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Article

Ruthenium-p-Cymene Complexes Incorporating Substituted Pyridine–Quinoline Ligands with –Br (Br-Qpy) and –Phenoxy (OH-Ph-Qpy) Groups for Cytotoxicity and Catalytic Transfer Hydrogenation Studies: Synthesis and Characterization

by
Alexandros Dritsopoulos
1,
Nikolaos Zacharopoulos
1,2,
Aigli-Eleonora Peyret
1,
Eftychia Karampella
1,
Nikolaos Tsoureas
1,
Antigoni Cheilari
3,
Christina Machalia
4,
Evangelia Emmanouilidou
4,
Aikaterini K. Andreopoulou
5,
Joannis K. Kallitsis
5 and
Athanassios I. Philippopoulos
1,*
1
Laboratory of Inorganic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
2
Department of Industrial Design and Production Engineering, School of Engineering, University of West Attica, Campus 2 Thivon 250, 12244 Aigaleo, Greece
3
Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
4
Laboratory of Biochemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
5
Department of Chemistry, University of Patras, 26504 Patras, Greece
*
Author to whom correspondence should be addressed.
Chemistry 2024, 6(4), 773-793; https://doi.org/10.3390/chemistry6040046 (registering DOI)
Submission received: 19 July 2024 / Revised: 15 August 2024 / Accepted: 16 August 2024 / Published: 21 August 2024
(This article belongs to the Section Inorganic and Solid State Chemistry)
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Versions Notes

Abstract

:
Organometallic ruthenium complexes with p-cymene = 1-methyl-4-(1-methylethyl)-benzene and N^N = bidentate polypyridyl ligands constitute interesting candidates with biological and catalytic properties. Towards this aim, we have synthesized four ruthenium(II)–arene complexes of the type [Ru(η6-p-cymene)(N^N)Cl][X] (N^N = Br-Qpy = 6-bromo-4-phenyl-2-pyridin-2-yl-quinoline, X = Cl− (1a); PF6− (1b); N^N = OH-Ph-Qpy = 4-(4-phenyl-2-(pyridin-2-yl)quinolin-6-yl)phenol, X = Cl− (2a); PF6− (2b)). This is the first report of ruthenium(II) p-cymene complexes incorporating substituted pyridine–quinoline ligands, with –Br and –C6H4OH groups in the 6-position of quinoline. We also refer to the cytotoxicity of the ligands and their possible effect of modulating the activity of the ruthenium(II) complexes. These were characterized by a combination of spectroscopic methods (ATR-IR, UV–Vis, multinuclear NMR), elemental analysis, and conductivity measurements. The solid-state structure of 2b, determined by single-crystal X-ray diffraction, reveals a three-legged piano-stool geometry. The in vitro cytotoxic activities of the new complexes were evaluated in HEK293T (human embryonic kidney cells) and in HeLa cells (cervical cancer cells), via the MTT assay. Poor in vitro anticancer activities were observed for the HeLa cancer cell line, with 2a being the most potent (IC50 = 75 μΜ). The cytotoxicity of Br-Qpy in HEK293T is comparable to that of cisplatin. Both complexes 1a and 1b successfully catalyze the transfer hydrogenation of benzophenone to benzhydrol by 2-propanol at 82 °C. The catalytic performance of 1a in the ratio of S:Cat:B = 400:1:40 (S = substrate, Cat = catalyst, B = base = KOiPr) leads to a conversion of 94%, within 3 h of reaction. Presumably, catalytic transformation takes place via ruthenium(II) hydride species being the active catalyst.

Graphical Abstract

1. Introduction

Over the last few decades, interest in ruthenium chemistry has remained constant, which can be mainly attributed to the important applications of the ruthenium complexes in different scientific domains, which span from biology [1], the development of new anticancer drugs [2,3,4,5,6], catalysis [7,8], photovoltaic devices [9], their use as photosensitizers in photo-redox processes [10], and photodynamic therapy [11]. More specifically, in the field of bioinorganic chemistry, ruthenium compounds are promising candidates of non-platinum agents, in efforts to overcome toxicity problems reported for the standard platinum drugs, such as nephrotoxicity [12], neurotoxicity [13], and nausea [14]. Generally, ruthenium complexes display lower systemic toxicity compared to the platinum congeners, and they have the possibility to obtain a wide range of oxidation states and comparable ligand exchange rates as for the platinum complexes [15]. Representative anticancer ruthenium complexes constitute the imidazolium and indazolium salts termed as NAMI-A (imidazolium trans-[tetrachloro(dimethylsulfoxide)imidazole ruthenium(III)]) and KP-1019 (indazolium trans-[tetrachlorobis(1H-indazole)ruthenium(III)]), respectively, which have successfully entered through phase I clinical trials [16,17] (Figure 1a). Although NAMI-A and KP-1019 display very similar structural characteristics, the pharmacological profile of both complexes is different, as expressed, for example, by the different in vitro and in vivo activities. Interestingly, NAMI-A entered phase II trials, but it did not proceed further for clinical development [18,19]. On the other hand, NKP-1339, the sodium salt of KP-1019, which shows higher aqueous solubility, has successfully entered early phase II clinical trials [20]. Searching for new ruthenium candidates with improved biological activities, organometallic half-sandwich complexes that contain the [Ru(p-cymene)Cl]+ or [Ru(p-cymene)]2+ core (p-cymene = 1-methyl-4-(1-methylethyl)-benzene) can be considered as alternatives to the classic platinum-based drugs [21,22,23]. Within the series of the complexes that have been studied, RAPTA-C, the [(η6-p-MeC6H4Pri)Ru(p-pta)Cl2] complex, where pta stands for 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1], developed from Dyson’s laboratory [24], is very active in vivo, inhibiting lung metastases in CBA mice, such as the antimetastatic agent NAMI-A [25].
Applications of ruthenium complexes in homogeneous catalysis for important chemical transformations, like C-H activation [29], C-C bond formation [30], olefin metathesis [31], and degradation of dyes [32], have also been reported. Additionally, they have been used as catalysts for classic hydrogenation or transfer hydrogenation reactions, a research topic with high impact, especially for the chemical industry [33]. Transfer hydrogenation (TH) is an eco-benign method that generally proceeds under relatively mild conditions (Figure 1b). It is a very powerful method alternative to standard hydrogenation, providing several important chemicals (hydrogenated compounds). In this process, the use of hazardous molecular hydrogen gas is not required, and a hydrogen donor (mainly 2-propanol or formic acid) is utilized as a sacrificial hydrogen source and a reaction medium [34,35,36,37]. In addition, the catalysts used generally are not air sensitive and are readily available. Interest in the mechanism describing this process has led to inner sphere and the outer sphere mechanisms. These are differentiated based on the substrate’s interaction with the metal center [34]. Among the plethora of metal complexes examined, those of ruthenium(II) constitute interesting examples of well-described catalyst precursors (Figure 1b). Moreover, recent reports have demonstrated the cytotoxicity and catalytic transfer hydrogenation studies of ruthenium–arene complexes, highlighting the research interest related to this class of compounds [38].
This study focuses to the synthesis, characterization, and investigation of the biological and catalytic properties of [Ru(N^N)(p-cymene)Cl][X] (N^N = Br-Qpy, X = Cl− (1a); PF6− (1b); N^N = OH-Ph-Qpy, X = Cl− (2a); PF6− (2b)) complexes incorporating substituted pyridine–quinoline ligands, where N^N stands for 6-bromo-4-phenyl-2-pyridin-2-yl-quinoline (Br-Qpy) and 4-(4-phenyl-2-(pyridin-2-yl)quinolin-6-yl)phenol (OH-Ph-Qpy), respectively. This is the first report of ruthenium complexes with Br-Qpy and OH-Ph-Qpy ligands, which display dual catalytic and biologic activities. In addition, the cytotoxicity properties of both ligands are reported for the first time. The choice of the ligands is mainly based on our previous knowledge and experience with pyridine–quinoline ligands [39,40] and in particular with the present ligands, where they have been successfully incorporated into a rhodium(III) center [41]. Therefore, the ruthenium(II) complexes reported herein, with substituted pyridine–quinoline ligands tethered by –Br and –C6H4OH groups in the 6-position of quinoline ring, will be potentially added to the relatively small number of coordination compounds bearing this fascinating class of organic ligand precursors.

