Biological activities of polypyridyl-type ligands: implications for bioinorganic chemistry and light-activated metal complexes

Abstract

Polypyridyl coordinating ligands are common in metal complexes used in medicinal inorganic chemistry. These ligands possess intrinsic cytotoxicity, but detailed data on this phenomenon are sparse, and cytotoxicity values vary widely and are often irreproducible. To provide new insights into the biological effects of bipyridyl-type ligands and structurally related metal-binding systems, reports of free ligand cytotoxicity were reviewed. The cytotoxicity of 25 derivatives of 2,2'-bipyridine and 1,10-phenanthroline demonstrates that there is no correlation between IC₅₀ values and ligand properties such as pKa, log D, polarizability volume, and electron density, as indicated by NMR shifts. As a result of these observations, as well as the various reported mechanisms of action of polypyridyl ligands, we offer the hypothesis that biological effects are governed by the availability of and affinity for specific metal ions within the experimental model.

Keywords: 1,10-Phenanthroline; Chemotherapy; Copper; Iron; Ligand; Natural products; Polypyridyl; Ruthenium.

Figure 1.. A) Timeline of studies on cytotoxic effects of bidentate polypyridyl ligands. B) and C) Bidentate free ligands discussed in this study.A)

2,2′-bipyridine (1) and derivative compounds 2–14 (blue). C) 1,10-phenanthroline (15) and derivative compounds 16–25 (red). IC₅₀ values (μM) in HL60 cells are included below compound numbers. The numbering schemes for 2,2′-bipyridine and 1,10-phenanthroline (red labels) and ¹³C-NMR (blue labels) are included (bottom-right inlay).

Figure 2.. Proposed model of ligand induced cell death mechanisms.

Ortho-substituted ligands induce cell death. An apoptotic mechanism (top right), driven by ROS production and DNA damage, may compete simultaneously or in a [Cu] dependent manner with a paraptotic mechanism (top left), driven by the unfolded protein response, endoplasmic reticulum stress, and caspase inhibition. A metal-depletion-type mechanism (bottom) is hypothesized for unsubstituted systems.

Figure 3.. The effect of trace copper contaminants on ligand cytotoxicity.

A. Cu homeostasis is strictly controlled to maintain cell health. Homeostasis is perturbed in the presence of a ligand, and cells experience the cytotoxic effect of Cu overload. B. Cytotoxicity values for 8 from 22 independent experiments collected in our laboratory over two months. Previously published A549 data are included as red triangles.[70, 90] C. In the absence of ligand, Cu levels in different batches of reagents vary but remain below the cytotoxic threshold. In the presence of an ionophoric ligand, different batches of media or FBS elicit cytotoxicity proportional to the metal concentration.

Chart 1.. Structures of various compounds investigated with different mechanisms of action.

Colchicine (26) and Windaus’ Colchicine (27); Terpyridine (28), is cytotoxic with an IC₅₀ of 2 μM[24]; Phendione (29) and Cuproinedione (30), which mediate Cu import, and perturb the GSH redox buffer[3]; 2,9-disecbutyl-1,10-phenanthroline (SBP) (31); Cu-pyrrolidine dithiocarbamate (32) and Hinokitiol (33) are ionophores that interfere with the ubiquitin-proteasome system[25, 26]; A Cu complex that activates the paraptotic pathway (34) [27]; c-Myc modulating compounds 35[28], APTO-253 (36), and Fe(APTO-253)₃ (37). Ruthenium complexes: [Ru(bpy)2dmbpy]²⁺ (38); [Ru(dmphen)₂]²⁺ scaffold (39); the third ligand can be any bidentate system; complexes 40–47; [Ru(dmbpy)₂]²⁺ scaffold containing a 1H-imidazo[4,5-f][1,10]phenanthroline ligand appended to various conjugated groups (48–52); [Ru(phen)₂dppz]²⁺ (53). The coordinating atoms of key ligands are highlighted by color.