Properties and biological activity of [Rh(COD)(N-N)]BF4 and [IrCl2(COD)(N-N)]BF4 polypyridyl complexes

Article abstract of DOI:10.1016/j.ica.2013.02.002

Square planar rhodium(I) complexes [Rh(COD)(N-N)]BF₄ (COD = 1,5-cyclooctadiene, N-N = 1,10-phenanthroline (phen) (1), 2,2′-bipyridine (bpy) (2), 4,7-diphenyl-1,10-phenanthroline (dpphen) (3), 4,4′-dimethyl-2, 2′-bipyridine (dmbpy) (4), dipyrido[3,2-a:2′,3′-c]-phenazine (dppz) (5), 2,9-dimethyl-1,10-phenanthroline (dmphen) (6)) and octahedral iridium(III) complexes [IrCl₂(COD)(N-N)]BF₄ (COD = 1,5-cyclooctadiene, N-N = 1,10-phenanthroline (phen) (7), 2,2′-bipyridine (bpy) (8), 4,4′-dimethyl-2,2′-bipyridine (dmbpy) (9)) have been obtained and characterized using spectroscopic methods. They are active agents towards Caco-2, Sk-mel, SNB-19 and C-32 tumor cells. Complexes 3, 5 and 6 are also efficient antibacterial agents against Gram-positive bacteria and compound 3 shows antifungal activity against AD1-9 and FY yeast strains.

Full text of DOI:10.1016/j.ica.2013.02.002

Inorganica Chimica Acta 400 (2013) 26–31
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Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Properties and biological activity of [Rh(COD)(N–N)]BF4
and [IrCl2(COD)(N–N)]BF4 polypyridyl complexes
a,
b
c
c
⇑
´
´
Urszula Sliwinska-Hill , Florian P. Pruchnik , Małgorzata Latocha , Dominika Nawrocka-Musiał ,
Stanisław Ułaszewski d
a Faculty of Pharmacy, Wrocław Medical University, Szewska 38, 50-139 Wrocław, Poland
b Faculty of Chemistry, University of Wrocław, Joliot-Curie 14, 50-383 Wrocław, Poland
c Faculty of Pharmacy, Medical University of Silesia, Narcyzów 1, 41-200 Sosnowiec, Poland
d Institute of Genetic and Microbiology, University of Wrocław, Przybyszewskiego 63/67, 51–148 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2012
Received in revised form 3 February 2013
Accepted 4 February 2013
Available online 15 February 2013
Square planar rhodium(I) complexes [Rh(COD)(N–N)]BF4 (COD = 1,5-cyclooctadiene, N–N = 1,10-phenan-
throline (phen) (1), 2,20-bipyridine (bpy) (2), 4,7-diphenyl-1,10-phenanthroline (dpphen) (3),
4,40-dimethyl-2,20-bipyridine (dmbpy) (4), dipyrido[3,2-a:20,30-c]-phenazine (dppz) (5), 2,9-dimethyl-
1,10-phenanthroline (dmphen) (6)) and octahedral iridium(III) complexes [IrCl2(COD)(N–N)]BF4
(COD = 1,5-cyclooctadiene, N–N = 1,10-phenanthroline (phen) (7), 2,20-bipyridine (bpy) (8), 4,40-
dimethyl-2,20-bipyridine (dmbpy) (9)) have been obtained and characterized using spectroscopic meth-
ods. They are active agents towards Caco-2, Sk-mel, SNB-19 and C-32 tumor cells. Complexes 3, 5 and 6
are also efficient antibacterial agents against Gram-positive bacteria and compound 3 shows antifungal
activity against AD1–9 and FY yeast strains.
Keywords:
Rhodium(I) and iridium(III) complexes
Polypyridyl complexes
Antitumor agents
Ó 2013 Elsevier B.V. All rights reserved.
Antibacterial agents
1. Introduction
tion of Rh–N bonds with cytosine or guanine bases, but intercala-
tion of polypyridyl ligands between nucleotide bases is also
Since the discovery of the antiproliferative properties of cis-
platin, many platinum complexes have been synthesized, charac-
terized and tested as antitumor agents. Non-platinum antitumor
compounds have gained considerable interest. A variety of antitu-
mor active agents based on transitions and main groups metals
have been found and evaluated. It has been proved that many com-
plexes of platinum group metals possess high antitumor activity,
especially rhodium, ruthenium, iridium, palladium and platinum
[1–5]. Many metal compounds show also high antibacterial activ-
ity [1].