2. Materials and Methods

All complexes described were synthesized according to standard Schlenk techniques and under an argon atmosphere. The synthesis of the organic ligands was performed under aerobic conditions. Analytical grade solvents were used, which were distilled and dried before use according to standard methods. The starting materials RuCl3∙H2O and α-terpinene were purchased from Riedel de Haën and Sigma-Aldrich, respectively. The ligand precursors 6-bromo-4-phenyl-2-pyridin-2-yl-quinoline (Br-Qpy), 4-(4-phenyl-2-(pyridin-2-yl)quinolin-6-yl)phenol (OH-Ph-Qpy) [41], and 4-carboxy-2-(pyridin-2-yl)quinoline (pqca) [42,43] were prepared according to the published procedures. The ruthenium(II) precursor [Ru(η6-p-cymene)(μ-Cl)Cl]2 was synthesized according to a published method [41,44]. Details regarding the instrumentation used in this study (FT-IR, NMR, UV–VIS, X-ray diffraction, melting point, and conductivemeter) are described in our recent report [45].

2.1. Synthesis and Characterization

2.1.1. Synthesis of [Ru(η6-p-cymene)(Br-Qpy)Cl][Cl] (1a)

In a Schleck tube and under an argon atmosphere, [Ru(η6-p-cymene)(μ-Cl)Cl]2 (62 mg, 0.101 mmol) and Br-pqy ligand (77 mg, 0.213 mmol) were mixed, and the solids were dried for approximately 10 min. Dry acetone (10 mL) was added, and the mixture was stirred for approximately 4 h to a gentle reflux. After cooling at ambient temperature, the orange suspension was stirred further overnight to ensure completion of the reaction. After filtration (in the air), the orange solid was washed with acetone (2 × 5 mL) and subsequently with diethyl ether (3 × 5 mL). The orange solid was dried in a desiccator over P2O5 and then in vacuo at 60 °C. Yield: 111 mg (85%). m.p. > 203 °C. (thermally stable). Anal. Calcd for C31H30BrCl2N2Ru∙0.03(Me2CO)∙2(H2O): C, 51.82; H, 4.77; N, 3.90. Found: C, 51.49; H, 4.36; N, 3.85%. FT-IR (ATR mode): FT-IR (ATR mode): ν[cm−1] = 3060(m), 3018 [ν(C-H)arom)], 2966(w) and 2872(w) [ν(C-H)aliph], 1606(s) and 1592(s) [δ(O-H) overlapped with [ν(C=C)], 1478(vs) [ν(C=N)], 1374(m), 1125(m) [ν(C-Br)], 797(w) [ν(Ru-C)], 785(s) and 714(m) [δ(C-H) out of plane]. UV–Vis (DMSO, λmax, nm, 8.1 × 10−6 M): 427 (ε = 4700 M−1 cm−1), 362 (ε = 14,600 M−1 cm−1), 305 (ε = 23,400 M−1 cm−1), 273 (ε = 23,900 M−1 cm−1). UV–Vis (H2O, λmax, nm, 10−5 M): 358 (ε = 24,600 M−1 cm−1), 345 sh (ε = 2970 M−1 cm−1), 295 (ε = 39,700 M−1 cm−1), 263 (ε = 35,600 M−1 cm−1), 243 sh (ε = 20,710 M−1 cm−1), 218 sh (ε = 43,800 M−1 cm−1). Λ(DMSO): 49 S cm2 mol−1. 1H NMR (DMSO-d6, 500 MHz, 298 K): δ 0.82 (t, J = 8.0, 6H, CH(CH3)2), 2.08 (s, 0.03H, CH3 of acetone), 2.25 (s, 3H, CH3-cym), 2.30 (sept, J = 4.0, 1H, CH(CH3)2 overlapped with CH3-cym), 6.03 (d, J = 5.0, 1H, H-cymar), 6.07 (d, J = 5.0, 1H, H-cymar), 6.14 (d, J = 5, 1H, H-cymar), 6.20 (d, J = 5.0, 1H, H-cymar), 7.71 (m, 5H, H9-H14), 7.91 (td, J = 5.0 and 10.0, 1H, H5′), 8.09 (s, 1H, H5), 8.25 (dd, J = 5.0, 1H, H7), 8.37 (t, J = 5.0 and 10.0, 1H, H4′), 8.76 (s, 1H, H3), 8.83 (d, J = 10.0, 1H, H8), 9.01 (d, J = 5.0, 1H, H3′), 9.60 (d, J = 5.0, 1H, H6′). 13C{1H} NMR (DMSO-d6, 125.75 MHz,) δC/ppm 18.28 (CH3-cym), 21.38 (CH-(CH3)2), 21.58 (CH-(CH3)2), 30.30 (CH-(CH3)2), 83.97 (C-Ccym-ar), 85.03 (C-Ccym-ar), 85.99 (C-Ccym-ar), 87.34 (C-Ccym-ar), 104.42 (Ccym-CH-(CH3)2), 104.88 (CH3-Ccym), 120.44 (C3), 123.25 (C8a), 125.94 (C3′), 128.11 (C5), 128.36 (C5′) 128.42 (C4a), 129.13 (C10/C14), 129.89 (C11/C13), 130.00 (C12), 132.65 (C8), 135.01 (C9), 135.32 (C7), 140.10 (C4′), 147.81 (C2′), 151.03 (C4), 154.51 (C2), 155.85 (C6), 156.44 (C6′).

2.1.2. Synthesis of [Ru(η6-p-cymene)(Br-Qpy)Cl][PF6] (1b)

Under aerobic conditions, the chlorido complex 1a (68 mg, 0.102 mmol) was dissolved in the minimum amount of water (5 mL), and a saturated aqueous solution of KPF6 (aq) was added (some drops). A yellow solid started to precipitate, and the mixture was stirred for approximately 1 h to ensure completion of the reaction. The yellow solid was filtered off and was washed subsequently with water (2 × 5 mL) and diethyl ether (2 × 5 mL) and dried in vacuo at 60 °C. Finally, the solid was dried in a desiccator over P2O5. Yield: 72 mg (91%). m.p. = 187 °C (dec). Anal. Calcd for C30H27BrClF6N2PRu: C, 46.38; H, 3.50; N, 3.61. Found: C, 45.94; H, 3.94; N, 3.66%. FT-IR (ATR mode): ν[cm−1] = 3083(w) [ν(C-H)arom)], 2967(m) and 2874(m) [ν(C-H)aliph], 1592(s) [ν(C=C)], 1478(vs) [ν(C=N)], 1125(m) [ν(C-Br)], 831(vs) [ν(P–F)], 783(s) and 702(s) [δ(C-H) out of plane], 555(s) [ν(P–F)]. UV–Vis (DMSO, λmax, nm, 8.1 × 10−6 M): 424 (ε = 4300 M−1 cm−1), 362 (ε = 16,600 M−1 cm−1), 346 (ε = 13,900), 306 (ε = 26,000), 274 sh (ε = 24,700). Λ(Me2CO): 150 S cm2 mol−1. 1H NMR (acetone-d6, 500 MHz, 298 K): 0.98 (d, J = 7.0, 3H, (CH(CH3)2), 1.00 (d, J = 7.0, 3H (CH(CH3)2), 2.33 (s, 3H, CH3-cym), 2.52 (sept, J = 7.0, 1H, CH(CH3)2, 6.06 (d, J = 7.0, 1H, H-cymar), 6.11 (d, J = 7.0, 1H, H-cymar), 6.13 (d, J = 7.0, 1H, H-cymar), 6.22 (d, J = 7.0, 1H, H-cymar), 7.72 (m, 3H, H11/H12/H13), 7.77 (m, 2H, H10/H14), 7.93 (t, J = 7.0, 1H, H5′), 8.21 (m, 2H, H5/H7), 8.41 (t, J = 7.0, 1H, H4′), 8.69 (s, 1H, H3), 8.97 (d, J = 7.0, 1H, H3′), 9.03 (d, J = 7.0, 1H, H8), 9.64 (d, J = 7.0, 1H, H6′). 13C{1H} NMR (125 MHz, acetone-d6, 298 K): 18.73 (CH3-cym), 21.96 (CH-(CH3)2), 22.32 (CH-(CH3)2), 31.81 (CH-(CH3)2), 85.93 (C-Ccym-ar), 86.75 (C-Ccym-ar), 86.78 (C-Ccym-ar), 87.91 (C-Ccym-ar), 105.45 (Ccym-CH-(CH3)2), 107.07 (CH3-Ccym), 121,35 (C3), 124.45 (C8a), 126.57 (C3′), 129.31 (C5′), 129.88 (C5), 130.02 (C12), 130.10 (C11/C13), 130.74 (C10/C14), 130.95 (C4a), 133.55 (C8), 136.30 (C7), 136.42 (C4), 141.06 (C4′), 152.86 (C9), 156.10 (C2′), 157.06 (C6), 157.27 (C6′).

