Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis
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. Burilov A. Salakhutdinov N. Sinyashin O. Alabugin I.
August 2023Multidisciplinary Digital Publishing Institute (MDPI)
International Journal of Molecular Sciences
2023#24Issue 16
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.
anticancer activity , apoptosis , cytotoxicity , electrochemical oxidation , glycolysis , mitochondrial membrane potential , molecular docking , quinone methides , sterically hindered phenol , urea
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Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Akad. Arbuzov St. 8, Kazan, 420088, Russian Federation
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, Russian Federation
The Department of General Organic and Petrochemical Synthesis Technology, The Kazan National Research Technological University, Karl Marx St. 68, Kazan, 420015, Russian Federation
Department of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Lavrentiev Av. 9, Novosibirsk, 630090, Russian Federation
Kurnakov Institute of General and Inorganic Chemistry of the Russian Academy of Sciences, Leninskii Prospekt, 31, Moscow, 119071, Russian Federation
Laboratory for Structural Analysis of Biomacromolecules, Kazan Scientific Center of Russian Academy of Science, 31, Kremlevskaya, Kazan, 420008, Russian Federation
Laboratory of Engineering Profile, Department of Engineering Technology, Korkyt Ata Kyzylorda University, 29A, Aiteke Bi Street, Kyzylorda, 120014, Kazakhstan
Department of Chemistry and Biochemistry, Florida State University, 95 Chieftan Way, Tallahassee, 32306-3290, FL, United States
Arbuzov Institute of Organic and Physical Chemistry
Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry
The Department of General Organic and Petrochemical Synthesis Technology
Department of Medicinal Chemistry
Kurnakov Institute of General and Inorganic Chemistry of the Russian Academy of Sciences
Laboratory for Structural Analysis of Biomacromolecules
Laboratory of Engineering Profile
Department of Chemistry and Biochemistry
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