Because DNA is a one of the potential target site for transition
metal anticancer compounds, the binding of rhodium and iridium
complexes to the double helix DNA was studied. Rhodium and irid-
ium(III) complexes with polypyridyl ligands can bind DNA through
intercalation of this ligands or via formation of coordination M–N
bond with purine and pyrimidine bases [6,7].
possible [8,9].
A number of rhodium(III) complexes show high anticancer
activity. The complexes containing dimethyl sulfoxide [RhCl3
(N–N)(DMSO)] (N–N = phen, bpy, dpphen, 1,10-phenanthroline-
5,6-dione,dmbpy) [9], [RhCl3(NH3)(DMSO)2] [4,5], [RhCl3
(Him)(DMSO)2] (Him – imidazole) [10] are active against many
cancers. Their activity is comparable with that of cisplatin.
Rhodium(II) carboxylato complexes [Rh2(
l-OOCR)4] and [Rh2
(l-OOCR)2(N–N)2(H2O)2] (RCOO)2 (R = alkyl, hydroxyalkyl, amino-
alkyl, etc., N–N = bpy, phen and their derivatives) were shown to
be active against oral carcinoma, Ehrlich ascites, leukemia P388
and L1210 leukemia [4,5]. Activity of complexes with polypyridyls
is greater than that of dirhodium tetracarboxylates. The mecha-
nism of action of dirhodium(II) complexes can be similar to that
of cisplatin. Dirhodium carboxylates form covalent Rh–DNA ad-
ducts, including interstrand cross-links, therefore DNA can be con-
Rhodium complexes belong to the very promising class of anti-
tumor agents. Biological activity characterizes mainly rhodium(I),
rhodium(II) and rhodium(III) compounds. Cytostatic activity of
rhodium complexes may be a result of their interaction with
DNA. The polypyridyl compounds can react with DNA via forma-
sidered a potential target for biological activity of these
compounds [11]. It has been shown that rhodium(II) carboxylates
inhibit enzymes having sulfhydryl groups in or near their active
site, while the enzymes without SH groups were not affected.
The reaction of rhodium(II) carboxylates with enzymes containing
SH groups closely parallels the toxicity and anti-tumor activity of
these complexes [12]. Interesting antitumor activity is also shown
by rhodium(I) complexes. Rhodium(I) square planar compounds
⇑
Corresponding author.
E-mail address: urszula.sliwinska-hill@am.wroc.pl (U. Sliwin´ ska-Hill).
´
0020-1693/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ica.2013.02.002

´
´
27
U. Sliwinska-Hill et al. / Inorganica Chimica Acta 400 (2013) 26–31
[RhCl(COD)(NH3)], [RhCl(COD)(piperidine)] and [Rh(acac)(COD)]
(COD = 1,5-cyclooctadiene) are efficient agents against leukemia
L1210, Ehrlich ascites carcinoma, sarcoma 180 and Lewis lung
carcinoma [13–15], and inhibit the development of metastases
[13–18]. The antitumor activity of acetylacetonato complexes is
interesting because it is comparable with that of cisplatin. Further-
more, they are only marginally nephrotoxic [13–15]. The cationic
rhodium complexes with Schiff bases of pyridine-2-carbaldehyde
[Rh(COD)(C5H4NC@NR)]Cl (R@Me, Et, CHMe2) exhibit activity
against Lewis lung carcinoma, P388 lymphocytic leukemia and
MCa mammary carcinoma and on the lung metastatic tumor
[16–18]. The dimeric rhodium(I) complexes – [Rh2Cl2(COD)2], [Rh2-
Cl2(NBD)2] and [Rh2Cl2(CH2@CHCH2CH2CH@CH2)2] display negligi-
ble effects on subcutaneous tumor growth, showing instead a
remarkable anti-metastatic effect [13–19]. Rhodium(I) complexes,
e.g. [Rh(COD)(2,20-bipyridine)]Cl also show antibacterial activity
[20]. Recently it has been found that ferrocenoylacetonato com-
plex, [Rh(COD)(fcacac)], show antitumor activity and is effective
radiosensitizers [21].
Scheme 1. Structures of the used ligands: 4,7-diphenyl-1,10-phenanthroline
(dpphen); dipyrido[3,2-a:20,30-c]-phenazine (dppz); 2,9-dimethyl-1,10-phenan-
throline (dmphen); 2,20-bipyridine (bpy); 4,40-dimethyl-2,20-bipyridine (dmbpy).
