumor cells. This work explores the biological activity of a family of 45 new hybrid molecules that combine SHPs equipped with an activating phosphonate moiety at the benzylic position with additional urea/thiourea fragments. The target compounds were synthesized by reaction of iso(thio)cyanates with C-arylphosphorylated phenols containing pendant 2,6-diaminopyridine and 1,3-diaminobenzene moieties. The SHP/urea hybrids display cytotoxic activity against a number of tumor lines. Mechanistic studies confirm the paradoxical nature of these substances which combine pronounced antioxidant properties in radical trapping assays with increased reactive oxygen species generation in tumor cells. Moreover, the most cytotoxic compounds inhibited the process of glycolysis in SH-SY5Y cells and caused pronounced dissipation of the mitochondrial membrane of isolated rat liver mitochondria. Molecular docking of the most active compounds identified the activator allosteric center of pyruvate kinase M2 as one of the possible targets. For the most promising compounds, 11b and 17b, this combination of properties results in the ability to induce apoptosis in HuTu 80 cells along the intrinsic mitochondrial pathway. Cyclic voltammetry studies reveal complex redox behavior which can be simplified by addition of a large excess of acid that can protect some of the oxidizable groups by protonations. Interestingly, the re-reduction behavior of the oxidized species shows considerable variations, indicating different degrees of reversibility. Such reversibility (or quasi-reversibility) suggests that the shift of the phenol-quinone equilibrium toward the original phenol at the lower pH may be associated with lower cytotoxicity.

Keywords: sterically hindered phenol; quinone methides; urea; anticancer activity; cytotoxicity; mitochondrial membrane potential; apoptosis; glycolysis; molecular docking; electrochemical oxidation

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MDPI and ACS Style

Gibadullina, E.; Neganova, M.; Aleksandrova, Y.; Nguyen, H.B.T.; Voloshina, A.; Khrizanforov, M.; Nguyen, T.T.; Vinyukova, E.; Volcho, K.; Tsypyshev, D.; et al. Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis. Int. J. Mol. Sci. 2023, 24, 12637. https://doi.org/10.3390/ijms241612637

AMA Style

Gibadullina E, Neganova M, Aleksandrova Y, Nguyen HBT, Voloshina A, Khrizanforov M, Nguyen TT, Vinyukova E, Volcho K, Tsypyshev D, et al. Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis. International Journal of Molecular Sciences. 2023; 24(16):12637. https://doi.org/10.3390/ijms241612637

Chicago/Turabian Style

Gibadullina, Elmira, Margarita Neganova, Yulia Aleksandrova, Hoang Bao Tran Nguyen, Alexandra Voloshina, Mikhail Khrizanforov, Thi Thu Nguyen, Ekaterina Vinyukova, Konstantin Volcho, Dmitry Tsypyshev, and et al. 2023. "Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis" International Journal of Molecular Sciences 24, no. 16: 12637. https://doi.org/10.3390/ijms241612637

APA Style

Gibadullina, E., Neganova, M., Aleksandrova, Y., Nguyen, H. B. T., Voloshina, A., Khrizanforov, M., Nguyen, T. T., Vinyukova, E., Volcho, K., Tsypyshev, D., Lyubina, A., Amerhanova, S., Strelnik, A., Voronina, J., Islamov, D., Zhapparbergenov, R., Appazov, N., Chabuka, B., Christopher, K., ... Alabugin, I. (2023). Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis. International Journal of Molecular Sciences, 24(16), 12637. https://doi.org/10.3390/ijms241612637

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Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis

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