Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen Complex
Aiming at reducing the unselective cytotoxicity of Pt(II) chemotherapeutics, a great deal of effort has been concentrated into the design of metal-containing drugs with different anticancer mechanisms of action. Inert Pt(IV) prodrugs have been proposed to be a valid alternative as they are activated...
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MDPI AG
2022-12-01
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| author | Vincenzo Vigna Stefano Scoditti Angelo Spinello Gloria Mazzone Emilia Sicilia |
| author_facet | Vincenzo Vigna Stefano Scoditti Angelo Spinello Gloria Mazzone Emilia Sicilia |
| author_sort | Vincenzo Vigna |
| collection | DOAJ |
| description | Aiming at reducing the unselective cytotoxicity of Pt(II) chemotherapeutics, a great deal of effort has been concentrated into the design of metal-containing drugs with different anticancer mechanisms of action. Inert Pt(IV) prodrugs have been proposed to be a valid alternative as they are activated by reduction directly into the cell releasing active Pt(II) species. On the other hand, a promising strategy for designing metallodrugs is to explore new potential biological targets rather than canonical B-DNA. G-quadruplex nucleic acid, obtained by self-assembly of guanine-rich nucleic acid sequences, has recently been considered an attractive target for anticancer drug design. Therefore, compounds capable of binding and stabilizing this type of DNA structure would be greatly beneficial in anticancer therapy. Here, computational analysis reports the mechanism of action of a recently synthesized Pt(IV)–salphen complex conjugating the inertness of Pt(IV) prodrugs with the ability to bind G-quadruplexes of the corresponding Pt(II) complex. The reduction mechanism of the Pt(IV) complex with a biological reducing agent was investigated in depth by means of DFT, whereas classical MD simulations were carried out to shed light into the binding mechanism of the released Pt(II) complex. The results show that the Pt(IV) prodrug may be reduced by both inner- and outer-sphere mechanisms, and the active Pt(II) complex, as a function of its protonation state, stabilizes the G-quadruplex DNA prevalently, either establishing π-stacking interactions with the terminal G-tetrad or through electrostatic interactions along with H-bonds formation. |
| first_indexed | 2024-03-09T16:20:53Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T16:20:53Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-99d216af8d244ba7970e374388780ddb2023-11-24T15:24:00ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0123241557910.3390/ijms232415579Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen ComplexVincenzo Vigna0Stefano Scoditti1Angelo Spinello2Gloria Mazzone3Emilia Sicilia4Department of Chemistry and Chemical Technologies, Università della Calabria, Via P. Bucci, 87036 Arcavacata di Rende, ItalyDepartment of Chemistry and Chemical Technologies, Università della Calabria, Via P. Bucci, 87036 Arcavacata di Rende, ItalyDipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Viale delle Scienze, Edificio 17, 90128 Palermo, ItalyDepartment of Chemistry and Chemical Technologies, Università della Calabria, Via P. Bucci, 87036 Arcavacata di Rende, ItalyDepartment of Chemistry and Chemical Technologies, Università della Calabria, Via P. Bucci, 87036 Arcavacata di Rende, ItalyAiming at reducing the unselective cytotoxicity of Pt(II) chemotherapeutics, a great deal of effort has been concentrated into the design of metal-containing drugs with different anticancer mechanisms of action. Inert Pt(IV) prodrugs have been proposed to be a valid alternative as they are activated by reduction directly into the cell releasing active Pt(II) species. On the other hand, a promising strategy for designing metallodrugs is to explore new potential biological targets rather than canonical B-DNA. G-quadruplex nucleic acid, obtained by self-assembly of guanine-rich nucleic acid sequences, has recently been considered an attractive target for anticancer drug design. Therefore, compounds capable of binding and stabilizing this type of DNA structure would be greatly beneficial in anticancer therapy. Here, computational analysis reports the mechanism of action of a recently synthesized Pt(IV)–salphen complex conjugating the inertness of Pt(IV) prodrugs with the ability to bind G-quadruplexes of the corresponding Pt(II) complex. The reduction mechanism of the Pt(IV) complex with a biological reducing agent was investigated in depth by means of DFT, whereas classical MD simulations were carried out to shed light into the binding mechanism of the released Pt(II) complex. The results show that the Pt(IV) prodrug may be reduced by both inner- and outer-sphere mechanisms, and the active Pt(II) complex, as a function of its protonation state, stabilizes the G-quadruplex DNA prevalently, either establishing π-stacking interactions with the terminal G-tetrad or through electrostatic interactions along with H-bonds formation.https://www.mdpi.com/1422-0067/23/24/15579Pt(IV) complexesG-quadruplexDFTMD |
| spellingShingle | Vincenzo Vigna Stefano Scoditti Angelo Spinello Gloria Mazzone Emilia Sicilia Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen Complex International Journal of Molecular Sciences Pt(IV) complexes G-quadruplex DFT MD |
| title | Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen Complex |
| title_full | Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen Complex |
| title_fullStr | Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen Complex |
| title_full_unstemmed | Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen Complex |
| title_short | Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen Complex |
| title_sort | anticancer activity reduction mechanism and g quadruplex dna binding of a redox activated platinum iv salphen complex |
| topic | Pt(IV) complexes G-quadruplex DFT MD |
| url | https://www.mdpi.com/1422-0067/23/24/15579 |
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