There are only a limited number of communications on the bio-
logical activity of iridium complexes. Iridium(III) complexes pos-
sess low-spin 5d6 configuration and are generally thought to be
too inert to show high reactivity. Indeed, the inertness of Ir(III)
has allowed to design of complexes performing function as rigid
scaffolds inhibiting kinase enzymes, important in angiogenesis
processes. The induction of new blood vessels is an important pro-
cess in tumor progression. The organometallic octahedral iridium
complex [IrCl2(COD)L] (COD = 1,5-cyclooctadiene, L = pyrido[2.3-
a]N-benzylpyrrolo[3,4-c]carbazole-5,7(6H)-dionate) is the first
compound of this type having antiangiogenic properties in vivo
and inhibits angiogenesis in developing zebrafish embryos and tu-
mor-cell-induced angiogenesis. The performed analysis prove that
iridium complex strongly inhibits vessels formation [22,23].
Some polypyridyl and half-sandwich iridium(III) complexes
show high anticancer activity. The antiproliferative activity of octa-
hedral complex fac-[IrCl3(DMSO)(5,6-dmphen)] toward breast
cancer MCF-7 cells line is considerably higher than that of fac-
[IrCl3(DMSO)(phen)]. This complex also causes significant inhibi-
tion of Jurkat leukemia cell proliferation and extensive apoptosis.
The antiproliferative activity of 5,6-dimethyl-1,10-phenanthroline
iridium complex is strongly selective toward MCF-7 and HT-29
cancer cells over normal HFF-1 and immortalized HEK-293 cells.
This complex also exhibits high selectivity toward BJAB lymphoma
cells relative to healthy leukocytes. The mer-[IrX3(DMSO)(phen)]
(X–Cl, Br) are significantly less cytotoxic than their fac isomers
[24,25].
Rhodium and iridium complexes with polypyridyl ligands unꢀdergo
redox reactions and many of them can also activate O2, O2 and
HO2 [28–30]. It is known that in tumor cells, levels of reactive
ꢀ
oxygen species (ROS) are enhanced [31]. Therefore, metal com-
plexes interacting with ROS can influence redox metabolism of
the cells and lead to cell death. Polypyridyl Rh(III) are intercalators
able to bind specifically in the destabilized regions near DNA base
mismatches and to cleave the DNA backbone [32]. Similar proper-
ties should show Ir(III) polypyridyl coordination compounds. Thus,
it seems that it is worthwhile to investigate properties and biolog-
ical activity of rhodium and iridium polypirydyl complexes.
The 1,5-cyclooctadiene complexes of Rh(I) containing polypyri-
dyl ligands and biological activity of these compounds were scar-
cely investigated and properties of Ir(III) complexes with these
ligands were not studied. We report here synthesis, properties,
cytotoxic, antibacterial and antifungal activity in vitro of 1,5-cyclo-
octadiene square planar rhodium(I) complexes [Rh(COD)(N–N)]BF4
and octahedral iridium(III) complexes [IrCl2(COD)(N–N)]BF4 with
2,20-bipyridine, 1,10-phenanthroline and their derivatives
(Scheme 1).
2. Experimental
Reagents and solvents (analytical grade), used as received, were
purchased from polish company POCH and Aldrich and [Rh2Cl2
(COD)2] and [Ir2Cl2(COD)2] from Aldrich.
Cyclometalated iridium(III) polypyridineindole complexes of
the type [Ir(N–C)2(N–N)](PF6) (N–C = 2-phenylpyridine, 7,8-benzo-
quinoline, etc.) show high cytotoxic activity toward HeLa cells. The
IC50 values of these complexes are significantly smaller than that of
cisplatin and related indole-free complexes, suggesting that the in-
dole unit renders the complexes more cytotoxic to HeLa cells [26].
The organometallic half-sandwich compounds of the type
Infrared spectra (KBr pellets and Nujol) were recorded with a
Bruker IFS 113v and Bruker 66/s, UV–Vis spectra on a Cary 500
and 1H NMR spectra on a Bruker AMX 300 and Bruker Avance
500. Elemental analyses of C, H and N were performed with a Vario
EL3 CHN analyzer and determination of Cl was performed using
mercurometric method.
