How to obtain Pt(iv) complexes suitable for conjugation to nanovectors from the oxidation of [PtCl(terpyridine)]⁺

Abstract

Oxidation of [PtCl(terpy)] (terpy = 2,2':6',2''-terpyridine) has been attempted with several oxidizing agents and under different experimental conditions in order to obtain a Pt(iv) complex suitable for the conjugation to nanovectors to be used in drug delivery targeting for anticancer therapy. The best compromise in terms of yield and purity of the final complex was obtained by microwave-assisted reaction at 70 °C in 50% aqueous HO for 2 h. Under these conditions the quantitative formation of [PtCl(OH)(terpy)] was observed. The subsequent synthetic steps were, (i) functionalization of [PtCl(OH)(terpy)] in the axial position with succinic anhydride to obtain [PtCl(OH)(succinato)(terpy)] and (ii) reaction of the latter with nonporous silica nanoparticles (SNPs) with an external shell containing primary amino groups to obtain a nanovector able to transport the Pt(iv) antitumor prodrug in the form of a conjugate Pt-SNP. Finally, the antiproliferative activity and cell accumulation of [PtCl(terpy)], [PtCl(OH)(terpy)], and the Pt-SNP conjugate were measured on three cancer cell lines. Despite highly effective accumulation of Pt-SNP in cells, a modest increase in activity was observed with respect to the molecular species. Further experiments showed that the Pt-SNP conjugate can release [PtCl(terpy)] upon reduction, but this metabolite may undergo hydrolysis, and the resulting aquo complex could coordinate once again the free amino groups of the SNPs. In the resulting tetraamine form, the Pt(ii) complex conjugated to the SNPs cannot completely perform its antiproliferative activity.

Bis‐conjugation of Bioactive Molecules to Cisplatin‐like Complexes through (2,2′‐Bipyridine)‐4,4′‐Dicarboxylic Acid with Optimal Cytotoxicity Profile Provided by the Combination Ethacrynic Acid/Flurbiprofen

“…The isolated product does not apparently differ from that obtained by using acetone as solvent (see above),according to analytical and spectroscopic analyses, but is soluble in CH 2 Cl 2 and CHCl 3 besides DMSO and DMF. Other procedures, that is, the reactions of L EB with [PtCl 2 (COD)] [37] and [Bu 4 N] 2 [PtCl 4 ], [38] were not satisfactory.…”

Ligand Evolution in the Photoactivatable Platinum(IV) Anticancer Prodrugs

“… Chemical structure of complexes 44 – 47 [adapted from Kasparkova et al (2015 ); Gabano et al (2017 ); Canil et al (2019 )]. …”

“…Following the synthesis of Pt(IV) complexes containing pyridine ligand, terpyridine-based Pt(IV) prodrugs have also been synthesized and reported. For example, Ravera et al synthesized a terpyridine-based Pt(IV) prodrug, [Pt (IV) Cl(OH) 2 (terpy)] + ( 45 ) ( Gabano et al, 2017 ). This complex is likely a precursor or an intermediate linking to nanoporous silica nanoparticles, of which the IC 50 s against A2780 (7.01 ± 0.56 μM) and sarcomatoid MM98 (10.5 ± 0.1 μM) cell lines are higher than those of cisplatin toward the same cell lines (0.5 ± 0.1 μM and 3.2 ± 1.0 μM, respectively), while its IC 50 toward cisplatin-resistant MM98R subline (8.09 ± 0.91 μM) is lower than that of cisplatin (19.4 ± 2.8 μM).…”

Three Reactions, One Catalyst: A Multi‐Purpose Platinum(IV) Complex and its Silica‐Supported Homologue for Environmentally Friendly Processes

“…Generally, Pt(IV) complexes are considered to have higher kinetic inertness due to their octahedral geometry and low‐spin d 6 electronic configuration and reduced side reactions with biomolecules, although exceptions were noticed . The synthesis, structure, anti‐tumor activity and mechanism of DNA binding of Pt complexes based on amino and pyridine ligands have been widely investigated …”

“…[27] The synthesis, structure, anti-tumor activity and mechanism of DNA binding of Pt complexes based on amino and pyridine ligands have been widely investigated. [28][29][30][31][32][33][34] Comparatively, platinum complexes with siloxane ligands are scarcely represented in the literature. [35][36][37][38][39] However, as mentioned, one of them (Karstedt's catalyst) is commonly known as one of the most powerful hydrosilylation catalysts, with industrial applications.…”