Binuclear dichlorido(η6-p-cymene)ruthenium(II) complexes with bis(nicotinate)- And bis (isonicotinate)-polyethylene glycol ester ligands

Article abstract of DOI:10.1002/aoc.3238

Neutral binuclear ruthenium complexes 1-8 of the general formula [{RuCl₂(η⁶-p-cym)}₂ μ-(N^∩N)] (N^∩N=bis(nicotinate)- and bis (isonicotinate)-polyethylene glycol esters: (3-py)COO(CH₂CH₂O)_nCO(3-py) and (4-py)COO(CH₂CH₂O)_nCO(4-py), n =1-4), as well as mononuclear [RuCl₂(η⁶-p-cym)((3-py)COO(CH₂CH₂OCH₃)-κN)], complex 9, were synthesized and characterized using elemental analysis and electrospray ionization high-resolution mass spectrometry, infrared, ¹H NMR and ¹³C NMR spectroscopies. Stability of the binuclear complexes in the presence of dimethylsulfoxide was studied. Furthermore, formation of a cationic complex containing bridging pyridine-based bidentate ligand was monitored using ¹H NMR spectroscopy. Ligand precursors, polyethylene glycol esters of nicotinic (L1·2HCl-L4·2HCl and L9·HCl) and isonicotinic acid dihydrochlorides (L5·2HCl-L8·2HCl), binuclear ruthenium(II) complexes 1-8 and mononuclear complex 9 were tested for in vitro cytotoxicity against 518A2 (melanoma), 8505C (anaplastic thyroid cancer), A253 (head and neck tumour), MCF-7 (breast tumour) and SW480 (colon carcinoma) cell lines.

Full text of DOI:10.1002/aoc.3238

Full Paper
Received: 15 August 2014
Revised: 20 September 2014
Accepted: 29 September 2014
Published online in Wiley Online Library: 6 November 2014
(wileyonlinelibrary.com) DOI 10.1002/aoc.3238
6
Binuclear dichlorido(η -p-cymene)ruthenium(II)
complexes with bis(nicotinate)- and bis
(isonicotinate)-polyethylene glycol ester
ligands
Thomas Eichhorna, Evamarie Hey-Hawkinsb, Danijela Maksimović-Ivanićc,
Marija Mojićc, Jürgen Schmidtd, Sanja Mijatovićc, Harry Schmidta
and Goran N. Kaluđerovića,b*
Neutral binuclear ruthenium complexes 1–8 of the general formula [{RuCl2(η6-p-cym)}2 μ-(N∩N)] (N∩N = bis(nicotinate)- and bis
(isonicotinate)-polyethylene glycol esters: (3-py)COO(CH2CH2O)nCO(3-py) and (4-py)COO(CH2CH2O)nCO(4-py), n =1–4), as well as
mononuclear [RuCl2(η6-p-cym)((3-py)COO(CH2CH2OCH3)-κN)], complex 9, were synthesized and characterized using elemental analysis
and electrospray ionization high-resolution mass spectrometry, infrared, 1H NMR and 13C NMR spectroscopies. Stability of the binuclear
complexes in the presence of dimethylsulfoxide was studied. Furthermore, formation of a cationic complex containing bridging
pyridine-based bidentate ligand was monitored using 1H NMR spectroscopy. Ligand precursors, polyethylene glycol esters of
nicotinic (L1 · 2HCl–L4 · 2HCl and L9 · HCl) and isonicotinic acid dihydrochlorides (L5 · 2HCl–L8 · 2HCl), binuclear ruthenium(II) complexes
1–8 and mononuclear complex 9 were tested for in vitro cytotoxicity against 518A2 (melanoma), 8505C (anaplastic thyroid cancer),
A253 (head and neck tumour), MCF-7 (breast tumour) and SW480 (colon carcinoma) cell lines. Copyright © 2014 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site
Keywords: ruthenium(II) complexes; nicotinic acid; isonicotinic acid; polyethylene glycol esters; cytotoxicity
ω-diphenylphosphino-functionalized alkylphenyl sulfide, sulfoxide and
Introduction
sulfone ligands (Fig. 1D and E).[19,20] Several complexes from both
As ‘drug of the twentieth century’, cisplatin stimulated many scientists
in search for new metal-based antitumor drugs.[1–6] Successful
application of cisplatin has been found against head and neck, testic-
ular, cervical, bladder, ovarian and small-cell lung cancers.[6,7] Besides
its effectiveness, cisplatin expresses unfavourable severe impacts on
various organs (causing neurotoxicity, nephrotoxicity, ototoxicity,
vomiting and nausea),[8] thus restricting its therapeutic applications.[9]
Therefore, in vitro examination of the cytotoxic activity of diverse
transition metal complexes has been, and still is, a very important
and active field in medicinal chemistry during the last two
decades.[10–13] Ruthenium-based anticancer drugs deserve a special
position in research not only because of their good cytotoxicity[14–20]
but also because of their antimetastatic activity.[21] Especially, several
ruthenium complexes combine good selectivity between normal and
tumour cells with activity against cisplatin-resistant tumour cell
lines.[22–24] Some of the in vitro active ruthenium(II) complexes are
depicted in Fig. 1. Arene ruthenium(II) complexes (Fig. 1A) bearing
ethylenediamine ligand demonstrated favourable in vitro and in vivo
anticancer activity.[25,26] RAPTA-C (Fig. 1B), a ruthenium(II) complex with
1,3,5-triaza-7-phosphaadamantane, exhibited moderate cytotoxicity
but expressed promising in vivo antimetastatic activity.[27] A ruthe-
nium(II) complex having isonicotinate ester moiety (Fig. 1C) showed
a high anticancer activity towards human ovarian cell line A2780.[28]
Recently, Steinborn et al. investigated neutral and cationic arene
ruthenium(II) complexes having κP and κP,κS respectively coordinated
groups exhibited in vitro cytotoxicities similar to or greater than that
of cisplatin.