2.1.3. Synthesis of [Ru(η6-p-cymene)(OH-Ph-Qpy)Cl][Cl] (2a)

In a Schleck tube and under an argon atmosphere, equivalent amounts of [Ru(η6-p-cymene)(μ-Cl)Cl]2 (50 mg, 0.082 mmol) and OH-Ph-pqy ligand (64 mg, 0.183 mmol) were mixed. An amount of 10 mL of dry acetone was added, and the orange-red suspension was stirred for approximately 4 h to a gentle reflux. After cooling at ambient temperature, the clear yellow solid was filtered off (in the air), washed with acetone (2 × 10 mL), and subsequently with diethyl ether (2 × 5 mL). The yellow solid was dried in a desiccator over P2O5 and in vacuo at 60 °C. Yield: 88 mg (79%). m.p. > 202 °C. (thermally stable). Anal. Calcd for C37H35Cl2N2ORu∙0.1(Me2CO)∙(H2O): C, 61.82; H, 5.27; N, 3.89. Found: C, 61.60; H, 5.16; N, 3.88%. FT-IR (ATR mode): ν[cm−1] = 3352(m) [ν(O-H)phenol)], 3056(m) [ν(C-H)arom)], 2966(m) and 2888(m) [ν(C-H)aliph], 1610(s) and 1588(s) [δ(O-H) overlapped with ν(C=C)], 1519(m), 1480(vs) [ν(C=N)], 1278(m) [δ(O-H) phenol], 1179 (m) [ν(C-O)phenol], 793(w) [ν(Ru-C)], 764(vs) and 703(s) [δ(C-H) out of plane], 531(m). UV–Vis (DMSO, λmax, nm, 8.5 × 10−6 M): 403 (ε = 16,900 M−1 cm−1), 315 (ε = 37,000 M−1 cm−1). UV–Vis (H2O, λmax, nm, 10−5 M): 385 (ε = 17,400 M−1 cm−1), 309 (ε = 41,400 M−1 cm−1). Λ(DMSO): 26 S cm2 mol−1. 1H-NMR (DMSO-d6, 500 MHz, 298 K),δ(ppm): δ 0.85 (d, J = 10.0, 3H, CH(CH3)2,), 0.83 (d, J = 10.0, 3H, CH(CH3)2,), 2.08 (s, 0.1H, CH3 of acetone), 2.27 (s, 3H, CH3-cym), 2.31 (sept, J = 5.0, 1H, CH(CH3)2 overlapped with CH3-cym), 6.03 (d, J = 10.0, 1H, H-cymar), 6.06 (d, J = 10.0, 1H, H-cymar), 6.14 (d, J = 8.0, 1H, H-cymar), 6.19 (d, J = 4.0, 1H, H-cymar), 6.95 (d, J = 8.0, 2H, H16/H20), 7.60 (d, J = 8.0, 2H, H17/H19), 7.70 (m, 3H, H11/H12/H13), 7.80 (d, J = 8.0, 2H, H10/H14), 7.88 (t, J = 8.0, 1H, H5′), 8.08 (s, 1H, H5), 8.35 (td, J = 4.0 and 8.0, 1H, H4′), 8.40 (dd, J = 4.0 and 12.0, 1H, H7), 8.69 (s, 1H, H3), 8.91 (d, J = 8.0, 1H, H8), 8.98 (d, J = 8.0, 1H, H3′), 9.59 (d, J = 4.0, 1H, H6′), 9.94 (br.s, 1H, OH). 13C{1H} NMR (DMSO-d6, 125.75 MHz) δC/ppm 18.30 (CH3-cym), 21.29 (CH-(CH3)2), 21.69 (CH-(CH3)2), 30.38 (CH-(CH3)2), 84.11 (C-Ccym-ar), 85.15 (C-Ccym-ar), 85.91 (C-Ccym-ar), 87.30 (C-Ccym-ar), 104.20 (Ccym-CH-(CH3)2), 104.57 (CH3-Ccym), 116.33 (C17/C21), 119.86 (C3), 121.62 (C5), 125.45 (C7), 127.63 (C13), 128.02 (C16), 128.46 (C18/C20), 128.78 (C6), 129.08 (C12/C14), 129.76 (C10), 129.93 (C15/C17), 131.10 (C3′), 135.66 (C4a), 140.02 (C4′), 141.04 (C5′), 148.05 (C2′), 151.61 (C4), 154.66 (C8a), 154.92 (C2), 156.30 (C19), 158.48 C6′), 158.50 (C8).

2.1.4. Synthesis of [Ru(η6-p-cymene)(OH-Ph-Qpy)Cl][PF6] (2b)

The synthesis of 2b was performed in a similar way to that reported for complex 1b, including drying of the relevant compound. The only difference is that after the addition of the saturated KPF6(aq) solution, the mixture was stirred further for approximately 3 h. Yield: 70 mg (92%). m.p. = 198 °C (dec). Anal. Calcd for C35H32ClF6N2ORPu: C, 54.02; H, 4.14; N, 3.60. Found: C, 53.80; H, 4.32; N, 3.56%. FT-IR (ATR mode): ν[cm−1] = 3630(m) and 3568(m) [ν(O-H)phenol)], 3202 (br) [ν(O-H)], 3065(m) [ν(C-H)arom)], 2974(m) [ν(C-H)aliph], 1610(s) and 1588(s) [δ(O-H) overlapped with ν(C=C)], 1481(vs) [ν(C=N)], 1277(m) [δ(O-H) phenol], 1177 (m) [ν(C-O)phenol], 830(vs) [ν(P–F)], 791(vs) and 705(s) [δ(C-H) out of plane], 557[ν(P–F)]. UV–Vis (DMSO, λmax, nm, 8.5 × 10−6 M): 403 (ε = 15,500 M−1 cm−1), 316 (ε = 37,000 M−1 cm−1). Λ(DMSO): 26 S cm2 mol−1. 1H NMR (acetone-d6, 500 MHz, 298 K): 0.97 (d, J = 7.0, 6H (CH(CH3)2), 1.01 (d, J = 7.0, 6H (CH(CH3)2), 2.36 (s, 3H, CH3-cym), 2.53 (sept, J = 7.0, 1H, CH(CH3)2,), 6.06 (d, J = 7.0, 1H, H-cymar), 6.10 (d, J = 7.0, 1H, H-cymar), 6.14 (d, J = 7.0, 1H, H-cymar), 6.21 (d, J = 7.0, 1H, H-cymar), 7.00 (d, J = 7.0, 2H, H17/H21), 7.65 (d, J = 7.0, H18/H20), 7.71 (m, 2H, H11/H15), 7.90 (t, J = 7.0, 1H, H5′), 8.22 (d, J = 7.0, 1H, H13), 8.40 (m, 2H, H4′/H7), 8.62 (s, 1H, H5), 8.78 (s, 1H, H3), 8.94 (d, J = 7.0, 1H, H3′), 9.10 (d, J = 7.0, 1H, H8), 9.64 (d, J = 7.0, 1H, H6′). 13C{1H} NMR (acetone-d6, 125 MHz, 298 K): 18.77 (CH3-cym), 21.90 (CH-(CH3)2), 22.38 (CH-(CH3)2), 31.84 (CH-(CH3)2), 85.95 (C-Ccym-ar), 86.85 (C-Ccym-ar), 85.93 (C-Ccym-ar), 87.89 (C-Ccym-ar), 105.29 (Ccym-CH-(CH3)2), 105.74 (CH3-Ccym), 117.16 (C17/C21), 120.74 (C3), 123.39 (C5), 126.08 (C3′), 126.85 (C5′), 129.31 (C18/C20), 129.55 (C2/C12/C14), 130.02 (C7), 132.11 (C8), 132.14 (C11/C15), 137.12 (C10), 140.94 (C4′), 142.75 (C16), 149.84 (C4), 153.43 (C4a), 155.85 (C2′), 153.52 (C6′), 157.11 (C6), 159.42 (C19).

