molecules Article Arene Ruthenium(II) Complexes Bearing the κ-P or κ-P,κ-S Ph2P(CH2)3SPh Ligand Sören Arlt 1, Vladana Petkovi´c 2, Gerd Ludwig 1, Thomas Eichhorn 3 , Heinrich Lang 4, Tobias Rüffer 4, Sanja Mijatovi´c 2, Danijela Maksimovi´c-Ivani´c 2 and Goran N. Kaluderovi´c¯ 3,5,* 1 Institute of Chemistry, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Straße 2, D-06120 Halle, Germany; [email protected] (S.A.); [email protected] (G.L.) 2 Institute for Biological Research “Sinisa Stankovic” National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia; [email protected] (V.P.); [email protected] (S.M.); [email protected] (D.M.-I.) 3 Department of Engineering and Natural Sciences, University of Applied Sciences Merseburg, Eberhard-Leibnitz-Strasse 2, DE-06217 Merseburg, Germany; [email protected] 4 Institute of Chemistry, Chemnitz University of Technology, Straße der Nationen 62, D-09111 Chemnitz, Germany; [email protected] (H.L.); [email protected] (T.R.) 5 Faculty of Pharmacy, University of Business Academy in Novi Sad, Trg Mladenaca 5, 21000 Novi Sad, Serbia * Correspondence: [email protected] 6 Abstract: Neutral [Ru(η -arene)Cl2{Ph2P(CH2)3SPh-κP}] (arene = benzene, indane, 1,2,3,4-tetrahydro- 6 naphthalene: 2a, 2c and 2d) and cationic [Ru(η -arene)Cl(Ph2P(CH2)3SPh-κP,κS)]X complexes (arene = mesitylene, 1,4-dihydronaphthalene; X = Cl: 3b, 3e; arene = benzene, mesitylene, indane, 1,2,3,4- tetrahydronaphthalene, and 1,4-dihydronaphthalene; X = PF6: 4a–4e) complexes were prepared Citation: Arlt, S.; Petkovi´c,V.; and characterized by elemental analysis, IR, 1H, 13C and 31P NMR spectroscopy and also by single- Ludwig, G.; Eichhorn, T.; Lang, H.; Rüffer, T.; Mijatovi´c,S.; crystal X-ray diffraction analyses. The stability of the complexes has been investigated in DMSO. Maksimovi´c-Ivani´c,D.; Kaluderovi´c,¯ Complexes have been assessed for their cytotoxic activity against 518A2, 8505C, A253, MCF-7 and G.N. Arene Ruthenium(II) SW480 cell lines. Generally, complexes exhibited activity in the lower micromolar range; moreover, Complexes Bearing the κ-P or they are found to be more active than cisplatin. For the most active ruthenium(II) complex, 4b, κ-P,κ-S Ph2P(CH2)3SPh Ligand. bearing mesitylene as ligand, the mechanism of action against 8505C cisplatin resistant cell line was Molecules 2021, 26, 1860. https:// determined. Complex 4b induced apoptosis accompanied by caspase activation. doi.org/10.3390/molecules26071860 Keywords: ruthenium(II); crystal structure; anticancer activity; apoptosis; autophagy Academic Editor: Fabio Marchetti Received: 29 December 2020 Accepted: 19 March 2021 1. Introduction Published: 25 March 2021 One of today’s most clinically used antitumor drug cisplatin was synthesized in 1845 Publisher’s Note: MDPI stays neutral by M. Peyrone. However, the structure remained unknown for the next 50 years [1,2]. A. with regard to jurisdictional claims in Werner deducted the square planar structure, and the cisplatin was distinguished from published maps and institutional affil- the trans analog. Cisplatin was approved in 1978 as an antitumor agent for testicular and iations. ovarian cancers [3–5]. A major disadvantage of cisplatin are its strong side effects due to its nephrotoxicity, neurotoxicity and ototoxicity [6,7]. This led to the development for alternative drugs (carboplatin, oxaliplatin, etc.) [8]. However, the side effects of the general high toxic properties of the platinum compounds were not suppressed. At the same time, attempts were made to circumvent the side effects using nonplatinum- Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. based cytotoxic metal compounds [9–12]. Very promising effects have been already found This article is an open access article with titanium(IV), gallium(III), gold(III), and tin(IV) compounds [13–20]. distributed under the terms and The organoruthenium(II/III) compounds seem to be particularly suitable because of conditions of the Creative Commons their lower general toxicity in comparison with cisplatin, as well as their ability to utilize iron Attribution (CC BY) license (https:// pathways in the body [21,22]. Keppler, Sadler and Dyson gave significant contribution in the creativecommons.org/licenses/by/ field of ruthenium-based anticancer drugs [23–25]. For some ruthenium compounds, it was 4.0/). shown that they express a very good cytotoxic activity; importantly,particular compounds also Molecules 2021, 26, 1860. https://doi.org/10.3390/molecules26071860 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 1860 2 of 15 Molecules 2021, 26, 1860 2 of 15 particular compounds also possess an antimetastatic activity [26,27]. In some cases, they possesscan overcome