In order to investigate how less lipophilic substituents, compared
to complexes having alkyl moieties (see Fig. 1C),[28] and the
presence of two ruthenium(II) centres affect cytotoxic activity,
herein is described the synthesis and characterization of new ruthe-
nium(II) complexes 1–8 of the general formula [{RuCl2(η6-p-cym)}2
(N∩N)] with polyethylene glycol esters of nicotinic (L1–L4) and
isonicotinic acids (L5–L8) as ligands in bridging mode. Also, a
ruthenium(II) complex containing ethylene glycol monomethyl
ether nicotinate (L9), complex 9, was prepared and characterized.
*
Correspondence to: Goran N. Kaluđerović, MLU Halle-Witteberg, Institut für
Chemie. E-mail: goran.kaluderovic@chemie.uni-halle.de
a Institute of Chemistry, Martin Luther University Halle-Wittenberg, Kurt-Mothes-
Straße 2, D-06120, Halle, Germany
b Institute of Inorganic Chemistry, Leipzig University, Johannisallee 29, D-04103,
Leipzig, Germany
c
Institute for Biological Research ‘Sinisa Stankovic’, University of Belgrade, Bulevar
despota Stefana 142, 11060, Belgrade, Serbia
d Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry,
Weinberg 3, D-06120, Halle (Saale), Germany
Appl. Organometal. Chem. 2015, 29, 20–25
Copyright © 2014 John Wiley & Sons, Ltd.

Binuclear Ru(II) complexes with nicotinate and isonicotinate esters
with thionyl chloride in the presence of DMF.[31] The aroyl
chloride hydrochloride was suspended in toluene and the ap-
propriate polyethylene glycol was added and the mixture was
stirred overnight at room temperature.[31] Details are given in
the supporting information.
Preparation of [{RuCl2(η6-p-cym)}2μ-(3-py)COO(CH2CH2O)nCO(3-
py)-κN,κN′)] (1–4), [{RuCl2(η6-p-cym)}2μ-(4-py)COO(CH2CH2O)n
CO(4-py)-κN,κN′)] (5–8) and [RuCl2(η6-p-cym)((3-py)COO
(CH2CH2OCH3)-κN)] (9)
[{RuCl2(η6-p-cym)}2] (for the synthesis of 1, 2, 5, 6: 0.20mmol; 3:
0.18 mmol; 4: 0.15 mmol; 7: 0.23 mmol; 8: 0.19mmol; 9: 0.13 mmol)
and 1 equiv. of the appropriate ligand precursor L1 ·2HCl–L8 ·2HCl
or 2 equiv. of L9 · HCl were suspended in isopropanol (20 ml). The re-
action mixture was heated to 40 °C and stirred for 4 h for binuclear
complexes or 2 h for mononuclear complexes and then was stored
at À47 °C. The product precipitated as orange powder, which was fil-
tered off, washed with small amounts of isopropanol and diethyl
ether (4 × 2 ml) and dried in air.
1, n =1. Yield 106 mg (60%). Anal. Found (%): C, 44.72; H, 4.29; N,
3.09. Calcd for C34H40Cl4N2O4Ru2 (884.65) (%): C, 46.16; H, 4.56; N,
3.17. ESI HRMS (CH3OH), positive mode: calcd for [C34H40Cl4N2
O1402Ru2Na]+ 906.97214, m/z 906.97186 [M + Na]+. ESI HRMS
(CH3OH), negative mode: calcd for [C34H40Cl5N2O1402Ru2]À
Figure 1. Some ruthenium-based in vitro active compounds.
The reactivity of novel ruthenium(II) complex 4 against DMSO and
the formation of cationic complex 10 were studied. Ligand
precursors and the corresponding ruthenium(II) complexes were
tested against cancer cell lines.
1
918.95232, m/z 918.95438 [M + Cl]À. H NMR (400 MHz, CDCl3, δ,
ppm): 1.28 (d, 3 J(H,H) =6.9 Hz, 12H, CgH3), 2.08 (s, 6H, CeH3), 2.96
(sept, 3 J(H,H) =6.9 Hz, 2H, CfH), 4.73 (s, 4H, OCH2), 5.27 (d, 3 J(H,H)
=5.7Hz, 4H, CbH), 5.45 (d, 3 J(H,H) =5.7Hz, 4H, CcH), 7.46 (dd, 3 J
(H5,H4) =7.5Hz, 3 J(H5,H6) =5.5 Hz, 2H, H5), 8.42 (d, 3 J(H,H) =7.5 Hz,
2H, H4), 9.22 (d, 3 J(H,H) =5.5Hz, 2H, H6), 9.61 (s, 2H, H2). 13C NMR
(100MHz, CDCl3, δ, ppm): 18.3 (Ce), 22.2 (Cg), 30.7 (Cf), 63.3 (CH2O),
82.5 (Cc), 82.6 (Cb), 97.1 (Ca), 103.8 (Cd), 124.4 (C5), 126.7 (C3), 138.9
(C4), 156.0 (C2), 158.2 (C6), 163.4 (COO). IR (ATR, cmÀ1): 3060(w),
2962(w), 1724(s), 1604(w), 1470(w), 1430(w), 1351(w), 1270(s),
1195(w), 1112(m), 1053(m), 1031(w), 875(w), 835(w), 744(s), 691
(m), 624(w), 396(w), 288(s).