2.2. Single-Crystal X-ray Structural Determination

Suitable yellow blocks of 2b were obtained upon the slow diffusion of pentane into an acetone solution of the complex, at ambient temperature. Data collections for 2b were performed on a dual-source (IμS Diamond Cu/Κα and Mo/Κα) Bruker D8-Venture SC-XRD instrument equipped with a Photon-III area detector and a 4-circle kappa goniometer at 100K using an Oxford Cryosystems 100 coldhead, as described in detail previously [45]. A numerical absorption correction (SADABS 2016/2) based on crystal faces was applied. Data solution [46] and model refinement [47,48] were achieved using the Olex2–1.5 software package [49]. All atoms were refined anisotropically, and hydrogen atoms were added using the riding model, unless otherwise stated.
Complex 2b shows significant signs of occupational disorder in both the PF6− counter-anions and the p-cymene ligand. In the case of the former, electron density corresponding to four different positions of the PF6− counter-anions was located in the asymmetric unit. This disorder was modelled with the help of the SUMP command by setting the overall counter-balancing charge of these anions to −1 and their overall occupancy to 1 (PARTS 2 to 5 with a freely refined occupancy of each part of ca 0.47:0.30:0.14:0.09, respectively), as evidenced by spectroscopic and analytical data. In the case of the p-cymene ligand, this was also found to occupy three positions, and the disorder was also modelled with the help of the SUMP command (PARTS 6 to 8 with a freely refined occupancy of ca 0.19:0.28:0.52, respectively).
For refinement to converge the extensive use of ISOR, SADI and DFIX restraints, and in certain cases the use of EADP constraints were necessary. The model converged after 32 refinement cycles and remained stable. There were 108 systematic absence violations but, despite repeated efforts to find a lower symmetry space group, this crystallographer was unsuccessful. In addition, 0.25 molecules per asymmetric unit of crystallization solvent (acetone) were also located in the Fourier difference map. Our attempts to model this electron density due to the crystallization solvent were unsuccessful, and it was removed using the Solvent Mask functionality in Olex 2–1.5 [50]. H1 (i.e.,hydrogen connected to O1) was located in the Fourier electron difference map, and its position was refined freely.
A summary of the crystal data, data collection, and refinement for the structure of complex 2b is given in Table 1. CCDC 2,367,946 (2b) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_reqeust/cif (accessed on 4 July 2024).

2.3. Biological Evaluation

2.3.1. Cell Lines

Both of the cell lines, HEK293T (immortalized human embryonic kidney cells) and HeLa (cervical cancer cells), used in this study were obtained from ATCC. Cells were cultivated at 37 °C and 5% CO2 in high glucose Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (FBS), penicillin (100 units/mL), and streptomycin (100 μg/mL).

2.3.2. MTT Assay

All ruthenium(II) complexes were diluted in stock solutions of 5–10 mM in dimethyl sulfoxide (DMSO). A 10 mM aqueous solution was prepared instead for cisplatin, which served as the control. Cells were seeded in sterile tissue culture 96-well plates at a density of 3000 cells per well. Subsequently, after 24 h, the medium was replaced with fresh media that contained various concentrations of the compounds to be tested, ranging from 1 μΜ, 10 μΜ, 20 μΜ, 40 μΜ, 60 μΜ, 80 μΜ, 100 μΜ, and 120 μΜ, and were further incubated for 24 h at 37 °C. DMSO was used as vehicle at ≤1%. Consequently, the culture medium containing the compounds (or DMSO) was removed and 100 μL of 0.5 mg/mL MTT (Applichem) diluted in DMEM was added to the cells for 3 h at 37 °C. After 3 h of incubation, the MTT reagent was removed and 200 μL of DMSO was added. Viability of the cells was measured spectrophotometrically by absorbance at 540 nm using a BioTek Synergy H1 microplate reader (Agilent). For evaluation, all compounds were tested in triplicate. The IC50 values were extracted after statistical analysis had been performed, using the nonlinear regression by GraphPad PRISM program (Version 9).

2.4. Transfer Hydrogenation of Benzophenone Catalyzed by 1a, 1b

In a two-necked round-bottom flask and under an argon atmosphere, a mixture of the catalyst precursor (0.008 mmol) and benzophenone (3.2 mmol) was introduced. The mixture was dried in vacuo for approximately 10 min and 2-propanol (10 mL) was introduced, providing a yellow suspension that dissolved upon heating to a gentle reflux. The flask was removed from the heating bath and KOiPr (0.32 mmol) was added. Upon addition of the base, the color of the solution became red and gradually turned to a pine green colour. The mixture was stirred at 82 °C, and the samples were withdrawn (0.1 mL of the mixture) at regular intervals. The reaction progress was monitored by 1H NMR. After the reaction period, the solvent was evaporated and the mixture was treated with hexanes. The hexane extracts were passed through a small pad of silica and, after evaporation of the solvent, the crude product was analyzed by 1H NMR spectroscopy.