an antimetastatic the resistance activity of cancer [26,27]. cells In some while cases, the ruthenium they can overcome complexes the hardly resistance affect of cancernormal cells cells while [17]. the For ruthenium certain cancer complexes lines, hardlyit has already affect normal been demonstrated cells [17]. For certain that their cancer re- lines,sistance it has to alreadyan organic been drug demonstrated can be overcome that their by resistance complexing to an to organic ruthenium drug can [28]. be A overcome problem byof complexingthe first anticancer to ruthenium active [ruthenium(III)-based28]. A problem of the compound, first anticancer fac-[Ru(NH active ruthenium(III)-3)3Cl3] (Figure based1A), is compound, the low solubilityfac-[Ru(NH [29]. 3Subsequently)3Cl3] (Figure, 1water-solubleA), is the low compounds solubility [ 29such].Subsequently, as the NAMI- water-solubleA (Figure 1B) compoundswere synthesized such as [26]. the NAMI-A (showsFigure inhibition1B ) were synthesized of the formation [26]. NAMI-Aof metas- showstases in inhibition the lung ofindependently the formation of of the metastases cytostat inic activity the lung without independently attacking of thethe cytostaticactual tu- activitymor. Certain without properties, attacking thesuch actual as faster tumor. ligan Certaind (aqua) properties, exchange such of asthe faster ruthenium ligand (aqua)in the exchangeoxidation of state the ruthenium+2 versus +3, in thesuggest oxidation that it state is more+2 versus suitable +3, for suggest reactions that it in is biological more suitable sys- fortems reactions [30,31]. in biological systems [30,31]. FigureFigure 1.1. ExamplesExamples ofof ruthenium(II/III)ruthenium(II/III) an anticancerticancer active compounds. ItIt waswas also also shown shown that that the the oxidation oxidation state state +2 +2 is stabilizedis stabilized through throughπ-bonded π-bonded arene arene lig- andsligands [32 ].[32]. Existing Existing problems problems such such as side as side effects, effects, solubility, solubility, and resistancesand resistances remain remain in part. in Severalpart. Several arene arene ruthenium(II) ruthenium(II) complexes complexes exhibited exhibited both in both vitro in andvitroin and vivo in promisingvivo promising anti- canceranticancer activity. activity. Such Such complexes complexes were activewere activein vitro inin vitro the rangein the of range 6–300 ofµ 6–300M against μM humanagainst cancerhuman cell cancer lines cell (Figure lines1C) (Figure [ 32,33 ].1C) Up [32,33]. to now, Up there to now, are barely there a are few barely cytotoxic a few active cytotoxic ruthe- nium(II)active ruthenium(II) complexes bearingcomplexes phosphorus bearing phosph ligandsorus (type ligands D–F; (type Figure D–F;1)[ 34Figure–36]. 1) Complex [34–36]. [Ru(η6-p-cymene)Cl (pta)] (pta = 1,3,5-triaza-7-phosphaadamantane; Figure1D) relived Complex [Ru(η6-p-cymene)Cl2 2(pta)] (pta = 1,3,5-triaza-7-phosphaadamantane; Figure 1D) almostrelived no almost anticancer no anticancer activity, but activity, on the but other on hand the other a promising hand a antimetastatic promising antimetastatic activity [37]. Our group has explored neutral arene ruthenium(II) and iridium(III) complexes having activity [37]. Our group has explored neutral arene ruthenium(II) and iridium(III) com- κP- and κP,κS-coordinated !-diphenylphosphino-functionalized alkyl phenyl sulfide, sul- plexes having κP- and κP,κS-coordinated ω-diphenylphosphino-functionalized alkyl foxide, and sulfone ligands (type F, Figure1) on their anticancer activity [ 34,35,38–40]. phenyl sulfide, sulfoxide, and sulfone ligands (type F, Figure 1) on their anticancer activity All complexes were found very active, importantly particular complexes showed in vitro [34,35,38–40]. All complexes were found very active, importantly particular complexes cytotoxicities equal or higher than cisplatin. showed in vitro cytotoxicities equal or higher than cisplatin. Here, we describe the synthesis and characterization of various neutral (2a, 2c and Here, we describe the synthesis and characterization of various neutral (2a, 2c and 2d) and cationic arene ruthenium(II) complexes (4a–4e, 3b, 3e) with κP- and κP,κS coor- 2d) and cationic arene ruthenium(II) complexes (4a–4e, 3b, 3e) with κP- and κP,κS coor- dinated, respectively, 3-diphenylphosphino-functionalized propyl phenyl sulfide ligand dinated, respectively, 3-diphenylphosphino-functionalized propyl phenyl sulfide ligand Ph2P(CH2)3SPh. Solvolysis as well as their cytotoxic activity, especially the influence of the Ph2P(CH2)3SPh. Solvolysis as well as their cytotoxic activity, especially the influence of the arene ligands, were explored.