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

Author:

Gibadullina Elmira1,Neganova Margarita12ORCID,Aleksandrova Yulia12ORCID,Nguyen Hoang Bao Tran3,Voloshina Alexandra1,Khrizanforov Mikhail1,Nguyen Thi Thu3ORCID,Vinyukova Ekaterina2,Volcho Konstantin4ORCID,Tsypyshev Dmitry4,Lyubina Anna1,Amerhanova Syumbelya1,Strelnik Anna1,Voronina Julia5ORCID,Islamov Daut6,Zhapparbergenov Rakhmetulla7,Appazov Nurbol7ORCID,Chabuka Beauty8,Christopher Kimberley8,Burilov Alexander1,Salakhutdinov Nariman4,Sinyashin Oleg1,Alabugin Igor18ORCID

Affiliation:

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

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.

Funder

Ministry of Science and Higher Education of the Russian Federation at the FRC Kazan Scientific Center

FRC Kazan Scientific Center of RAS

non-profit joint-stock company “Korkyt Ata Kyzylorda University”

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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