3. Results and Discussion

3.1. Chemistry

Substituted pyridine–quinoline ligands Br-Qpy and OH-Ph-Qpy were synthesized according to well-described protocols [41]. A literature survey revealed that reports about the coordination chemistry of those ligands are rather limited. Besides a series of Rh(III) analogues [41], a Zn(II) complex [51], and a series of gold(I) complexes [52], no other reports exist. Based on the previous experience collected with these ligands, we wanted to explore their coordination chemistry with the [Ru(p-cymene)Cl]+ core. In addition, cytotoxic studies and transfer hydrogenation reactions have also not been reported. As a result, we set out to synthesize new ruthenium(II) p-cymene complexes with these ligands and study their catalytic and cytotoxic properties.
Upon treatment of both ligands with equimolar amounts of the ruthenium dinuclear complex [Ru(η6-p-cymene)(μ-Cl)Cl]2 in acetone, the corresponding organometallic mononuclear complexes of the formulae [Ru(η6-p-cymene)(Br-Qpy)Cl][Cl] (1a) and [Ru(η6-p-cymene)(OH-Ph-Qpy)Cl][Cl] (2a) were isolated as orange and yellow solids. The choice of solvent was critical for obtaining both organometallic complexes analytically pure and in high yields, as they precipitate out from the reaction mixture. The synthetic route and reaction conditions are depicted in Scheme 1.
Characterization of the new complexes is based on a combination of FT-IR, multinuclear NMR spectroscopy, and satisfactory elemental analyses, along with UV–Vis spectroscopy and molar conductivity measurements. Both complexes are air stable in the solid-state and are soluble in DMSO and methanol and are less soluble in water and in CHCl3. The compounds are stable up to 200 °C.
The FT-IR spectra (ATR mode) of both complexes are very similar. For 1a, the ν(C-H) aromatic and aliphtic stretching vibration modes of the ligand appear at 3060 cm−1, and in the region of 2966–2872 cm−1. The medium intensity band at ∼830 cm−1 is typical for the stretching vibration mode of ν(Ru-C) [53], while that at 1050 cm−1 can be assigned to the stretching vibration mode of ν(C-Br) [41]. The latter has been shifted to lower wavenumbers compared to the uncoordinated Br-Qpy ligand (1117 cm−1). In the region of 800–600 cm−1, the spectrum displays very strong in-plane and out-of-plane deformation bands from the pyridine ring of the Br-Qpy ligand. For 2a, characteristic is the broad and medium intensity band at 3352 cm−1, which is typical for the intermolecular hydrogen bonded stretch of ν(O-H) from the pending -Ph-OH moiety [54].
The 1H and 13C{1H} solution NMR spectra of 1a and 2a were recorded in DMSO-d6 at ambient temperature, since solubility in other solvents is not sufficient to provide appropriate spectra. The NMR data are consistent with the presence of a single ligand environment (Br-Qpy or OH-Ph-Qpy), along with the characteristic set of resonances of p-cymene ligands, supporting the proposed formulae of the compounds [41]. Atom numbering for NMR assignment is included in the Supplementary Materials. Accordingly, coordination of Br-Qpy and/or OH-Ph-Qpy to the [Ru-(p-cymene)Cl]+ core becomes evident by the downfield shift of the H8 proton at δ 8.83 (1a) and δ 8.91 (2a), in comparison to the corresponding resonance signals of the non-coordinated Br-Qpy ligand or OH-Ph-Qpy ligand at δ 8.68 and δ 8.67, respectively [41]. For (2a), the broad resonance signal at δ 9.94 is attributed to the phenolic hydroxyl proton (–OH), while the well-resolved resonance signals in the region of δ 6.03–6.20 and in a ratio of 1:1:1:1 correspond to the p-cymene ring protons. The septet resonance signals at δ 2.30 for 1a and δ 2.31 for 2a are indicative of the -CH(CH3)2 proton, while the triplets at δ 0.82 (1a) and δ 0.85 (2a) are due to the methyl protons of the isopropyl group. Assignment of the resonance signals of 1a (Figures S1–S4) and 2a (Figures S5–S8) was made possible by two-dimensional 1H–1H COSY, 1H–13C HSQC, and 1H–13C HMBC methods and was comparable with the literature data from similar complexes [55]. Their 13C{1H} NMR spectra display the expected number of resonance signals for the pyridyl and quinoline ring carbons, also including the typical signals from the carbon atoms of the p-cymene ring atoms. Thus, the singlet resonance signals at δ 18.28, 21.38, 21.58 (1a) and δ 18.30, 21.69, 21.29 (2a) correspond to the CH3-cym and -CH-(CH3)2 carbon atoms of the p-cymene ligand.
Subsequently, the chlorido complexes 1a and 2a were transformed to the corresponding PF6− analogues 1b and 2b via a metathesis reaction in water, with a saturated aqueous KPF6 solution. These were isolated as yellow to light yellow solids that decomposed upon heating at 187 °C and 198 °C, respectively.
The FT-IR spectra of the hexafluorido complexes are very similar to those of 1a and 2a, except for the two very strong vibration bands at 831 cm−1, 555 cm−1 (1b) and at 829 cm−1, 558 cm−1 (2b), which are attributed to the vibration modes of the PF6− counter anion. For 2b, the medium intensity peaks at 3634 cm−1 and 3658 cm−1 can be tentatively assigned to the ν(O-H) stretching vibration modes of phenol without hydrogen bonding [56]. A comparison of the FT-IR spectra of 1a vs. 1b and 2a vs. 2b is provided in the Supplementary Materials Figures S9 and S10.
The 1H and 13C{1H} solution NMR spectra of 1b and 2b were recorded in Me2CO-d6 at ambient temperature. The high purity of the complexes is evident, suggesting further that the exchange reaction (Cl− vs. PF6 −) was complete. The characteristic singlet resonance at δ 8.76 (2b), indicative of the H3 proton of the ligand, is shifted towards the lower fields as compared to that of non-coordinated Oh-Ph-Qpy. The characteristic doublet resonance signals at δ 9.04, 9.65 (1b) and δ 9.11, 9.64 (2b) are attributed to the H8 and H6′ protons, respectively. Characteristic NMR spectra for 1b and 2b are provided in Figures S11–S15 and Figures S16–S20, respectively. The Λ values of 1a, 2a, and 2b upon dissolution in DMSO were 49, 26, and 26 S cm2 mol−1, respectively, while for 1b the molar conductivity in Me2CO was 150 S cm2 mol−1 [57]. The molar conductivity data are consistent with a 1:1 electrolyte in these media [58].
All our efforts to obtain single-crystal of 1a, 1b, and 2a were unsuccessful, providing only powders or microcrystalline materials. However, we have succeeded in crystallizing complex 2b. The solid-state structure of 2b was determined by single-crystal X-ray diffraction studies. The molecular structure of the complex cation of 2b is illustrated in Figure 2. Selected bond lengths and angles with estimated standard deviations are provided in the legend of the Figure. Complex 2b crystallizes in the monoclinic crystal system and space group P21/c. The ruthenium metal center is coordinated in an η6-fashion to the p-cymene ligand, and all other vacant sites are occupied by a chlorine atom and two N atoms of the chelating ligand Oh-Ph-Qpy. The overall structure around ruthenium can be described as a three-legged piano-stool coordination geometry. The Ru–N1 and Ru–N2 bond lengths of 2.104 Å and 2.073 Å and all other structural features, like the Ru–Cl bond length (2.396 Å), comply with those values reported in the literature for similar ruthenium(II) p-cymene complexes [59,60]. The p-cymene ligand in the solid-state structure of 2b displays occupational disorder over three positions, with a mean Ru-centroid length of 1.703 Å.
In the unit cell of 2b, the set of molecules are orientated in a head to tail fashion, as has been reported for the protonated form of the ligand Oh-Ph-Qpy [41]. The planes defined by the (C16–C20–N1) and (C19–C24) rings of quinoline deviate from planarity by 6.88°. Also, the phenyl group on C8 containing the ring atoms (C31–C36) is twisted out of the plane of bipyridine (C16–C20–N1) by 64.66°.

Electronic Spectra

The electronic spectra of the new complexes were recorded in DMSO, at ambient temperature, immediately after dissolution (Figure 3). This is the medium that is used for the biological assays performed. The absorption spectra of 1a and 1b show several absorption bands with maxima at 273, 305, 362 nm (1a) and 274, 306, 362 nm (1b), respectively, which are typical of ligand-centered π–π* transitions and metal-to-ligand charge transfer absorption bands (MLCT). Both complexes also display a weak absorption centered at 427 nm (1a) or 424 nm (1b), in accordance with the literature reports for ruthenium(II) half-sandwich arene complexes [61]. By analogy, for 2a and 2b, the spectra display two broad absorption bands centered at 315 nm (2a), 316 nm (2b), and 403 nm, respectively. Ongoing from 1a to 2a, and from 1b to 2b, the absorption bands become more intense (higher ε values), while the MLCT band at 427 nm (2a) and 424 nm (2b) blue-shifts to 403 nm. Moreover, within the series, the absorption coefficient values for these transitions range from 4700 to 37,000 dm3 mol−1 cm−1, with the OH-Ph-Qpy analogs 2a and 2b displaying the higher extinction coefficient value of ∼~37,000 dm3 mol−1 cm−1, respectively. The stability of 1a and 2a in DMSO solution over a period of 24 h shows new peaks and isosbestic points at ~322 nm and ~375 nm, indicating solvolysis of the Ru-Cl bond in DMSO (Figures S21 and S22) [62].
The stability of the chlorido complexes 1a and 2a was also studied by UV–Vis spectroscopy in H2O at ambient temperature over 24 h. The visible spectrum of 1a shows changes in the region of 200–500 nm, with isosbestic points at 297, 334, 397, and 447 nm, which can be attributed to the conversion of the Ru-Cl complex 1a to the relevant aqua species (Figure 4a) [62]. For 2a, the peak maxima are red shifted by 6 nm and 19 nm, respectively (Figure 4b).

