Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis
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 molec...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-08-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/16/12637 |
| _version_ | 1797584461365248000 |
|---|---|
| author | Elmira Gibadullina Margarita Neganova Yulia Aleksandrova Hoang Bao Tran Nguyen Alexandra Voloshina Mikhail Khrizanforov Thi Thu Nguyen Ekaterina Vinyukova Konstantin Volcho Dmitry Tsypyshev Anna Lyubina Syumbelya Amerhanova Anna Strelnik Julia Voronina Daut Islamov Rakhmetulla Zhapparbergenov Nurbol Appazov Beauty Chabuka Kimberley Christopher Alexander Burilov Nariman Salakhutdinov Oleg Sinyashin Igor Alabugin |
| author_facet | Elmira Gibadullina Margarita Neganova Yulia Aleksandrova Hoang Bao Tran Nguyen Alexandra Voloshina Mikhail Khrizanforov Thi Thu Nguyen Ekaterina Vinyukova Konstantin Volcho Dmitry Tsypyshev Anna Lyubina Syumbelya Amerhanova Anna Strelnik Julia Voronina Daut Islamov Rakhmetulla Zhapparbergenov Nurbol Appazov Beauty Chabuka Kimberley Christopher Alexander Burilov Nariman Salakhutdinov Oleg Sinyashin Igor Alabugin |
| author_sort | Elmira Gibadullina |
| collection | DOAJ |
| description | 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, <b>11b</b> and <b>17b</b>, 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. |
| first_indexed | 2024-03-10T23:53:02Z |
| format | Article |
| id | doaj.art-1071746952fa40ceb533c9ed9f0a574a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:53:02Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1071746952fa40ceb533c9ed9f0a574a2023-11-19T01:26:29ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124161263710.3390/ijms241612637Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of ApoptosisElmira Gibadullina0Margarita Neganova1Yulia Aleksandrova2Hoang Bao Tran Nguyen3Alexandra Voloshina4Mikhail Khrizanforov5Thi Thu Nguyen6Ekaterina Vinyukova7Konstantin Volcho8Dmitry Tsypyshev9Anna Lyubina10Syumbelya Amerhanova11Anna Strelnik12Julia Voronina13Daut Islamov14Rakhmetulla Zhapparbergenov15Nurbol Appazov16Beauty Chabuka17Kimberley Christopher18Alexander Burilov19Nariman Salakhutdinov20Oleg Sinyashin21Igor Alabugin22Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Akad. Arbuzov St. 8, Kazan 420088, RussiaArbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Akad. Arbuzov St. 8, Kazan 420088, RussiaArbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Akad. Arbuzov St. 8, Kazan 420088, RussiaThe Department of General Organic and Petrochemical Synthesis Technology, The Kazan National Research Technological University, Karl Marx St. 68, Kazan 420015, RussiaArbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Akad. Arbuzov St. 8, Kazan 420088, RussiaArbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Akad. Arbuzov St. 8, Kazan 420088, RussiaThe Department of General Organic and Petrochemical Synthesis Technology, The Kazan National Research Technological University, Karl Marx St. 68, Kazan 420015, RussiaInstitute 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, RussiaDepartment of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Lavrentiev Av. 9, Novosibirsk 630090, RussiaDepartment of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Lavrentiev Av. 9, Novosibirsk 630090, RussiaArbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Akad. Arbuzov St. 8, Kazan 420088, RussiaArbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Akad. Arbuzov St. 8, Kazan 420088, RussiaArbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Akad. Arbuzov St. 8, Kazan 420088, RussiaKurnakov Institute of General and Inorganic Chemistry of the Russian Academy of Sciences, Leninskii Prospekt, 31, Moscow 119071, RussiaLaboratory for Structural Analysis of Biomacromolecules, Kazan Scientific Center of Russian Academy of Science, 31, Kremlevskaya, Kazan 420008, RussiaLaboratory of Engineering Profile, Department of Engineering Technology, Korkyt Ata Kyzylorda University, 29A, Aiteke Bi Street, Kyzylorda 120014, KazakhstanLaboratory of Engineering Profile, Department of Engineering Technology, Korkyt Ata Kyzylorda University, 29A, Aiteke Bi Street, Kyzylorda 120014, KazakhstanDepartment of Chemistry and Biochemistry, Florida State University, 95 Chieftan Way, Tallahassee, FL 32306-3290, USADepartment of Chemistry and Biochemistry, Florida State University, 95 Chieftan Way, Tallahassee, FL 32306-3290, USAArbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Akad. Arbuzov St. 8, Kazan 420088, RussiaDepartment of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Lavrentiev Av. 9, Novosibirsk 630090, RussiaArbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Akad. Arbuzov St. 8, Kazan 420088, RussiaArbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Akad. Arbuzov St. 8, Kazan 420088, RussiaThe 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, <b>11b</b> and <b>17b</b>, 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.https://www.mdpi.com/1422-0067/24/16/12637sterically hindered phenolquinone methidesureaanticancer activitycytotoxicitymitochondrial membrane potential |
| spellingShingle | Elmira Gibadullina Margarita Neganova Yulia Aleksandrova Hoang Bao Tran Nguyen Alexandra Voloshina Mikhail Khrizanforov Thi Thu Nguyen Ekaterina Vinyukova Konstantin Volcho Dmitry Tsypyshev Anna Lyubina Syumbelya Amerhanova Anna Strelnik Julia Voronina Daut Islamov Rakhmetulla Zhapparbergenov Nurbol Appazov Beauty Chabuka Kimberley Christopher Alexander Burilov Nariman Salakhutdinov Oleg Sinyashin Igor Alabugin 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 sterically hindered phenol quinone methides urea anticancer activity cytotoxicity mitochondrial membrane potential |
| title | Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis |
| title_full | Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis |
| title_fullStr | Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis |
| title_full_unstemmed | Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis |
| title_short | Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis |
| title_sort | hybrids of sterically hindered phenols and diaryl ureas synthesis switch from antioxidant activity to ros generation and induction of apoptosis |
| topic | sterically hindered phenol quinone methides urea anticancer activity cytotoxicity mitochondrial membrane potential |
| url | https://www.mdpi.com/1422-0067/24/16/12637 |
| work_keys_str_mv | AT elmiragibadullina hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT margaritaneganova hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT yuliaaleksandrova hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT hoangbaotrannguyen hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT alexandravoloshina hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT mikhailkhrizanforov hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT thithunguyen hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT ekaterinavinyukova hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT konstantinvolcho hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT dmitrytsypyshev hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT annalyubina hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT syumbelyaamerhanova hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT annastrelnik hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT juliavoronina hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT dautislamov hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT rakhmetullazhapparbergenov hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT nurbolappazov hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT beautychabuka hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT kimberleychristopher hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT alexanderburilov hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT narimansalakhutdinov hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT olegsinyashin hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis AT igoralabugin hybridsofstericallyhinderedphenolsanddiarylureassynthesisswitchfromantioxidantactivitytorosgenerationandinductionofapoptosis |