2, n =2. Yield: 148 mg (80%). Anal. Found (%): C, 46.38; H, 4.73; N,
3.02. Calcd for C36H44Cl4N2O5Ru2 (928.71) (%): C, 46.56; H, 4.78; N,
3.02. ESI HRMS (CH3OH), negative mode: calcd for [C36H44
Cl5N2O5102Ru2]À 962.97744, m/z 962.97853 [M + Cl]À. 1H NMR
(400MHz, CDCl3, δ, ppm): 1.30 (d, 3 J(H,H) =7.0Hz, 12H, CgH3), 2.07
(s, 6H, CeH3), 2.96 (sept, 3 J(H,H) =7.0 Hz, 2H, CfH), 3.86 (m, 4H,
OCH2), 4.53 (m, 4H, COOCH2), 5.24 (d, 3 J(H,H) =6.0Hz, 4H, CbH),
5.44 (d, 3 J(H,H) =6.0Hz, 4H, Cc), 7.34 (dd, 3 J(H5,H4) =7.9 Hz, 3 J(H5,
H6) =5.8 Hz, 2H, H5), 8.16 (d(b), 3 J(H,H) =7.9 Hz, 2H, H4), 9.14 (d(b),
3 J(H,H) =5.8Hz, 2H, H6), 9.61 (s, 2H, H2). 13C NMR (100 MHz, CDCl3,
δ, ppm): 18.4 (Ce), 22.4 (Cg), 30.8 (Cf), 64.9 (CH2COO), 69.1 (CH2O),
82.4 (Cc), 82.9 (Cb), 97.3 (Ca), 103.8 (Cd), 124.7 (C5), 127.1 (C3), 138.5
(C4), 155.8 (C2), 158.4 (C6), 163.6 (COO). IR (ATR, cmÀ1): 3066(w),
3046(w), 2966(w), 1732(s), 1602(w), 1470(m), 1429(w), 1376(m),
1290(s), 1140(m), 1122(s), 1054(m), 1023(w), 872(m), 842(w), 748
(s), 691(m), 457(w), 282(s), 229(s).
Experimental
Materials and Methods
All reactions and manipulations were carried out under argon
using standard Schlenk techniques. Toluene was dried over
Na/benzophenone, dichloromethane over CaH2 and isopropanol
over 3 Å molecular sieve and degassed with argon prior to use. 1H
NMR, 13C NMR and 31P NMR spectra were recorded at 300 K with
Inova 500 (500 MHz) or VXR (400 MHz) spectrometers. Chemical
shifts were recorded relative to solvent signals (CDCl3: δΗ
7.26 ppm, δC 77.16 ppm; D2O: δΗ 4.79 ppm) as internal references
and δ(31P) relative to external H3PO4 (85%). Microanalyses (C, H, N)
were performed at the Microanalytical Laboratory of the Univer-
sity of Halle using a CHNS-932 (LECO) elemental analyser.
Electrospray high-resolution mass spectrometry (ESI HRMS) was
carried out in positive- and negative-ion modes with a Bruker
Apex III (FTR-ICR) mass spectrometer. IR spectra were measured
from 250 to 4000 cmÀ1 with a Bruker Tensor 27 FT-IR spectrom-
eter with diamond ATR.
The starting compounds [{RuCl2(η6-p-cym)}2], [RuCl2(η6-p-cym)
(nic)] and [RuCl2(η6-p-cym)(inic)] were prepared according to litera-
ture procedures.[29,30] Thionyl chloride, nicotinic acid, isonicotinic
acid and polyethylene glycols were commercially available. Ethane-
1,2-diol was distilled prior to use and all other polyethylene glycols
were dried with sodium sulfate.
3, n =3. Yield: 138 mg (78%). Anal. Found (%): C, 45.97; H, 4.69; N,
2.80. Calcd for C38H48Cl4N2O6Ru2 (972.76) (%): C, 46.92; H, 4.97; N,
2.88. ESI HRMS (CH3OH), negative mode: calcd for [C38H48
Cl5N2O6102Ru2]À 1007.00475, m/z 1007.01415 [M + Cl]À. 1H NMR
(400MHz, CDCl3, δ, ppm): 1.31 (d, 3 J(H,H) =6.9Hz, 12H, CgH3), 2.11
(s, 6H, CeH3), 2.98 (sept, 3 J(H,H) =6.9 Hz, 2H, CfH), 3.73 (s, 4H, OCH2),
3.84 (m, 4H, OCH2), 4.51 (m, 4H, COOCH2), 5.26 (d, 3 J(H,H) =6.0 Hz,
4H, Cb), 5.46 (d, 3 J(H,H) =6.0 Hz, 4H, Cc), 7.39 (dd, 3 J(H5,H4) =7.8Hz, 3 J
Preparation of ligand precursors (L1 · 2HCl–L8 · 2HCl, L9 · HCl)
Ligand precursors were prepared using an adapted literature
procedure. Firstly, nicotinic and isonicotinic acid chloride hydro-
chlorides were synthesized by reaction of the appropriate acid
Appl. Organometal. Chem. 2015, 29, 20–25
Copyright © 2014 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

T. Eichhorn et al.
(H5,H6) =5.8 Hz, 2H, H5), 8.16 (d, 3 J(H,H) =7.8 Hz, 2H, H4), 9.14 (d, 3 J(H,H)
=5.8 Hz, 2H, H6), 9.61 (s, 2H, H2). 13C NMR (100 MHz, CDCl3, δ, ppm): 18.4
(Ce), 22.4 (Cg), 30.8 (Cf), 65.4 (CH2COO), 69.1, 71.1 (CH2O), 82.4 (Cc), 82.9
(Cb), 97.3 (Ca), 103.8 (Cd), 124.4 (C5), 127.4 (C3), 138.7 (C4), 156.1 (C2),
158.2 (C6), 163.7 (COO). IR (ATR, cmÀ1): 3064(w), 2964(w), 2874(w),
1722(s), 1600(w), 1428(w), 1376(w), 1284(s), 1198(w), 1105(s), 1053
(m), 870(w), 750(s), 693(m), 284(s), 234(s).
