Pincer‐Based Heterobimetallic Pt(II)/Ru(II), Pt(II)/Ir(III), and Pt(II)/Cu(I) Complexes: Synthesis and Evaluation of Antiproliferative Properties

Abstract

Platinum pincer‐based complexes [(O^N^O)Pt(L)] (L = DMSO, pyridine, triphenylphosphine or 1,3‐dimethylbenzimidazol‐2‐ylidene) carrying an (N^N) coordination site were used as starting materials to synthesize a series of seven cationic heterobimetallic Pt(II)/Ru(II), Pt(II)/Ir(III), and Pt(II)/Cu(I) presenting a [(p‐cymene)RuCl]+, a [(Cp*)IrCl]+ (Cp* = η5‐pentamethylcyclopentadienyl), and a [(NHCiPr)Cu]+ {NHCiPr = 1,3‐bis(2,6‐diisopropylphenyl)imidazole‐2‐ylidene} moiety, respectively. The X‐ray structure of one of the bimetallic Pt(II)/Ir(III) complexes showed a distortion of the organic platform to accommodate the coordination geometry of both metal centers, as already observed for previous Pt(II)/Re(I) complexes. The antiproliferative activity of the complexes was first screened on the triple negative breast cancer cell line MDA‐MB‐231. Then the IC50 of the most active candidates was determined on a wider panel of human cancer cells (MDA‐MB‐231, MCF‐7 and A2780) as well as on a non‐tumorigenic cell line (MCF‐10A). The most toxic compound, namely the Pt(II)/Cu(I) heterobimetallic complex 4c, showed antiproliferative activity down to the nanomolar level.

Metallodrugs in cancer nanomedicine

“…It is not surprising that this versatile Pt(IV) prodrug chemistry has resulted in a considerable number of reported dual, [120][121][122] triple [123][124][125][126][127] and even quadruple 128 action Pt(IV) complexes that aim to interact with multiple cellular targets and processes via a single structure which, once reduced in cancer cells to the active Pt(II), releases the axially bound bioactive scaffolds as well. [129][130][131][132] This approach has even been expanded towards multi-metal compounds for (but not limited to) photo-chemotoxicity (e.g., Pt(IV)-Ru(II) 133 and Pt(IV)-Re(I) 134 ) and theranostic purposes (Gd(III)-Pt(IV) 135 for MRI), which offer higher speciation control over the equatorial modification of Pt(II) compounds (e.g., Pt(II)-Ru(II) 136,137 or Gd(III)-Pt(II) 138 ). This and other potential options for combined therapies by chemical functionalization will be further discussed in Section 2.2.…”

“…, Pt( iv )–Ru( ii ) 133 and Pt( iv )–Re( i ) 134 ) and theranostic purposes (Gd( iii )–Pt( iv ) 135 for MRI), which offer higher speciation control over the equatorial modification of Pt( ii ) compounds ( e.g. , Pt( ii )–Ru( ii ) 136,137 or Gd( iii )–Pt( ii ) 138 ). This and other potential options for combined therapies by chemical functionalization will be further discussed in Section 2.2.…”

Copper(II) complexes with a benzimidazole functionalized Schiff base: Synthesis, crystal structures, and role of ancillary ions in phenoxazinone synthase activity

“…[39][40][41][42] Because copper(II) and benzimidazole play a significant role in many disciplines, it is important to study the copper-benzimidazole interaction, and chemists have made use of this interaction to build up some fascinating classes of molecules that show many interesting properties. [43][44][45] As a part of our interest in developing copper-based coordination compounds for mimicking the bio-inspired oxidation reactions, we report a straightforward synthesis of 1-(4-methoxybenzyl)-2-(4-methoxyphenyl)benzimidazole (L) ligand under ambient conditions. To elucidate the use of such type of ligand in coordination and applied chemistry research field, we have prepared two structurally similar mononuclear copper(II) complexes with L, namely, [Cu(L) 2 Cl 2 ] 2 (1)…”

Platinum-containing heterometallic complexes in cancer therapy: advances and perspectives

“…Most recently, Bertrand et al synthesized a family of pincer-based heterobimetallic Pt( ii )–M complexes [M = Ru( ii ), Ir( iii ), and Cu( i )]. 85 Among them, the Pt( ii )–Cu( i ) complex PtCu 11 (Fig. 14) was the most cytotoxic one with nanomolar to sub-micromolar IC 50 values against a panel of cancer cells including MDA-MB-231, MCF-7, and A2780.…”

“…In the presence of H 2 O 2 , PtCu 10 induced oxidative DNA cleavage, which was identical to the Cu(II) mononuclear complex. In stark con- 85 Among them, the Pt(II)-Cu(I) complex PtCu 11 (Fig. 14) was the most cytotoxic one with nanomolar to submicromolar IC 50 values against a panel of cancer cells including MDA-MB-231, MCF-7, and A2780.…”