Dendritic Pyridine-Imine Copper Complexes as Metallo-Drugs

Abstract

Since the discovery of cisplatin in the 1960s, the search for metallo-drugs that are more efficient than platinum complexes with negligible side effects has attracted much interest. Among the other metals that have been examined for potential applications as anticancer agents is copper. The interest in copper was recently boosted by the discovery of cuproptosis, a recently evidenced form of cell death mediated by copper. However, copper is also known to induce the proliferation of cancer cells. In view of these contradictory results, there is a need to find the most suitable copper chelators, among which Schiff-based derivatives offer a wide range of possibilities. Gathering several metal complexes in a single, larger entity may provide enhanced properties. Among the nanometric objects suitable for such purpose are dendrimers, precisely engineered hyperbranched macromolecules, which are outstanding candidates for improving therapy and diagnosis. In this review article, we present an overview of the use of a particular Schiff base, namely pyridine-imine, linked to the surface of dendrimers, suitable for complexing copper, and the use of such dendrimer complexes in biology, in particular against cancers.

Keywords: PAMAM; Schiff base; cancer; carbosilane; copper; dendrimer; metallo-drugs; phosphorus; pyridine–imine.

Figure 1

Copper complex of the generation 0 PAMAM dendrimer functionalized with four pyridine–imine groups.

Figure 2

Phosphorus dendrimers from generations 1 to 3 functionalized with three types of pyridine–imine ligands and complexes and the corresponding monomers. Only the full structure of the first generation functionalized with N-(pyridin-2-ylmethylene) ethanamine ligand is shown. All the other dendrimers are represented in a linear form, with parenthesis after each branching point.

Figure 3

Percentage of inhibition of the proliferation of the HL60 cell line at 1 µM of all compounds from series 2-compounds.

Figure 4

Percentage of inhibition at 1 µM of the proliferation of the KB and HL60 cell lines at 1 µM of the third-generation dendrimers with either free or complexing CuCl₂.

Figure 5

IC₅₀ of free (2-G₃) and complexed dendrimer (2-G₃-Cu₄₈) in six cancerous cell lines (left part) and two non-cancerous cell lines (right part).

Figure 6

Random functionalization on the surface of the third-generation dendrimers, with polyethylene glycol (PEG) moieties, copper and gold complexes, and eventually free pyridine–imine ligands.

Figure 7

IC₅₀ values of four dendrimeric complexes functionalized with copper (red), gold (brown), or a mixture of both metals and free pyridine–imine (blue) or PEG (green) toward cancerous cells (KB and HL60) and non-cancerous cells (EPC and MRC5).

Figure 8

First-generation dendrons bearing a C₁₁ or C₁₇ alkyl chain at the core and complexing either copper or gold on the surface.

Figure 9

IC₅₀ values of the dendrons shown in Figure 8 towards cancerous (4T1 and MCF-7) and non-cancerous (NIH-3T3 and MRC5) cell lines.

Figure 10

Three series of dendrons bearing diverse types of pyridine–imine/hydrazone derivatives on the surface and a reactive group at the core. Evaluation of their toxicity at 10⁻⁵ M.

Figure 11

Illustration of the grafting of dendrons onto graphene oxide (GO) by click chemistry.

Figure 12

Generation zero dendrons bearing two alkyl chains at the core and five copper or gold complexes on the surface.

Figure 13

Comparison of viability of SF188 cells in the presence of either 9-G₀-Cu₅ or 9-G₀-[Au₅][AuCl₄]₅ compared to temozolomide, the clinical standard. NTC, non-treated control.

Figure 14

Generations zero and one carbosilane dendrimers functionalized with copper complexes of pyridine–imine.

Figure 15

IC₅₀ values of carbosilane dendrimers towards cancerous cell lines (left) and healthy cell lines (right).

Figure 16

MCF-7 cell viability in the presence of methotrexate (MTX) alone, dendrimers alone, or combination of methotrexate and dendrimers.

Figure 17

IC₅₀ of the functionalized carbosilane dendrimer complexes against HeLa and MCF-7 cell lines.