4H, CbH), 5.48 (d, 3 J(H,H) =6.0 Hz, 4H, CcH), 7.83 (d, 3 J(H,H) =6.5 Hz,
4H, H3), 9.23 (d, 3 J(H,H) =6.5 Hz, 4H, H2). 13C NMR (100 MHz, CDCl3,
δ, ppm): 18.4 (Ce), 22.4 (Cg), 30.9 (Cf), 65.4 (CH2OOC), 69.0, 70.9
(CH2O), 82.5 (Cc), 83.3 (Cb), 97.6 (Ca), 103.9 (Cd), 123.7 (C3), 138.7 (C4),
156.0 (C2), 164.0 (COO). IR (ATR, cmÀ1): 3063(w), 2962(w), 2874(w),
1729(s), 1412(m), 1278(s), 1119(s), 1056(m), 864(m), 769(s), 694(m),
449(w), 283(s).
4, n =4. Yield: 119 mg (77%). Anal. Found (%): C, 46.03; H, 4.93; N,
2.70. Calcd for C40H52Cl4N2O7Ru2 (1016.81) (%): C, 47.25; H, 5.15; N,
2.76. ESI HRMS (CH3OH), negative mode: calcd for [C40H52
Cl5N2O7102Ru2]À 1051.02987, m/z 1051.03641 [M + Cl]À. 1H NMR
(400 MHz, CDCl3, δ, ppm): 1.33 (d, 3 J(H,H) =6.9 Hz, 12H, CgH3), 2.13
(s, 6H, CeH3), 2.99 (sept, 3 J(H,H) =6.9Hz, 2H, CfH), 3.69 (m, 8H,
OCH2), 3.84 (m, 4H, OCH2), 4.52 (m, 4H, COOCH2), 5.27 (d, 3 J(H,H)
=6.0Hz, 4H, CbH), 5.47 (d, 3 J(H,H) =6.0 Hz, 4H, CcH), 7.43 (dd, 3 J
(H5,H4) =7.7 Hz, 3 J(H5,H6) =5.8 Hz, 2H, H5), 8.34 (d, 3 J(H,H) =7.7 Hz,
2H, H4), 9.23 (d, 3 J(H,H) =5.8 Hz, 2H, H6), 9.62 (s, 2H, H2). 13C NMR
(100 MHz, CDCl3, δ, ppm): 18.4 (Ce), 22.4 (Cg), 30.8 (Cf), 65.3
(CH2COO), 69.0, 70.8, 70.9 (CH2O), 82.4 (Cc), 82.9 (Cb), 97.4 (Ca),
103.8 (Cd), 124.4 (C5), 127.4 (C3), 138.8 (C4), 156.1 (C2), 158.1 (C6),
163.6 (COO). IR (ATR, cmÀ1): 3065(w), 2960(w), 2873(w), 1724(s),
1600(w), 1468(w), 1424(w), 1377(w), 1284(s), 1199(w), 1111(s),
1053(m), 1028(m), 940(w), 867(m), 802(w), 746(s), 692(m), 451(w),
397(w), 284(s), 232(s).
8, n =4. Yield: 180 mg (91%). Anal. Found (%): C, 47.41; H, 4.90; N,
2.83. Calcd for C40H52Cl4N2O7Ru2 (1016.81) (%): C, 47.25; H, 5.15; N,
2.76. ESI HRMS (CH3OH), negative mode: calcd for [C40H52
Cl5N2O7102Ru2]À 1051.02987, m/z 1051.03653 [M + Cl]À. 1H NMR
(400 MHz, CDCl3, δ, ppm): 1.31 (d, 3 J(H,H) =7.0 Hz, 12H, CgH3), 2.09 (s,
6H, CeH3), 2.98 (sept, 3 J(H,H) =7.0 Hz, 2H, CfH), 3.65 (m, 8H, OCH2),
3.82 (m, 4H, OCH2), 4.52 (m, 4H, COOCH2), 5.25 (d, 3 J(H,H) =5.6 Hz,
4H, CbH), 5.47 (d, 3 J(H,H) =5.6 Hz, 4H, CcH), 7.84 (d, 3 J(H,H) =6.4 Hz,
4H, H3), 9.22 (d, 3 J(H,H) =6.4 Hz, 4H, H2). 13C NMR (100 MHz, CDCl3, δ,
ppm): 18.5 (Ce), 22.5 (Cg), 30.9 (Cf), 65.6 (CH2OOC), 69.1, 70.9, 71.0
(CH2O), 82.6 (Cc), 83.4 (Cb), 97.7 (Ca), 104.0 (Cd), 123.8 (C3), 138.9 (C4),
156.0 (C2), 164.1 (COO). IR (ATR, cmÀ1): 3060(w), 2964(w), 2874(w),
1730(s), 1416(m), 1279(s), 1118(s), 1058(m), 864(m), 766(s), 696(m),
452(w), 286(s), 233(s).