3.2. Evaluation of Biological Activity

The cytotoxicity assays of the new organometallic ruthenium(II) complexes 1a, 1b, 2a, and 2b described herein were carried out in DMSO, while cisplatin (used as control) was dissolved in water. Freshly prepared samples were utilized within a short period of time.

Cell Viability Assay

Cell viability tests of the pyridine–quinoline ligand precursors, the dinuclear complex [Ru(η6-p-cymene)(μ-Cl)Cl]2, and the new complexes 1a, 1b, 2a, and 2b were conducted in two different cell lines: epithelial-like HEK293T cells (human embryonic kidney cells) and tumor-derived HeLa cells (cervical cancer cells). Cell viability was assessed using the MTT colorimetric assay (MTT = 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide), after 24 h of incubation. Cisplatin was used as control. Stock solutions at a concentration range of 5–10 mM of the complexes were prepared in DMSO (or H2O for cisplatin) and then diluted to reach the final concentration (Part 2.3.2). The cytotoxicity results of all substances studied in both cell lines, expressed as IC50 mean values (μM), are summarized in Table 2. To calculate the IC50 values, a dose-response model was used, which was obtained from sigmoidal fitting of dose-response curves [63].
From Table 2 and the curves of Figure 5 and Figure 6, for both cell lines, a variation on the cytotoxicity profile of each compound is evident.
For the HEK293T cell line, the organic ligands Br-Qpy and OH-Ph-Qpy display IC50 values comparable to those of the control, indicating high toxicity in this line. By analogy, the ruthenium(II) complexes 2b, 1b, and 2a are quite potent, with IC50 values ranging from 23 to 36 μM. In any case, the chlorido analogue 1a, bearing the Br-Qpy ligand, is the least effective, displaying an IC50 value of 102.9 ± 3.4 μM, while the cytotoxicity of the ruthenium precursor is moderate. As a result, we may suggest that, in this cell line, cytotoxicity drops in the following order: Br-Qpy > cisplatin > OH-Ph-Qpy ≅  2b > 2a  ≅  3b > [Ru(p-cymene)Cl2]2 > 1a.
On the other hand, for the tumor-derived HeLa cells, significant changes on the cytotoxicity potencies of the ligand precursors and the ruthenium–arene complexes were observed. The chlorido analogue 2a, incorporating the OH-Ph-Qpy ligand, followed by the relevant hexafluorido complex 2b, exhibited activities comparable to that of the non-coordinated OH-Ph-Qpy ligand. The dinuclear ruthenium precursor [Ru(p-cymene)Cl2]2 displays an IC50 value of 48.9 ± 1.7 μM. Within the experimental error of the measurements, the chlorido analogue 2a was more potent than the hexafluorido analogue 2b (75.0 μM vs. 85.1 μM). We may suggest that the combination of the OH-Ph-Qpy ligand and the [Ru(p-cymene)Cl]+ core has a positive effect on the cytotoxic profile of 2a in the Hela cell line, as reflected by the relevant IC50 values. Apparently, the presence of the OH-Ph-tethered group in the Qpy moiety is more effective compared to that of –Br in the Br-Qpy analog. The cytotoxicity profile therefore decreases in the following order: cisplatin > [Ru(p-cymene)Cl2]2 > 2a > 2b  ≅ OH-Ph-Qpy > 1a > Br-Qpy ≅  1b.
By comparing the cytotoxicity results (Table 2) for the set of complexes 1a/1b and 2a/2b in both cell lines, interesting outcomes arise. Thus, for the HEK293T cell line a drop of the IC50 value is observed that is more profound when going from the chlorido analog 1a (IC50 = 102.9 ± 3.4 μM) to the relevant hexafluorido 1b (IC50 = 36.2 ± 1.2 μM). On the other hand, for the tumor-derived HeLa cells, the hexafluorido analogs 1b and 2b were less potent when compared with the chlorido congeners 1a and 2a. The results reported in this cell line can be potentially compared to those of [Ru(p-cymene)Cl2(μ-(4ampy)], where the 4ampy = 4-aminopyridine acts as a monodentate ligand. The latter displays an IC50 value of 1.6 ± 0.0 mM, which is almost four orders of magnitude higher [64]. Analogous bioactivities were reported for the neutral [(η6-p-cymene)RuCl2L], (L = 2-aminophenol, IC50 = 82.9 μM; L = 4-aminophenol, IC50 = 171.1 μM), and cationic complexes [(η6-p-cymene)RuClL2]PF6 (L = 2-aminophenol, IC50 = 57.6 μM), respectively [63], also including the quinoline–BODIPY-based ruthenium–arene complexes with IC50 > 100 μM, for the same cancer cell line [65]. The results from the present study comply well with those from other similar ruthenium-p-cymene complexes displaying poor cytotoxicity [66]. However, it has been demonstrated that cytotoxicity differs upon moving from one cancer cell line to another one, which is in favor of the results reported herein [63]. As a typical example, we may refer to the [Ru(N^N)(p-cymene)Cl]Cl complex, where N^N is the 4,4′-dicarboxy-2,2′-bipyridine ligand, which is selective toward carcinoma human T24-bladder cells and is not toxic to other cell lines [67].
Based on the literature reports for similar ruthenium–cymene complexes, we may hypothesize that, for the ruthenium complexes described herein, DNA may not be the primary target [68]. A different profile of activity may be suggested, including interaction with bioactive components such as blood serum proteins and/or with cell membrane and cytoplasmic enzymes. The observed slow solvolysis of the Ru-Cl bond in aqueous medium, forming aqua species that are stable over 24 h, is in favor of the highly accepted mechanism of drug activation, as reported for the RAPTA-C analog [24]. The relevant ruthenium analogs comprising the pyridine–quinoline moieties are positively charged, a characteristic that facilitates diffusion across the negatively charged cell membranes. Thus, interaction with the main targets (DNA, proteins) that often hold a negative charge is plausible. Currently, we are working towards investigating the possible biological targets of the new organometallic complexes presented in this study.

