Half-Sandwich Ru(II) Halogenido, Valproato and 4-Phenylbutyrato Complexes Containing 2,2'-Dipyridylamine: Synthesis, Characterization, Solution Chemistry and In Vitro Cytotoxicity

Abstract

Halogenido and carboxylato Ru(II) half-sandwich complexes of the general composition [Ru(η⁶-p-cym)(dpa)X]PF₆ (1-5) were prepared and thoroughly characterized with various techniques (e.g., mass spectrometry, NMR spectroscopy and X-ray analysis); dpa = 2,2'-dipyridylamine; p-cym = p-cymene; X = Cl^- (for 1), Br^- (for 2), I^- (for 3), valproate(1-) (for 4) or 4-phenylbutyrate(1-) (for 5). A single-crystal X-ray analysis showed a pseudo-octahedral piano-stool geometry of [Ru(η⁶-p-cym)(dpa)I]PF₆ (3), with a η⁶-coordinated p-cymene, bidentate N-donor dpa ligand and iodido ligand coordinated to the Ru(II) atom. The results of the ¹H-NMR solution behaviour studies proved that the complexes 1-5 hydrolyse were in the mixture of solvents used (10% MeOD-d₄/90% D₂O). Complexes 1-5 were in vitro inactive against the A2780 human ovarian carcinoma cell line, up to the highest tested concentration (IC₅₀ > 100 μM).

Keywords: 2,2′-dipyridylamine; X-ray structure; half-sandwich; in vitro cytotoxicity; ruthenium; solution behaviour.

Figure 1

General structural formula of the studied complexes 1–5 given with the atom numbering scheme for the p-cym and dpa ligands; p-cym = p-cymene; dpa = 2,2′-dipyridylamine; X = Cl⁻ (1), Br⁻ (2), I⁻ (3), valproate(1−) (4) or 4-phenylbutyrate(1−) (5).

Figure 2

ESI+ mass spectra of the carboxylato complexes [Ru(η⁶-p-cym)(dpa)(VP)]PF₆ (4; top) and [Ru(η⁶-p-cym)(dpa)(PB)]PF₆ (5; bottom), given with a comparison of the experimental and simulated isotopic distributions of the [Ru(p-cym)(dpa)(VP)]⁺ and [Ru(p-cym)(dpa)(PB)]⁺ species (insets).

Figure 3

¹H-NMR spectra of [Ru(η⁶-p-cym)(dpa)Cl]PF₆ (1; top) and [Ru(η⁶-p-cym)(dpa)VP]PF₆ (4; bottom), given together with the general assignment of the observed signals, as follows; green dots for the dpa signals, blue dots for the p-cym signals and red dots for the VP signals.

Figure 4

Molecular structure of [Ru(η⁶-p-cym)(dpa)I]PF₆ (3). Non-hydrogen atoms are drawn as thermal ellipsoids at the 50% probability level. The PF₆⁻ counterion has been omitted for clarity.

Figure 5

Parts of the ¹H-NMR spectra of complex 1 and its mixture with 2 molar equivalents of the reduced glutathione (GSH), both after 48 h of standing at ambient temperature. ¹H-NMR spectrum of free GSH is given for comparative purposes.

Figure 6

A schema of the hydrolysis of complex [Ru(η⁶-p-cym)(dpa)(VP)]PF₆ (4) given together with the tentative compositions of the hydrolysates, i.e., the [Ru(η⁶-p-cym)(dpa)(H₂O)]²⁺ and [Ru(η⁶-p-cym)(dpa)(OH)]⁺ species (top). ¹H-NMR spectra of the representative signal of the terminal C25–H methyl group of released valproate(1–) anion (ca. 0.78 ppm; red) and the valproato ligand (ca. 0.62 ppm; green), as observed for complex 4, without or with the addition of the reduced glutathione (GSH) at different time points. ¹H-NMR spectrum of free sodium valproate (NaVP) is given for comparative purposes (bottom).

Figure 7

Progress of hydrolysis of the carboxylato complexes 4 (blue) and 5 (dark yellow), with (circles) or without (squares) the addition of 2 molar equivalents of the reduced glutathione (GSH). Complexes were dissolved in 10% MeOD-d₄/90% D₂O and the ¹H-NMR spectra were recorded on the fresh solutions (0 h) and after 0.5, 1, 2, 4, 6, 24 and 48 h of standing at ambient temperature.

Figure 8

Structural formula of the complex cation in [Ru(η⁶-p-cym)(dpa)Cl]PF₆ (1).

Figure 9

Structural formula of the complex cation in [Ru(η⁶-p-cym)(dpa)Br]PF₆ (2).

Figure 10

Structural formula of the complex cation in [Ru(η⁶-p-cym)(dpa)I]PF₆ (3).

Figure 11

Structural formula of the complex cation in [Ru(η⁶-p-cym)(dpa)(VP)]PF₆ (4); VP = valproato(1–).

Figure 12

Structural formula of the complex cation in [Ru(η⁶-p-cym)(dpa)(PB)]PF₆ (5); PB = 4-phenylbutyrato(1–).