9. Yield: 122 mg (96%). Anal. Found (%): C, 46.56; H, 4.85; N, 2.86.
Calcd for C19H25Cl2NO3Ru (487.38) (%): C, 46.82; H, 5.17; N, 2.78. ESI
HRMS (CH3OH), positive mode: calcd for [C19H25ClNO936Ru]+
446.05936, m/z 446.05947 [M À Cl]+. 1H NMR (400 MHz, CDCl3, δ,
ppm): 1.32 (d, 3 J(H,H) =6.9 Hz, 6H, CgH3), 2.14 (s, 3H, CeH3), 3.00
(sept, 3 J(H,H) =6.9 Hz, 1H, CfH), 3.43 (s, 3H, OCH3), 3.73 (t, 3 J(H,H)
5, n =1. Yield: 166 mg (94%). Anal. Found (%): C, 45.44; H, 4.41; N,
3.31. Calcd for C34H40Cl4N2O4Ru2 (884.65) (%): C, 46.16; H, 4.56; N,
3.17. ESI HRMS (CH3OH), positive mode: calcd for [C34H40
Cl4N2O4102Ru2Na]+ 906.97214, m/z 906.97214 [M + Na]+. ESI HRMS
(CH3OH), negative mode: calcd for [C34H40Cl5N2O1402Ru2]À
=5.0 Hz, 2H, OCH2), 4.51 (t, 3 J(H,H) =5.0 Hz, 2H, COOCH2), 5.26 (d, 3
J
(H,H) =6.0 Hz, 2H, CbH), 5.45 (d, 3 J(H,H) =6.0 Hz, 2H, CcH), 7.41
1
3
918.95232, m/z 918.95401 [M + Cl]À. H NMR (400 MHz, CDCl3, δ,
(dd, 3 J(H5,H4) =7.7Hz, JH5,H6 = 5.7 Hz, 1H, H5), 8.36 (d, 3 J(H,H)
ppm): 1.31 (d, 3 J(H,H) =6.9 Hz, 12H, CgH3), 2.11 (s, 6H, CeH3), 3.00
(sept, 3 J(H,H) =6.9Hz, 2H, CfH), 4.73 (s, 4H, OCH2), 5.25 (d, 3 J(H,H)
=5.9Hz, 4H, CbH), 5.46 (d, 3 J(H,H) =5.9 Hz, 4H, CcH), 7.81 (d, 3 J(H,H)
=6.2 Hz, 4H, H3), 9.24 (d, 3 J(H,H) =6.2Hz, 4H, H2). 13C NMR
(100 MHz, CDCl3, δ, ppm): 18.5 (Ce), 22.2 (Cg), 30.9 (Cf), 67.7 (CH2O),
82.6 (Cc), 83.1 (Cb), 97.6 (Ca), 104.2 (Cd), 123.4 (C3), 138.1 (C4), 156.1
(C2), 163.7 (COO). IR (ATR, cmÀ1): 3056(w), 2963(w), 1726(s), 1600
(w), 1468(w), 1429(w), 1270(s), 1197(w), 1111(s), 1056(m), 878(w),
746(s), 689(m), 626(w), 396(w), 289(s), 234(s).
=7.7 Hz, 1H, H4), 9.23 (d, 3 J(H,H) =5.7 Hz, 1H, H6), 9.63 (s, 1H, H2). 13
C
NMR (100 MHz, CDCl3, δ, ppm): 18.4 (Ce), 22.4 (Cg), 30.8 (Cf), 59.2
(CH3O), 65.1 (CH2OOC), 70.3 (CH2O), 82.5 (Cc), 82.7 (Cb), 97.4 (Ca),
104.0 (Cd), 124.2 (C5), 127.4 (C3), 138.7 (C4), 156.3 (C2), 158.0 (C6),
163.6 (COO). IR (ATR, cmÀ1) 3062(w), 2962(w), 2880(w), 1726(s),
1604(w), 1451(w), 1425(w), 1370(w), 1282(s), 1198(m), 1125(s), 1100
(m), 1053(m), 1028(m), 867(m), 802(w), 747(s), 695(m), 666(w), 542
(w), 455(w), 374(w), 284(s), 228(s).
6, n =2. Yield: 139 mg (76%). Anal. Found (%): C, 45.76; H, 4.72; N,
2.81. Calcd for C36H44Cl4N2O5Ru2 (928.71) (%): C, 46.56; H, 4.78; N,
3.02. ESI HRMS (CH3OH), positive mode: calcd for [C36H44
Cl3N2O5102Ru2]+ 893.03973, m/z 893.04128 [M À Cl]+. ESI HRMS
(CH3OH), negative mode: calcd for [C36H44Cl5N2O1502Ru2]À
Preparation of {di-μ-[(3-py)COO(C2H4O)4CO(3-py)-κN,κN′][RuCl
(η6-p-cym)]2} hexafluorido phosphate (10)
The ligand precursor L4 · 2HCl (0.2 mmol, n =4) and lithium
hydroxide (0.4 mmol) were suspended in isopropanol (20 ml).
The reaction mixture was stirred for 1 h at 40 °C. Dichlorido(η6-
p-cymene)ruthenium(II) dimer (76 μmol) was added and the
orange reaction mixture stirred for an additional 4 h and cooled
to room temperature. Dichloromethane (10 ml) was added until
the precipitated neutral ruthenium(II) complex was redissolved.
Excess ammonium hexafluoridophosphate (1.5 mmol) was
added in one portion and solid lithium hydroxide (8 μmol) was
added in small portions over 2 h. The crude product precipitated
out of the reaction mixture at À47 °C and was redissolved in
dichloromethane, filtered and the product was then obtained
by evaporation of dichloromethane.
1
962.97744, m/z 962.97962 [M + Cl]À. H NMR (400 MHz, CDCl3, δ,
ppm): 1.31 (d, 3 J(H,H) =6.9 Hz, 12H, CgH3), 2.08 (s, 6H, CeH3), 2.98
(sept, 3 J(H,H) =6.9 Hz, 2H, CfH), 3.83 (m, 4H, OCH2), 4.52 (m, 4H,
COOCH2), 5.34 (d, 3 J(H,H) =6.0Hz, 4H, CbH), 5.54 (d, 3 J(H,H)
=6.0 Hz, 4H, CcH), 7.76 (d, 3 J(H,H) =6.6Hz, 4H, H3), 9.27 (d, 3 J(H,H)
=6.6 Hz, 4H, H2). 13C NMR (100 MHz, CDCl3, δ, ppm): 18.4 (Ce), 22.5
(Cg), 30.9 (Cf), 65.0 (CH2OOC), 69.0 (CH2O), 82.3 (Cc), 83.6 (Cb), 97.8
(Ca), 103.6 (Cd), 123.6 (C3), 138.6 (C4), 156.1 (C2), 163.9 (COO). IR
(ATR, cmÀ1): 3060(w), 2964(w), 2875(w), 1730(s), 1416(m), 1377(w),
1284(s), 1228(m), 1129(s), 1059(m), 865(m), 769(s), 696(m), 452(w),
287(s), 234(s).
