New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular Modeling
Deoxycholic acid derivatives containing various heterocyclic functional groups at C-3 on the steroid scaffold were designed and synthesized as promising dual tyrosyl-DNA phosphodiesterase 1 and 2 (TDP1 and TDP2) inhibitors, which are potential targets to potentiate topoisomerase poison antitumor the...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-01-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/29/3/581 |
| _version_ | 1797318494845403136 |
|---|---|
| author | Oksana V. Salomatina Tatyana E. Kornienko Alexandra L. Zakharenko Nina I. Komarova Chigozie Achara Jóhannes Reynisson Nariman F. Salakhutdinov Olga I. Lavrik Konstantin P. Volcho |
| author_facet | Oksana V. Salomatina Tatyana E. Kornienko Alexandra L. Zakharenko Nina I. Komarova Chigozie Achara Jóhannes Reynisson Nariman F. Salakhutdinov Olga I. Lavrik Konstantin P. Volcho |
| author_sort | Oksana V. Salomatina |
| collection | DOAJ |
| description | Deoxycholic acid derivatives containing various heterocyclic functional groups at C-3 on the steroid scaffold were designed and synthesized as promising dual tyrosyl-DNA phosphodiesterase 1 and 2 (TDP1 and TDP2) inhibitors, which are potential targets to potentiate topoisomerase poison antitumor therapy. The methyl esters of DCA derivatives with benzothiazole or benzimidazole moieties at C-3 demonstrated promising inhibitory activity in vitro against TDP1 with IC<sub>50</sub> values in the submicromolar range. Furthermore, methyl esters <b>4d</b>–<b>e</b>, as well as their acid counterparts <b>3d</b>–<b>e</b>, inhibited the phosphodiesterase activity of both TDP1 and TDP2. The combinations of compounds <b>3d</b>–<b>e</b> and <b>4d</b>–<b>e</b> with low-toxic concentrations of antitumor drugs topotecan and etoposide showed significantly greater cytotoxicity than the compounds alone. The docking of the derivatives into the binding sites of TDP1 and TDP2 predicted plausible binding modes of the DCA derivatives. |
| first_indexed | 2024-03-08T03:53:14Z |
| format | Article |
| id | doaj.art-f7a6940d786f428597863fdfcc30635e |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-08T03:53:14Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-f7a6940d786f428597863fdfcc30635e2024-02-09T15:18:42ZengMDPI AGMolecules1420-30492024-01-0129358110.3390/molecules29030581New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular ModelingOksana V. Salomatina0Tatyana E. Kornienko1Alexandra L. Zakharenko2Nina I. Komarova3Chigozie Achara4Jóhannes Reynisson5Nariman F. Salakhutdinov6Olga I. Lavrik7Konstantin P. Volcho8N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, 9, Lavrent’ev Ave., Novosibirsk 630090, RussiaInstitute of Chemical Biology and Fundamental Medicine, SB RAS, 8, Lavrent’ev Ave., Novosibirsk 630090, RussiaInstitute of Chemical Biology and Fundamental Medicine, SB RAS, 8, Lavrent’ev Ave., Novosibirsk 630090, RussiaN.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, 9, Lavrent’ev Ave., Novosibirsk 630090, RussiaSchool of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle-under-Lyme, Staffordshire ST5 5BG, UKSchool of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle-under-Lyme, Staffordshire ST5 5BG, UKN.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, 9, Lavrent’ev Ave., Novosibirsk 630090, RussiaInstitute of Chemical Biology and Fundamental Medicine, SB RAS, 8, Lavrent’ev Ave., Novosibirsk 630090, RussiaN.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, 9, Lavrent’ev Ave., Novosibirsk 630090, RussiaDeoxycholic acid derivatives containing various heterocyclic functional groups at C-3 on the steroid scaffold were designed and synthesized as promising dual tyrosyl-DNA phosphodiesterase 1 and 2 (TDP1 and TDP2) inhibitors, which are potential targets to potentiate topoisomerase poison antitumor therapy. The methyl esters of DCA derivatives with benzothiazole or benzimidazole moieties at C-3 demonstrated promising inhibitory activity in vitro against TDP1 with IC<sub>50</sub> values in the submicromolar range. Furthermore, methyl esters <b>4d</b>–<b>e</b>, as well as their acid counterparts <b>3d</b>–<b>e</b>, inhibited the phosphodiesterase activity of both TDP1 and TDP2. The combinations of compounds <b>3d</b>–<b>e</b> and <b>4d</b>–<b>e</b> with low-toxic concentrations of antitumor drugs topotecan and etoposide showed significantly greater cytotoxicity than the compounds alone. The docking of the derivatives into the binding sites of TDP1 and TDP2 predicted plausible binding modes of the DCA derivatives.https://www.mdpi.com/1420-3049/29/3/581deoxycholic acidoxiranethiolsTDP1 inhibitorTDP2 inhibitorcancer |
| spellingShingle | Oksana V. Salomatina Tatyana E. Kornienko Alexandra L. Zakharenko Nina I. Komarova Chigozie Achara Jóhannes Reynisson Nariman F. Salakhutdinov Olga I. Lavrik Konstantin P. Volcho New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular Modeling Molecules deoxycholic acid oxirane thiols TDP1 inhibitor TDP2 inhibitor cancer |
| title | New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular Modeling |
| title_full | New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular Modeling |
| title_fullStr | New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular Modeling |
| title_full_unstemmed | New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular Modeling |
| title_short | New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular Modeling |
| title_sort | new dual inhibitors of tyrosyl dna phosphodiesterase 1 and 2 based on deoxycholic acid design synthesis cytotoxicity and molecular modeling |
| topic | deoxycholic acid oxirane thiols TDP1 inhibitor TDP2 inhibitor cancer |
| url | https://www.mdpi.com/1420-3049/29/3/581 |
| work_keys_str_mv | AT oksanavsalomatina newdualinhibitorsoftyrosyldnaphosphodiesterase1and2basedondeoxycholicaciddesignsynthesiscytotoxicityandmolecularmodeling AT tatyanaekornienko newdualinhibitorsoftyrosyldnaphosphodiesterase1and2basedondeoxycholicaciddesignsynthesiscytotoxicityandmolecularmodeling AT alexandralzakharenko newdualinhibitorsoftyrosyldnaphosphodiesterase1and2basedondeoxycholicaciddesignsynthesiscytotoxicityandmolecularmodeling AT ninaikomarova newdualinhibitorsoftyrosyldnaphosphodiesterase1and2basedondeoxycholicaciddesignsynthesiscytotoxicityandmolecularmodeling AT chigozieachara newdualinhibitorsoftyrosyldnaphosphodiesterase1and2basedondeoxycholicaciddesignsynthesiscytotoxicityandmolecularmodeling AT johannesreynisson newdualinhibitorsoftyrosyldnaphosphodiesterase1and2basedondeoxycholicaciddesignsynthesiscytotoxicityandmolecularmodeling AT narimanfsalakhutdinov newdualinhibitorsoftyrosyldnaphosphodiesterase1and2basedondeoxycholicaciddesignsynthesiscytotoxicityandmolecularmodeling AT olgailavrik newdualinhibitorsoftyrosyldnaphosphodiesterase1and2basedondeoxycholicaciddesignsynthesiscytotoxicityandmolecularmodeling AT konstantinpvolcho newdualinhibitorsoftyrosyldnaphosphodiesterase1and2basedondeoxycholicaciddesignsynthesiscytotoxicityandmolecularmodeling |