Purity of complexes was also checked by HPLC on Agilent 1200
chromatograph using a reversed phase C8 column and an isocratic
elution with methanol as well as by ESI-MS. Purity of all prepared
complexes was above 99%. The mass spectra were recorded on a
Bruker MicrOTOF-Q spectrometer (Bruker Daltonik, Bremen,
Germany), equipped with an Apollo II electrospray ionization
source with an ion funnel. The mass spectrometer was operated in
the positive ion mode. The instrumental parameters were as fol-
lows: scan range m/z 100–2000, dry gas–nitrogen, temperature
200 °C, ion source voltage 4500 V. The spectra of the compounds
were recorded in methanol solutions. Before analysis the instru-
ment was calibrated externally with the Tunemix™ mixture (Bruker
Daltonik, Germany) in the quadratic regression mode. The stoichi-
ometry of the analyzed ions was confirmed by the isotopic patterns.
[(
tadienyl, N–N-1,10-phenanthroline, 2,20-bipyridine, ethylenedia-
mine) and [( picolinate)
5-C5Me4C6H4C6H5)Ir(pico)Cl] (pico
show good activity toward A2780 human ovarian cancer cells.
Complexes of the type [(
5-C5Me4C6H4C6H5)Ir(N–N)Cl]PF6
g g
5-Cpxph)Ir(N–N)Cl]+, ( 5-Cpxph-tetramethyl-(phenyl)-cyclopen-
g
–
g
(N–N-1,10-phen, 2,20-bpy) exhibit high cytotoxicity toward
A2780 cell line. The complexes without phenyl groups in Cp⁄ moi-
ety are not active against this cell line, suggesting that phenyl
groups in the Cp⁄ ring play a crucial role in the mechanism of
action [27]. Complexes [(
g
5-C5Me4C6H5)Ir(phen)Cl]PF6 and
[(
g
5-C5Me4C6H4C6H5)Ir(phen)Cl]PF6 can exhibit dual mode bind-
ing to DNA–iridium binding to G-N7 accompanied by potential
intercalation of the phenyl substituents on the Cp⁄ ring [27].

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´
U. Sliwinska-Hill et al. / Inorganica Chimica Acta 400 (2013) 26–31
28
2.1. Syntheses
90m; 103w; 109w; 124w; 129w; 137vw; 147w; 169w; 173w;
179vw; 184w; 199vw; 205vw; 220w; 225w; 230w; 239m;
254m; 272w; 286w; 298w; 307w; 325m; 342m; 363s; 384w;
391m; 411m; 416m; 444s; 462s; 482s; 493vs; 505m; 520vs;
548s; 577s; 580s; 594m; 614vw; 633m; 668w; 672w; 707s;
734s; 770s; 815w; 822w; 833m; 845s; 854w; 866m; 873m;
879w; 893w; 907w; 935w; 960m; 970w; 979m; 995m; 1004m;
1027s; 1066vs; 1161m; 1180m; 1188m; 1201w; 1222m; 1229m;
1283w; 1298m; 1303m; 1312w; 1332m; 1355m; 1377m;
1390m; 1406m; 1422s; 1446s; 1457s; 1463s; 1484m; 1506w;
1522s; 1561s; 1576m; 1593s; 1622m;1903w; 1958w; 2340w;
2361w; 2598m; 2727m; 2854vs; 2870vs; 2923vs; 2953vs;
3003s; 3033m; 3057m; 3075w; 3086w; 3101w.