7, n =3. Yield: 188 mg (84%). Anal. Found (%): C, 45.65; H, 4.78; N,
2.76. Calcd for C38H48Cl4N2O6Ru2 (972.76) (%): C, 46.92; H, 4.97; N,
2.88. ESI HRMS (CH3OH), negative mode: calcd for [C38H48
Cl5N2O6102Ru2]À 1007.00475, m/z 1007.00303 [M + Cl]À. 1H NMR
(400 MHz, CDCl3, δ, ppm): 1.31 (d, 3 J(H,H) =6.9 Hz, 12H, CgH3), 2.09
(s, 6H, CeH3), 2.98 (sept, 3 J(H,H) =6.9 Hz, 2H, CfH), 3.68 (s, 4H, OCH2),
3.82 (m, 4H, OCH2), 4.51 (m, 4H, COOCH2), 5.26 (d, 3 J(H,H) =6.0 Hz,
Yield: 40 mg (39%). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.15 (d, 3 J(H,
H) =6.9 Hz, 12H, CgH3), 1.75 (s, 6H, CeH3), 2.58 (sept, 3 J(H,H) =6.9 Hz, 2H,
CfH), 3.68 (m, 16H, OCH2), 3.78 (m, 8H, OCH2), 4.49 (m, 8H, COOCH2),
5.72 (d, 3 J(H,H) =5.9 Hz, 4H, CbH), 5.96 (d, 3 J(H,H) =5.9 Hz, 4H, CcH),
7.74 (dd, 3 J(H5,H4) =7.8Hz, 3 J(H5,H6) =5.8Hz, 4H, H5), 8.46 (d, 3 J(H,H)
=7.8 Hz, 2H, H4), 9.43 (m,8H, H2,H6). 13C NMR (100 MHz, CDCl3, δ,
ppm): 18.0 (Ce), 22.4 (Cg), 31.1 (Cf), 66.2 (CH2COO), 68.9, 70.8, 71.6
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Appl. Organometal. Chem. 2015, 29, 20–25

Binuclear Ru(II) complexes with nicotinate and isonicotinate esters
(CH2O), 82.4 (Cc), 88.8 (Cb), 102.1 (Ca), 103.0 (Cd), 127.1 (C5), 128.4 (C3),
140.5 (C4), 153.2 (C2), 159.3 (C6), 163.2 (COO). 31P NMR (162 MHz, CDCl3,
δ, ppm): À141.7 (sept, J(P,F) =713 Hz, PFÀ6 ).
polyethylene glycol bis(isonicotinate) dihydrochlorides ((4-py)COO
(CH2CH2O)nCO(4-py); n =1, L5 · 2HCl; 2, L6· 2HCl; 3, L7 · 2HCl; 4,
L8· 2HCl), previously used for the preparation of silver and copper
coordination networks,[31,33] affords binuclear ruthenium(II) com-
plexes 1–8 with the general formula [{RuCl2(η6-p-cym)}2 μ-(N∩N)]
(Scheme 1), while starting binuclear ruthenium(II) dimer reacts with
ethylene glycol monomethyl ether nicotinate hydrochloride
(L9 · HCl, Scheme 1), in molar ratio 1:2, yielding mononuclear
[RuCl2(η6-p-cym)((3-py)COO(CH2CH2OCH3)-κN)] complex. The com-
plexes 1–9 are obtained as orange powders in good to very good
yields (60–96%). Compounds 1–9 are stable in air over weeks and
are soluble in dichloromethane, acetonitrile and DMF. Slow decom-
position occurs in all these solvents and resonances of free p-
cymene were detected in 1H NMR and 13C NMR spectra.
In vitro study
Foetal calf serum, RPMI-1640, phosphate-buffered saline and DMF
were obtained from Sigma (St. Louis, MO). Human thyroid
carcinoma 8505C, submandibular gland carcinoma A253, breast
adenocarcinoma MCF7, melanoma 518A2 and colon cancer
SW480 cell lines were obtained from ATCC. Cells were routinely
maintained in HEPES-buffered RPMI-1640 medium supplemented
with 10% foetal calf serum, 2 mM L-glutamine, 0.01% sodium
pyruvate and antibiotics (culture medium) at 37 °C in a humidified
atmosphere with 5% CO2. After standard trypsinization, cells were
seeded at a density of 1 × 103–2.5 × 103 cells per well in 96-well
plates for viability. Stock solutions of investigated compounds
(20 mM) were freshly prepared in DMF and diluted to various work-
ing concentrations with medium.
Elemental analyses of all complexes were carried out to prove
the composition. ESI MS, recorded in methanol as solvent, gives ev-
idence for molecular composition. Namely, [M+ Na]+ ions (for 1, 5)
or [MÀ Cl]+ ions (for 9) in positive mode and [M + Cl]À ions (for 1–8)
in negative mode are formed.
Ruthenium(II) complexes 1–9 show comparable NMR spectra.