3.3. Catalytic Transfer Hydrogenation Studies

Apart from the cytotoxicity studies performed, the chloride–ruthenium complexes (1a, 2a) were also tested in the transfer hydrogenation of benzophenone as the model substrate, using 2-propanol as a hydrogen donor in the presence of KOH at 82 °C (Figure 7). The relevant hexafluorido analogs were not studied since we have realized from previous studies on similar systems that generally their conversion efficiencies were within the same range as the chlorido congeners [69]. The identity of the group attached to the pyridine–quinoline moiety (–Br vs. –C6H4OH) substantially affected the catalytic activities of complexes 1a and 2a, as described below.
Initial attempts were conducted in the molar ratio of S:Cat:B = 100:1:10 (S = substrate, Cat = catalyst, B = base = KOiPr), and conversion was monitored over time after 1 h, 3 h, and 24 h, respectively. The percent conversion of benzophenone to benzhydrol was monitored over time by 1H NMR spectroscopy, and the results are summarized in Table 3. The spectra of the samples obtained each time were compared by the relevant spectra of authentic samples (benzophenone and benzhydrol), respectively [40].
From this Table, it can be clearly seen that both complexes reduce benzophenone almost quantitative after 24 h. Changing the molar ratio of S:Cat:B, from 100:1:10 to that of 400:1:40, resulted in a drastic increase of the catalytic conversion of 1a, as it reached a 94% efficiency but within a shorter period of time (3 h vs. 24 h). The time-dependent conversion of benzophenone by 1a is shown in Figure 8.
For complex 2a instead, no significant changes of the conversion efficiencies were observed when comparing the two different S:Cat:B molar ratios. Upon careful study of the results, we may suggest that, in this case, an induction period is required for the transfer hydrogenation of benzophenone. It seems that, for 2a, the formation of the active catalyst requires approximately an hour to become active, reaching an efficiency of 70% after 3 h. Finally, after 24 h it reaches its maximum performance of 94%. This could be attributed to the position of the –OH group on the pyridine–quinoline scaffold [34,69].
These findings are in accord with literature reports from similar ruthenium(II) catalyst precursors [70,71]. Both complexes, 1a and 2a, can be considered as good catalyst precursors for the reduction of benzophenone to benzhydrol. In particular, this is of interest since, in general, diaryl ketones are substrates that are difficult to reduce [72]. The TOFs achieved by both complexes, within the first 3 h, vary from 97 h−1 to 324 h−1. For 2a, the TOF achieved was higher compared to that of the cationic half-sandwich ruthenium(II) complex with pyridyl-triazole ligands [73], which gave a TOF of 152 h−1 but for a longer period of time (6 h).
Generally, it has been proposed that, upon addition of the base, a ruthenium(II) alkoxide is formed, which subsequently undergoes β-H elimination. A Ru-H species generated in situ may be considered as the catalytically active species [74]. To support this, we performed the reaction of 2a with KOiPr (Cat:B = 1:10) in 2-propanol and under reflux, over a period of 1 h, but without the presence of the substrate (benzophenone). During the reaction, the color changed from dark red to blue-green and finally to dark green, which may indicate the formation of different species in the solution. After evaporation of the solvent, a pine green solid was isolated and characterized by 1H NMR spectroscopy (in CH3OD). In the hydridic region, a characteristic, rather broad, singlet resonance signal at δ –4.58 is observed, indicating the formation of ruthenium hydride species. The very low intensity of the signal may be indicative of the instability of the relevant species in solution (Figure S23). In addition, the FT-IR (ATR mode) spectrum of the CH3OD sample, after evaporation of the solvent and drying for a short period of time, displays a low intensity stretching vibration for ν(M-H) at 2040 cm−1 (Figure S24), within the expected region of reported terminal ruthenium hydrido complexes [75].
To obtain further insight on the possible nature of the catalytic species formed, we have studied the reaction of the pine-green solid reported previously, with benzophenone in the molar ratio of Cat:S = 1:16, in 2-propanol and in the absence of a base [76]. Interestingly, an approximate 10–15% conversion efficiency for the reduction of benzopheneone to benzhydrol was observed. Presumably, the low efficiency can be attributed to the instability of the relevant Ru-H species formed under these experimental conditions. These findings can be considered as additional sign of proof for a plausible catalytic cycle that may contain Ru-hydride as the active intermediate species [8,77].
Optimization of the reaction conditions is underway, including reaction time and molar ratios among the catalyst, the base and the substrate. Currently, we are working to further investigate the nature of the active catalyst.

4. Conclusions

In summary, we have developed a series of air-stable organometallic complexes with substituted pyridine–quinoline ligands incorporating -Br and -C6H4OH pendant groups, in the 6-position of quinoline. Characterization of the new complexes has been performed by several spectroscopic techniques, which support the proposed structure of the relevant complexes. Solution stability studies were also assessed by UV–Vis spectroscopy, revealing slow solvolysis of the Ru-Cl bond in both complexes containing the Cl− counter anion. In water and after 24 h, formation of the relevant aqua species may be suggested.
The cytotoxic profiles of the ruthenium–arene complexes under evaluation in tumor-derived HeLa cells is poor, which is in accordance with that reported in other similar ruthenium complexes, while the organic ligand precursors are quite potent.
In addition, the catalytic activity of the catalyst precursor 1a, for the transfer hydrogenation of benzophenone, is higher compared to that of the more sterically encumbered complex 1b. To this end, we may comment that this is the first report of ruthenium(II) complexes displaying dual cytotoxic and catalytic potencies for this interesting and yet unexplored class of organic ligands. Further studies are currently underway including other in vitro cancer cell lines, along with DNA and/or protein targeting experiments, also including improvement of the catalytic activity of 1a.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/chemistry6040046/s1, Figures S1–S4: NMR spectra of 1a; Figures S5–S8: NMR spectra of 2a; Figure S9: Comparison of FT-IR spectra of 1a (black line) vs. 1b (red line); Figure S10: Comparison of FT-IR spectra of 2a (black line) vs. 2b (red line); Figures S11–S15: NMR spectra of 1b; Figures S16–S20: NMR spectra of 2b; Figure S21: The UV–Vis spectrum of 1a in DMSO after 24 h; Figure S22: The UV–Vis spectrum of 2a in DMSO after 24 h; Figure S23: 1H NMR spectrum (CH3OD) of a sample (pine green solid) showing the formation of Ru-H species; Figure S24: FT-IR spectrum of Ru-H species formed, upon treatment of 2a with KOiPr (Cat:B = 1:10) in 2-propanol (pine green solid).

Author Contributions

Conceptualization, A.I.P.; methodology, A.D., N.Z., A.-E.P. and E.K.; formal analysis, A.D., N.Z. and A.C.; investigation, A.D., N.Z., A.-E.P., E.K. and C.M.; resources, N.T., A.C., E.E., J.K.K. and A.I.P.; data curation, A.I.P., N.T., A.C., C.M., E.E. and A.K.A.; writing—original draft preparation, A.I.P. and N.T.; writing—review and editing, A.I.P.; supervision, A.I.P., E.E. and J.K.K.; project administration, A.I.P.; funding acquisition, A.I.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded (in part) by The Special Research Account of the National and Kapodistrian University of Athens (NKUA), grant number 15244 (to A.Ι.P.).

