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In situ activation of Pt(IV) to Pt(II) species is a promising strategy to control anticancer activity and overcome off-target toxicity linked to classic platinum chemotherapeutic agents. Herein, we present the design and synthesis of two new asymmetric Pt(IV) derivatives of cisplatin and oxaliplatin (1·TARF and 2·TARF, respectively) bearing a 2',3'...
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... Furthermore, the incorporation of flavins onto hydrogels could be exploited for engineering catalytic delivery devices for cisplatin. 9 In these catalytic reactions (Figure 1), the light-irradiated flavin catalyst is first reduced in the presence of an electron donor (e.g. NADH or ascorbate) to form the doubly reduced flavin hydroquinone FlH2 (or FlH -at pH > 7). ...
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... this contribution, we describe the synthesis, characterization and reactivity of two new flavo-Pt(IV) prodrug complexes of cisplatin and oxaliplatin (Figure 1). For this purpose, we synthesized the Pt(IV) precursors 1 and 2 and their flavin-conjugated version 1•TARF and 2•TARF, whereby a functionalized TARF (2',3',4',5'-tetraacetylriboflavin) is covalently linked to the Pt-coordinated axial succinato ligand. ...
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... included in this work were fully characterized by 1 H, 13 C and 195 Pt-NMR spectroscopy, mass spectrometry and UV-vis (Supporting information section, Figure S1-S14). ...
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... the kinetic inertness of Pt(IV) centers is typically considered a significant improvement compared to Pt(II) analogues for decreasing unwanted side effects. 1 Nevertheless, recent work highlighted that Pt(IV) prodrugs can also hydrolyze relatively rapidly under biologically relevant conditions. 3,29 Therefore, we initially performed a series of 1 H NMR experiments to evaluate the stability of 1•TARF and 2•TARF in methanol and DMSO, finding that both complexes were not decomposing over 48 h ( Figure S15 and S16). We next determined by UV-vis the stability of the two derivatives in aqueous solutions containing DMSO or DMF, since these solvents are commonly used to assist the dissolution of drug candidates in cell studies (vide infra). ...
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... next determined by UV-vis the stability of the two derivatives in aqueous solutions containing DMSO or DMF, since these solvents are commonly used to assist the dissolution of drug candidates in cell studies (vide infra). Under such conditions, no significant changes in the absorption profile were observed for 1•TARF and 2•TARF over 72 h at 310 K ( Figure S17). Similar results were also obtained by dissolving the complexes in RPMI medium and monitoring changes in the UV-vis over 16 h at 310 K ( Figure S18). ...
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... such conditions, no significant changes in the absorption profile were observed for 1•TARF and 2•TARF over 72 h at 310 K ( Figure S17). Similar results were also obtained by dissolving the complexes in RPMI medium and monitoring changes in the UV-vis over 16 h at 310 K ( Figure S18). ...
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... reactivity of the two Pt(IV)-TARF complexes was then evaluated using three reducing agents that are present in the cell milieu ( Figure 3, Figure S19 and S20), NADH, sodium ascorbate, and glutathione (GSH). We co-incubated 1•TARF and 2•TARF (1 mM) with such electron donors (4 mM) in an 8% DMF-d7/D2O mixture, and monitored by 1 H NMR the reductive elimination of the axial acetato ligands from the complexes over time (Figure 3). ...
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... NMR helped characterize the nature of the Pt-species generated by these activation reactions ( Figure 3, Figure S21). We recorded 195 Pt NMR spectra of 1·TARF and 2·TARF (D2O/DMF-d7, 80/20) treated with 4 equivalents of NADH, observing the disappearance of the Pt(IV) peaks of the prodrugs (1089.6 and 1604.5 ppm respectively) and the appearance of new signals in the Pt(II) region corresponding to cisplatin and oxaliplatin (-2149.2 ...