The polyethylene oxide spacer protons of bridging ligands give
resonances in 1H NMR spectra in the range 4.7–3.5 ppm and
pyridine resonances are found from 7.2 to 9.7ppm. The hydrogen
atoms belonging to p-cymene ligand give chemical shifts similar
to literature values.[29] The N-coordination of ligands L1–L9
generates a strong downfield shift of all proton resonances of
the pyridine ring. For instance, the resonances of the protons in
o-positions to the coordinated nitrogen atom shift up to 9.6ppm
(Δδ =0.2ppm) for nicotinate ester ligands and up to 9.3ppm
(Δδ =0.2 ppm) for the isonicotinate moiety (see Experimental
section). The same tendencies are observed in 13C NMR spectra
and the resonances of the carbon atoms bound to coordinated
nitrogen are shifted downfield and found at 158 and 156 ppm for
complexes with nicotinate moieties and at 156 ppm for isonicotinate
moieties. The region with all the resonances of the polyethylene gly-
The viability of adherent viable cells was measured using
sulforhodamine-B (SRB) assay.[32] Cells were exposed to a wide range
of doses of the compounds for 96 h and then fixed with 10% trichlo-
roacetic acid for 2 h at 4 °C. After fixation, cells were washed in
distilled water, stained with 0.4% SRB solution for 30 min at room
temperature, washed and dried overnight. The dye was dissolved
in 10 mM Tris buffer and the absorbance was measured at 540 nm
with a reference wavelength of 640 nm. Results are expressed as
percentage of control that was arbitrarily set to 100%.
Results and Discussion
Syntheses and Characterization
The reaction of dichlorido(η6-p-cym)ruthenium(II) dimer with one
equivalent of ligand precursor, N∩N · 2HCl, polyethylene glycol bis
(nicotinate) ester dihydrochlorides ((3-py)COO(CH2CH2O)nCO(3-
py); n =1, L1 · 2HCl; 2, L2· 2HCl; 3, L3 · 2HCl; 4, L4 · 2HCl) and
1
col bridging group remains unchanged below 4.7 ppm in H NMR
spectra and between 60 and 75 ppm in 13C NMR spectra. Addition-
ally, in 13C NMR spectra of complexes 1–9 the resonances of the
carbon atoms from p-cymene ligand can be assigned.
In the IR spectra of 1–9 characteristic and most prominent bands
are seen and discussed herein. All observed bands in the spectra of
the ruthenium(II) complexes remain unchanged in comparison to li-
gand precursors. Weaker bands are observed near 3020 cmÀ1 for
heteroaromatic and aromatic vibrations of C–H bonds of the pyridine
ring and the p-cymene ligand. The bands near 2980 cmÀ1 are assigned
to the C–H vibrations of the alkyl groups. Strong absorption at
1730 cmÀ1 is assigned to the C=O from the ester function, while those
found at approximately 1280 and 1110 cmÀ1 are typical bands for
carbon–oxygen single bonds.[34] The band at around 750 cmÀ1 also
remains unchanged in the same region upon coordination. Those
absorptions are slightly stronger than in the ligand precursors,
due to the presence of the additional aromatic moiety. The band
at 285 cmÀ1 is assigned to the ruthenium–chlorine
vibration.[30,35]
Reversible Dissociation in DMSO
All complexes 1–9 dissociate in DMSO (Scheme 2) and 1H NMR and
13C NMR resonances of the corresponding free ligands and
dichlorido(η6-p-cymene)ruthenium(II) were monitored. Partial disso-
ciation is observed if small amounts of DMSO are added to chloro-
form solutions of the complexes. A higher molar ratio of DMSO in
Scheme 1. Synthesis of binuclear (1–8; for n see text) and mononuclear (9)
arene ruthenium(II) complexes and assignment of pyridine part of
coordinated ligands (see NMR data in text).
Appl. Organometal. Chem. 2015, 29, 20–25
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T. Eichhorn et al.
solution corresponds to higher resonance intensities of the dissoci-
ated complexes. The complexes are recovered by decreasing the
concentration of DMSO (addition of toluene and pentane, cooling
to À47 °C, DMSO precipitates) or by precipitation of complex (addi-
tion of EtOH, pentane and diethyl ether) from the reaction mixture.
Results from this study are in agreement with similar findings for (ar-
ene)ruthenium(II) complexes containing N-heterocyclic ligands.[36]
from the reaction mixture. The formation of derivative of complex
4 with just one pyridine-based ligand is also observed, if the
isolated cationic ruthenium(II) complex 10 is dissolved in alcohols.
The formation of cationic ruthenium(II) complex 10 is confirmed
using multinuclear NMR spectroscopy. The 1H NMR spectrum
shows the expected chemical shift pattern as already discussed
above for neutral complexes. With reaction 4 → 10 the most
prominent changes in the 1H NMR spectra are observed for
bound p-cymene moiety; thus the proton resonances for the
methyl and isopropyl groups are shifted to higher field while
those arising from the aromatic protons are shifted downfield.
The 13C NMR spectrum shows also the resonance differences
for carbon atoms from p-cymene moiety in comparison to
neutral complexes (Δδ up to 5 ppm). All other carbon
resonances are found to be nearly unshifted. The carbon atom
resonances of the coordinated p-cymene are found at approx-
imately 82.4, 88.8, 102.1 and 103.0 ppm. The 31P NMR spectrum
shows the expected septet for the hexafluoridophosphate ion
at À141.7 ppm.
Synthesis of cationic binuclear complex 10
Further attempts were made to synthesize a cationic N∩N bridged
ruthenium(II) complex. After neutralization of ligand precursor
L4 · 2HCl and addition of dichlorido(η6-p-cymene)ruthenium(II), ex-
cess of ammonium hexafluoridophosphate and lithium hydroxide,
new cationic complex 10 is obtained. The first attempts to synthe-
size cationic ruthenium(II) complex (Scheme 3) yielded mixtures of
complexes with one (4) or two coordinated L4 ligands (10). The ra-
tio of product formation was determined using the intensities of
the p-cymene and pyridine-based ligand resonances. The fast direct
reaction to cationic complex 10 and a slow back reaction to the
neutral complex 4 are identified using 1H NMR spectroscopy
(Fig. S37). A chemical equilibrium is formed in solution between 4
and 10. This equilibrium is shifted to the formation of cationic
complex 10 by multiple additions of lithium hydroxide, in order
to neutralize the formed HCl, and complex 10 can be precipitated
Biological Studies
The biological activity of the bidentate ligand precursors L1 · 2HCl–
L8· 2HCl, L9 · HCl and the prepared ruthenium(II) complexes 1–9
was studied in vitro. The cells were cultured in the presence of in-
creasing concentrations (up to 100 μM) of the ligand precursors
or corresponding ruthenium(II) complexes for 96 h. Afterwards the
cell viability was analysed using a sulforhodamine-B (SRB) assay.[32]
Results are summarized in Table 1 along with the cytotoxicity data
of ruthenium(II) complexes containing nicotinic (nic) and
isonicotinic acid (inic) ligands, [RuCl2(η6-p-cym)(nic)] and [RuCl2
(η6-p-cym)(inic)], as well as of cisplatin for comparison.