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Acknowledgments

A.Ι.P would like to thank A.C. Filippou for access to the elemental analyses center of the University of Bonn, Chemistry Department. We also thank the National and Kapodistrian University of Athens Core Facility for access to SC-XRD instrumentation.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Structures of (a) cytotoxic ruthenium complexes NAMI-A [16], KP1019 [17], and NPK 1339 [20]; (b) transfer hydrogenation ruthenium catalysts ([26] (Ru-CNC), [27] (Ru-OH2), [28] (Ru-P)]).
Figure 1. Structures of (a) cytotoxic ruthenium complexes NAMI-A [16], KP1019 [17], and NPK 1339 [20]; (b) transfer hydrogenation ruthenium catalysts ([26] (Ru-CNC), [27] (Ru-OH2), [28] (Ru-P)]).
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Scheme 1. Reaction scheme and conditions for the organometallic ruthenium(II) complexes reported herein.
Scheme 1. Reaction scheme and conditions for the organometallic ruthenium(II) complexes reported herein.
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Figure 2. ORTEP diagram of the molecular structure of complex cation [Ru(η6-p-cymene)(OH-Ph-Qpy)Cl]+ in the solid-state. Thermal ellipsoids are set at 50% probability. Hydrogen atoms and the PF6− counter anion are omitted for clarity. Selected bond lengths (Å) and angles (°) for the cation of 2b: Ru-(cym) ring centroid = 1.703(3), Ru-Cl = 2.396(10), Ru-N(1) = 2.104(3), Ru-N(2) = 2.073(3); N(2)-Ru-N(1) = 76.72(11).
Figure 2. ORTEP diagram of the molecular structure of complex cation [Ru(η6-p-cymene)(OH-Ph-Qpy)Cl]+ in the solid-state. Thermal ellipsoids are set at 50% probability. Hydrogen atoms and the PF6− counter anion are omitted for clarity. Selected bond lengths (Å) and angles (°) for the cation of 2b: Ru-(cym) ring centroid = 1.703(3), Ru-Cl = 2.396(10), Ru-N(1) = 2.104(3), Ru-N(2) = 2.073(3); N(2)-Ru-N(1) = 76.72(11).
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Figure 3. (a) The UV–Vis spectra of 1a (black line, C = 8.1 × 10−6 M) and 2a (red line, C = 8.1 × 10−6 M) in DMSO; (b) The UV–Vis spectra of 1b (black line, C = 8.5 × 10−6 M) and 2b (red line, C = 8.5 × 10−6 M) in DMSO.
Figure 3. (a) The UV–Vis spectra of 1a (black line, C = 8.1 × 10−6 M) and 2a (red line, C = 8.1 × 10−6 M) in DMSO; (b) The UV–Vis spectra of 1b (black line, C = 8.5 × 10−6 M) and 2b (red line, C = 8.5 × 10−6 M) in DMSO.
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Figure 4. (a) The UV–Vis spectrum of 1a (t = 0, black line, C = 1.0 × 10−5 M) and 1a (t = 24 h, red line) in H2O; (b) The UV–Vis spectrum of 2a (t = 0, black line C = 1.0 × 10−5 M) and 2a (t = 24 h, red line) in H2O.
Figure 4. (a) The UV–Vis spectrum of 1a (t = 0, black line, C = 1.0 × 10−5 M) and 1a (t = 24 h, red line) in H2O; (b) The UV–Vis spectrum of 2a (t = 0, black line C = 1.0 × 10−5 M) and 2a (t = 24 h, red line) in H2O.
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Figure 5. Viability curves of ruthenium complexes with Br-Qpy (a) or OH-Ph-Qpy (b) ligands compared with the ligand alone or cisplatin in HEK293T and HeLa cell lines. The Cl−- and PF6−-based complexes are compared in each graph.
Figure 5. Viability curves of ruthenium complexes with Br-Qpy (a) or OH-Ph-Qpy (b) ligands compared with the ligand alone or cisplatin in HEK293T and HeLa cell lines. The Cl−- and PF6−-based complexes are compared in each graph.
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Figure 6. Viability curves of ruthenium complexes with Br-Qpy (a) or OH-Ph-Qpy (b) ligands compared with cisplatin in HEK293T and HeLa cell lines.
Figure 6. Viability curves of ruthenium complexes with Br-Qpy (a) or OH-Ph-Qpy (b) ligands compared with cisplatin in HEK293T and HeLa cell lines.
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Figure 7. Catalytic transfer hydrogenation of benzophenone by catalysts 1a and 2a.
Figure 7. Catalytic transfer hydrogenation of benzophenone by catalysts 1a and 2a.
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Figure 8. Time-dependence of transfer hydrogenation of benzophenone by complex 1a.
Figure 8. Time-dependence of transfer hydrogenation of benzophenone by complex 1a.
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Table 1. Summary of crystallographic data and structure refinement for complex 2b.
Table 1. Summary of crystallographic data and structure refinement for complex 2b.
Compound2b
Color, habitOrange, Plate
Size/mm0.411 × 0.127 × 0.072
Empirical formulaC36H32ClF6N2OPRu × 0.25C3H6O
FW807.11
Crystal systemMonoclinic
Space groupP21/c
a/Å13.6107(5)
b/Å10.5278(3)
c/Å25.8896(11)
α/°90
β/°92.702(2)
γ/°90
V/Å33705.6(2)
Z4
μ/mm−10.628
T/K100
θmin/max/full (°)2.089/28.294/25.242
Completeness to θmax/full (%)99.9/99.9
Reflections Total/
Independent		95,535/8017
Parameters/restraints726/340
Rint0.0517
Final R1, wR20.0586/0.1787
Goodness-of-fit1.077
Largest peak, hole/e.Å−31.9/−0.9
ρcalc/g.cm−31.447
Table 2. IC50 values (μM) of the pyridine–quinoline containing complexes against the HEK293T and Hela cell lines. Cisplatin is used as a control. Values are the mean ± SD.
Table 2. IC50 values (μM) of the pyridine–quinoline containing complexes against the HEK293T and Hela cell lines. Cisplatin is used as a control. Values are the mean ± SD.
CompoundsHEK293T (IC50 in μM)HeLa (IC50 in μM)
Br-Qpy13.7 ± 0.3108.5 ± 3.6
OH-Ph-Qpy23.4 ± 0.784.5 ± 2.2
[Ru(p-cymene)Cl2]248.3 ± 1.748.9 ± 1.7
1a102.9 ± 3.4106.9 ± 1.1
1b36.2 ± 1.2109.6 ± 1.5
2a35.2 ± 4.675.0 ± 1.0
2b22.7 ± 1.285.1 ± 1.8
cisplatin20.8 ± 0.09.5 ± 0.0
Table 3. Summary of the transfer hydrogenation of benzophenone data using catalysts 1a and 2a a.
Table 3. Summary of the transfer hydrogenation of benzophenone data using catalysts 1a and 2a a.
CatalystConversion (%) bTime (h)TOF (h−1)
1a *73173
76325
92244
1a **811324
943125
2a *45145
70323
94244
2a **421168
73397
* Reaction conditions: ketone (2 mmol), catalyst (1.0 mmol %), KOH (10 mmol %) (molar ratio 100:1:10). ** Reaction conditions: ketone (2 mmol), catalyst (0.25 mmol %), KOH (10 mmol %) (molar ratio 400:1:40). a Temperature: 82 °C, hydrogen donor: 2-propanol. b Conversion was monitored by 1H-NMR spectroscopy and are the average of two runs.
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Dritsopoulos, A.; Zacharopoulos, N.; Peyret, A.-E.; Karampella, E.; Tsoureas, N.; Cheilari, A.; Machalia, C.; Emmanouilidou, E.; Andreopoulou, A.K.; Kallitsis, J.K.; et al. Ruthenium-p-Cymene Complexes Incorporating Substituted Pyridine–Quinoline Ligands with –Br (Br-Qpy) and –Phenoxy (OH-Ph-Qpy) Groups for Cytotoxicity and Catalytic Transfer Hydrogenation Studies: Synthesis and Characterization. Chemistry 2024, 6, 773-793. https://doi.org/10.3390/chemistry6040046

AMA Style

Dritsopoulos A, Zacharopoulos N, Peyret A-E, Karampella E, Tsoureas N, Cheilari A, Machalia C, Emmanouilidou E, Andreopoulou AK, Kallitsis JK, et al. Ruthenium-p-Cymene Complexes Incorporating Substituted Pyridine–Quinoline Ligands with –Br (Br-Qpy) and –Phenoxy (OH-Ph-Qpy) Groups for Cytotoxicity and Catalytic Transfer Hydrogenation Studies: Synthesis and Characterization. Chemistry. 2024; 6(4):773-793. https://doi.org/10.3390/chemistry6040046

Chicago/Turabian Style

Dritsopoulos, Alexandros, Nikolaos Zacharopoulos, Aigli-Eleonora Peyret, Eftychia Karampella, Nikolaos Tsoureas, Antigoni Cheilari, Christina Machalia, Evangelia Emmanouilidou, Aikaterini K. Andreopoulou, Joannis K. Kallitsis, and et al. 2024. "Ruthenium-p-Cymene Complexes Incorporating Substituted Pyridine–Quinoline Ligands with –Br (Br-Qpy) and –Phenoxy (OH-Ph-Qpy) Groups for Cytotoxicity and Catalytic Transfer Hydrogenation Studies: Synthesis and Characterization" Chemistry 6, no. 4: 773-793. https://doi.org/10.3390/chemistry6040046

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