Vanadium(IV) Complexes with Methyl-Substituted 8-Hydroxyquinolines: Catalytic Potential in the Oxidation of Hydrocarbons and Alcohols with Peroxides and Biological Activity

Abstract

Methyl-substituted 8-hydroxyquinolines (Hquin) were successfully used to synthetize five-coordinated oxovanadium(IV) complexes: [VO(2,6-(Me)₂-quin)₂] (1), [VO(2,5-(Me)₂-quin)₂] (2) and [VO(2-Me-quin)₂] (3). Complexes 1-3 demonstrated high catalytic activity in the oxidation of hydrocarbons with H₂O₂ in acetonitrile at 50 °C, in the presence of 2-pyrazinecarboxylic acid (PCA) as a cocatalyst. The maximum yield of cyclohexane oxidation products attained was 48%, which is high in the case of the oxidation of saturated hydrocarbons. The reaction leads to the formation of a mixture of cyclohexyl hydroperoxide, cyclohexanol and cyclohexanone. When triphenylphosphine is added, cyclohexyl hydroperoxide is completely converted to cyclohexanol. Consideration of the regio- and bond-selectivity in the oxidation of n-heptane and methylcyclohexane, respectively, indicates that the oxidation proceeds with the participation of free hydroxyl radicals. The complexes show moderate activity in the oxidation of alcohols. Complexes 1 and 2 reduce the viability of colorectal (HCT116) and ovarian (A2780) carcinoma cell lines and of normal dermal fibroblasts without showing a specific selectivity for cancer cell lines. Complex 3 on the other hand, shows a higher cytotoxicity in a colorectal carcinoma cell line (HCT116), a lower cytotoxicity towards normal dermal fibroblasts and no effect in an ovarian carcinoma cell line (order of magnitude HCT116 > fibroblasts > A2780).

Keywords: 8-hydroxyquinoline; biological activity; catalytic properties; cytotoxicity studies; vanadium(IV) complexes.

Figure 1

The molecular structures of 1 [symmetry code: (a) = −x, y, 1/2 − z] (a) and 2 (b). Displacement ellipsoids are drawn at the 50% probability level.

Figure 2

The X-band EPR spectra of 1–3 at 77 K together with the spectrum calculated by computer simulation of the experimental spectra with spin Hamiltonian parameters given in the text.

Figure 3

EPR frozen solution spectra (at 77 K) of compounds 1–3; in aqueous 2% DMSO.

Figure 4

EPR stability spectra (frozen solution at 77 K in aqueous 2% DMSO) of compounds 1–3. Spectra were recorded every for 24 h.

Figure 5

UV–Vis stability spectra in DMSO (10⁻⁴ M) for compounds 1 (a) and 2 (b). Spectra were recorded every 2 h for 24 h.

Figure 6

Oxidation of cyclohexane to cyclohexanol (curves 1 and 3) and cyclohexanone (curve 2) with hydrogen peroxide catalyzed by compound 1 in the presence of PCA (curves 1 and 2) and in the absence of PCA (curve 3). Conditions: cyclohexane (0.46 M); H₂O₂ (2.0 M, 50% aqueous); complex 1 (5 × 10⁻⁴ M); PCA (2 × 10⁻³ M) in MeCN at 50 °C. Concentrations of cyclohexanone and cyclohexanol were measured after reduction of the aliquots with solid PPh₃.

Figure 7

Oxidation of cyclohexane to cyclohexanol (curves 1) and cyclohexanone (curve 2) with hydrogen peroxide catalyzed by compound 1 in the presence of HNO₃. Conditions: cyclohexane (0.46 M); H₂O₂ (2.0 M, 50% aqueous); complex 1 (5 × 10⁻⁴ M); HNO₃ (0.05 M) in MeCN at 50 °C. Concentrations of cyclohexanone and cyclohexanol were measured after reduction of the aliquots with solid PPh₃.

Figure 8

Oxidation of cyclohexane to cyclohexanol (curves 1 and 3) and cyclohexanone (curve 2) with hydrogen peroxide catalyzed by compound 2 in the presence of PCA (curves 1 and 2) and in the absence of PCA (curve 3); symbols marked by the number 4 show the reaction carried out in the absence of PCA and HNO₃. Conditions: cyclohexane (0.46 M); H₂O₂ (2.0 M, 50% aqueous); complex 2 (5 × 10⁻⁴ M); PCA (2 × 10⁻³ M), HNO₃ (0.05 M) in MeCN at 50 °C. Concentrations of cyclohexanone and cyclohexanol were measured after reduction of the aliquots with solid PPh₃.

Figure 9

Accumulation of cyclohexanol (curve 1) and cyclohexanone (curve 2) in the oxidation of cyclohexane (0.46 M) with hydrogen peroxide (2.0 M, 50% aqueous) catalyzed by compound 3 (5 × 10⁻⁴ M); PCA (2 × 10⁻³ M) in MeCN at 50 °C. Concentrations of cyclohexanone and cyclohexanol were measured after reduction of the aliquots with solid PPh₃. The yield of cyclohexane oxidation products was 48%.

Figure 10

Antiproliferative effect of complexes 1–3 in the HCT116 and A2780 cancer cell lines, after 48 h, evaluated by the MTS method. Cell viabilities were normalized to DMSO 0.1% (v/v) (vehicle control). The results presented are mean ± standard deviation of three independent assays. An asterisk indicates a p-value inferior to 0.05.

Figure 11

Internalization of complexes evaluated by the determination of the amount of vanadium (determined by ICP-AES) present in the cellular fraction of HCT116 after exposure of HCT116 cells to 20 × IC₅₀ concentrations of complexes 1–3 for 3 and 6 h at 4 °C and 37 °C. The results presented are mean ± standard deviation of three independent assays.

Figure 12

Apoptosis induction in the HCT116 cell line evaluated by flow cytometry after 48 h exposure to IC₅₀ concentrations of complexes 1–3. DMSO 0.1% (v/v) was used as a negative control and Cisplatin 15 μM was used as a positive control. The results presented are mean ± standard deviation of three independent assays. An asterisk indicates a p-value inferior to 0.05.

Figure 13

Autophagy induction in the HCT116 cell line evaluated by flow cytometry after 48 h exposure to IC₅₀ concentrations of complexes 1–3. DMSO 0.1% (v/v) was used as a negative control and Cisplatin 15 μM and rapamycin 50 nM were used as positive controls. The results presented are mean ± standard deviation of three independent assays. An asterisk indicates a p-value inferior to 0.05.

Figure 14

Intracellular ROS production in the HCT116 cell line after 48 h exposure to IC₅₀ concentrations of complexes 1–3, evaluated by flow cytometry. DMSO 0.1% (v/v) was used as a negative control and Cisplatin 15 μM and H₂O₂ 50 μM were used as positive controls. The results presented are mean ± standard deviation of three independent assays. An asterisk indicates a p-value inferior to 0.05.

Figure 15

Alterations of the mitochondrial membrane potential in the HCT116 cell line after 48 h exposure to IC₅₀ concentrations of complexes 1–3, evaluated by flow cytometry. DMSO 0.1% (v/v) was used as a negative control and Cisplatin 15 μM was used as a positive control. The results presented are mean ± standard deviation of three independent assays.

Figure 16

Accumulation of cyclohexanol and cyclohexanone in the oxidation of cyclohexane (0.46 M) with H₂O₂ (2.0 M) catalyzed by complex 2 (5 × 10⁻⁴ M) at 50 °C in acetonitrile. Concentrations of products were measured by GC before (Graph (A)) and after (Graph (B)) the reduction of the reaction samples with solid PPh₃.