Tested ligand precursors show no cytotoxic activity at investi-
gated concentrations (IC50 > 100 μM). Similar results are observed
when cells are treated with binuclear complexes 2–8. Only
ruthenium(II) complex 1 shows moderate activity against the inves-
tigated cell lines. Complex 1 exhibits higher activity than ruthenium
(II) complexes containing nicotinic or isonicotinic acid, but lower
activity than cisplatin. Complex 1, as well as 2–8, has two equiva-
lents of metal per complex unit relative to cisplatin. Furthermore,
mononuclear complex 9, which possesses a methyl group instead
of the second [RuCl2(η6-p-cym)(nic)] moiety in binuclear complex
1 shows no activity against the selected cell lines (IC50 > 100 μM).
The in vitro activity of [RuCl2(η6-p-cym)(nic)] and [RuCl2(η6-p-cym)
(inic)] was investigated recently (IC50 > 200 μM).[29] Comparing
previous results of [RuCl2(η6-p-cym)(nic)] and 1, it is obvious that
the activity of 1 is greater because of the presence of derivatized nic-
otinic acid ligand. Moreover, the cytotoxicity is influenced by the
presence of two ruthenium(II) centres (1 versus 9). In comparison
to complex 1, introducing two to four ethylene oxide units in
binuclear ruthenium(II) complexes decreases the activity which
might be related to the lower lipophilicity of 2–4 than 1. Further-
more, the use of the isonicotinate instead of nicotinate esters does
not result in more active ruthenium(II) complexes. In contrast
to these findings, ruthenium(II) complexes with substituted
isonicotinates shown in Fig. 1C show much higher activity (2–
7 μM).[28] These results give evidence for the importance of the
effect of lipophilicity of the tested compounds on the biological
activity. Thus, ruthenium(II) complexes containing ligands with
more lipophilic side chains, such as alkyl[28] in comparison to
polyethylene glycol moieties, are found to be superior in cyto-
toxic activity than those with more hydrophilic chains.
Scheme 2. Dissociation and recovery of ruthenium(II) complexes in DMSO.
Scheme 3. Synthesis of cationic complex 10 and assignment of pyridine
part of coordinated L4 ligand (see NMR data in text).
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Appl. Organometal. Chem. 2015, 29, 20–25

Binuclear Ru(II) complexes with nicotinate and isonicotinate esters
Table 1. IC50 valuesa (in μM) of investigated compounds L1 · 2HCl–
L8 · 2HCl, L9 · HCl, 1–9, [RuCl2(η6-p-cym)(nic)] (nic = nicotinic acid),
[RuCl2(η6-p-cym)(inic)] (inic = isonicotinic acid) and cisplatin
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518A2 8505C A253 MCF-7 SW480
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53 1 > 100 57 10 80 16 92 11
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2
> 100 > 100 > 100 > 100 > 100
> 100 > 100 > 100 > 100 > 100
> 100 > 100 > 100 > 100 > 100
> 100 > 100 > 100 > 100 > 100
> 100 > 100 > 100 > 100 > 100
> 100 > 100 > 100 > 100 > 100
> 100 > 100 > 100 > 100 > 100
> 100 > 100 > 100 > 100 > 100
> 100 > 100 > 100 > 100 > 100
> 100 > 100 > 100 > 100 > 100
1.5 0.25.0 0.220.8 0.12.0 0.13.2 0.2
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3
4
5
6
7
8
9
[RuCl2(η6-p-cym)(nic)]
[RuCl2(η6-p-cym)(inic)]
Cisplatin
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Conclusions
A series of binuclear dichlorido(η6-p-cymene)ruthenium(II) com-
plexes [{RuCl2(η6-p-cym)}2 μ-(N∩N)] with bridging N∩N bis(nicotinate)-
and bis(isonicotinate)-polyethylene glycol ester ligands, (3-py)COO
(CH2CH2O)nCO(3-py) and (4-py)COO(CH2CH2O)nCO(4-py) respec-
tively (n =1–4), as well as a mononuclear [RuCl2(η6-p-cym)((3-py)
COO(CH2CH2OCH3)-κN)] complex were synthesized and character-
ized. Dissociation of the Ru–N bond was observed for all complexes
in DMSO and initial complexes were recovered by dilution of DMSO
solution. Corresponding cationic complexes containing two bridging
N∩N ligands can be formed as proved by NMR monitoring for com-
plex 10. The in vitro cytotoxicity of ligand precursors and correspond-
ing ruthenium(II) complexes was tested against five human cancer
cell lines. From the tested compounds, only complex 1, with the
shortest oxyethylene spacer and nicotinate moieties, exhibited mod-
erate activity (e.g. against 518A2: IC50 =53 1μM).
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Acknowledgements
[34] G. N. Kaluđerović, H. Kommera, S. Schwieger, H. Schmidt, A. Paethanom,
M. Kunze, R. Paschke, D. Steinborn, Dalton Trans. 2009, 10720.
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EHH and GNK gratefully acknowledge the European Union and the
Free State of Saxony (project no. 100099597) and DMI, MM and SM
the Ministry of Education, Science and Technological Development
(project no. 173013).
Supporting Information
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