2.1.1. [Rh(COD)(phen)]BF4 2H2O (1)
A solution of [Rh2Cl2(COD)2] (0.1 mmol), 1,10-phenanthroline
(0.2 mmol) and HBF4 (0.025 ml, 40% water solution) in 5 mL of eth-
anol was stirred at room temperature for 18 h. The red-orange
product was filtrated off, washed with ethanol and dried under
vacuum. Yield 65%. Anal. Calc. for C20H24N2O2BF4Rh: C, 46.72; H,
4.70; N, 5.45. Found: C, 46.88; H, 4.35; N, 5.63%. 1H NMR in
DMSO-d6 (ppm): 8.92(dd, 2H, 4,7H, J(4,3/7,8) = 8.2 Hz; J(2,4/
9,7) = 1.1 Hz); 8.48 (d, 2H, 2,9H, J(2,3/9,8) = 5.1 Hz); 8.27 (s, 2H,
5,6H); 8.04 (dd, 2H, 3,8H); 4.82 (s, 4H, CH COD); 2.55 (m, 4H, CH2
COD); 2.15 (m, 4H, CH2 COD). 13C NMR in DMSO-d6 (ppm):
150.40 (CH phen); 146.14 (C–C phen); 140.37 (CH phen); 129.85
(C–C phen); 127.54 (CH phen); 126.09 (CH phen); 84.42 (d, CH
2.1.4. [Rh(COD)(dmbpy)]BF4(4)
COD); 29.72 (CH2 COD). UV–VIS in DMSO, (k, nm, (
e
, L molꢀ1
-
Yield 73%. Anal. Calc. for C20H24N2BF4Rh: C, 49.82; H, 5.02; N,
cmꢀ1)): 479 (255); 368 (1320); 304 (3740); 278 (7530). IR (Nu-
jol/KBr, cmꢀ1): 62w; 66w; 72w; 77m; 81m; 91w; 94w; 102w;
109w; 114w; 127vw; 130vw; 136vw; 145vw; 165w; 179w;
191vw; 199vw; 208vw; 219vw; 225vw; 246m; 258w; 273w;
284w; 306w; 331m; 347m; 357m; 417m; 449s; 477s; 492s;
502s; 511m; 520vs; 558w; 647vw; 718s; 736w; 771w; 787w;
805w; 820w; 827w; 844s; 875w; 896w; 913w; 964m; 991m;
1007m; 1035s; 1053vs; 1086s; 1109s; 1148m; 1176w; 1189w;
1221m; 1249w; 1282w; 1305m; 1329w; 1342w; 1366w;
1377m; 1429s; 1453m; 1462m; 1481m; 1491m; 1519m; 1558w;
1585w; 1601w; 1628w; 2853s; 2923vs; 2953vs; 3069m; 3082w;
3098w.
5.81. Found: C, 49.50; H, 4.92; N, 5.68%. 1H NMR in CDCl3 (ppm):
0
6,60
8.40 (s, 2H, 3,3 H); 7.58 (d, 2H,
H, J(6,5/60,50) = 5.5 Hz); 7.35 (d,
0
2H, 5,5 H); 4.49 (s, 4H, CH COD); 2.59 (s, 4H, CH2 COD + 6H, CH3);
2.11 (m, CH2 COD). 13C NMR in CDCl3 (ppm): 156.24 (C–C);
154.94 (C–C); 146.98 (CH); 127.85 (CH); 125.13 (CH); 84.69 (d,
CH COD); 30.23 (CH2 COD); 21.58 (CH3). UV–VIS in CHCl3, (k, nm,
(e
, L molꢀ1 cmꢀ1)): 463 (284); 321 (4900); 266 (4530). IR (Nujol/
KBr, cmꢀ1): 53w; 68w; 79w; 87m; 89m; 115w; 129w; 140w;
155m; 162m; 180m; 205m; 235m; 246m; 253m; 268m; 297m;
311m; 329m; 354s; 424s; 440m; 472s; 491m; 514vs; 523vs;
561m; 605vw; 688vw; 724vw; 775w; 817w; 833s; 860w; 879w;
889w; 927vw; 954m; 973w; 990w; 1023m; 1039s; 1057vs;
1076s; 1103s; 1128w; 1143w; 1178w; 1221w; 1246w; 1289w;
1307w; 1331w; 1383m; 1413w; 1429m; 1454s; 1478m; 1494m;
1503w; 1559w; 1616s; 1823vw; 1864vw; 1965vw; 2518w;
2727w; 2854vs; 2924vs; 2953vs; 3024m; 3088m; 3121w.
The complexes 2–6 were prepared analogously as compound 1.
2.1.2. [Rh(COD)(bpy)]BF4 (2)
Yield 59%. Anal. Calc. for C18H20N2BF4Rh; C, 47.61; H, 4.44; N,
6.17. Found: C, 47.18; H, 4.20; N, 6.12%. 1H NMR in DMSO-
3,30
0
d6(ppm): 8.58 (d, 2H,
H, J(3,4/30,40) = 8.0 Hz;); 8.30 (t, 2H, 4,4 H,
2.1.5. [Rh(COD)(dppz)]BF4 4H2O (5)
0
J(4,3/40,30) = J(4,5/40,50) = 7.8 Hz); 8.02 (d, 2H, 6,6 H, J(6,5/
Yield 75%. Anal. Calc. for C26H30N4BF4O4Rh: C, 47.88; H, 4.64; N,
8.59. Found: C, 48.04; H, 3.90; N, 8.22%. 1H NMR in DMSO-d6
(ppm): 9.74 (d, 2H, 4,7H, J(4,3/7,8) = 8.1 Hz); 8.53 (d, 2H, 2,9H,
J(2,3/9,8) = 5.0 Hz); 8.46 (dd, 2H, 3,8H, J(3,2/8,9) = 6.5 Hz; J(3,4/
8,7) = 3.4 Hz); 8.19 (m, 4H, PhH); 4.84 (s, 4H, CH COD); 2.61 (m,
4H, CH2 COD); 2.19 (m, 4H, CH2 COD). 13C NMR in DMSO-d6
(ppm): 151.64 (CH dppz); 149.21 (C–C dppz); 141.90 (CH dppz);
139.12 (C–C dppz); 136.62 (CH dppz); 132.69 (CH dppz); 129.33
(C–H dppz); 128.94 (C–C dppz); 127.52 (C–H dppz); 84.99 (d, CH
0
60,50) = 5.1 Hz); 7.72 (m, 2H, 5,5 H); 4.60 (s, 4H, CH COD); 2.53
(4H, CH2 COD); 2.10(m, 4H, CH2 COD). 13C NMR in DMSO-
d6(ppm): 155.85 (C–C bpy); 149.43 (CH bpy); 141.44 (CH bpy);
127.73 (CH bpy); 123.53 (CH bpy); 84.73 (d, CH COD); 29.75
(CH2 COD). UV–VIS in DMSO (k, nm, (e
, L molꢀ1 cmꢀ1)): 478
(770); 350 (4990); 327 (14870). IR (Nujol/KBr, cmꢀ1): 55w; 61w;
66w; 71m; 81m; 86m; 91m; 117w; 123w; 143w; 155vw; 165w;
174vw; 184vw; 191vw;200vw; 205vw; 211vw; 219vw; 242w;
251w; 274vw; 286vw; 300w; 317w; 343m; 359m; 365m; 384w;
416s; 422m; 447s; 459m; 471m; 484.s; 507m; 522vs; 551w;
641w; 648vw; 689vw; 729m; 741w; 768s; 786w; 807w; 820w;
838vw; 868w; 895w; 905w; 959w; 970m; 984w; 1000m; 1025s;
1035s; 1044s; 1050s; 1065vs; 1091s; 1102s; 1124m; 1161w;
1183w; 1224w; 1247w; 1286w; 1306m; 1321m; 1332w;
1377m; 1429m; 1445s; 1466s; 1474s; 1492w; 1501w; 1568w;
1601m; 1606m; 1785vw; 1915vw; 1958vw; 2000vw; 2349w;
2854vs; 2872vs; 2922vs; 2954vs; 3030m; 3082m; 3099m;
3118m; 3124m.
COD); 29.83 (CH2 COD). UV–VIS in DMSO, (k, nm, (e -
, L molꢀ1
cmꢀ1)): 484 (890); 381 (15740); 363 (15940). IR (Nujol/KBr,
cmꢀ1): 56vw; 60w; 78w; 84w; 112m; 115m; 126m; 140m;
157m; 172w; 187w; 203w; 209w; 220w; 241w; 255w; 278w;
331m; 361s; 382m; 425vs; 450vs; 475s; 484s; 506s; 521vs;
551s; 564s; 569s; 580s; 618w; 638w; 650w; 687vw; 725s;
772m; 810m; 846w; 873w; 895vw; 904vw; 966w; 975w; 998m;
1051vs; 1062vs; 1098s; 1134m; 1150w; 1179w; 1213w; 1220w;
1234w; 1285w; 1302w; 1330w; 1342m; 1360s; 1377m; 1422m;
1464s; 1495m; 1504m; 1546vw; 1580w; 1601w; 1635w;
1653w; 2728w; 2854vs; 2869vs; 2923vs; 2952vs; 3085m;
3099w; 3136w.
2.1.3. [Rh(COD)(dpphen)]BF4 (3)
Yield 71%. Anal. Calc. for C32H28N2BF4Rh; C, 60.98; H, 4.48; N,
4.44. Found: C, 60.82; H, 4.26; N, 4.41%. 1H NMR in CDCl3 (ppm):
8.40 (d, 2H, 2,9H, J(2,3/8,9) = 5.2 Hz); 8.02 (s, 2H, 5,6H); 7.97 (d,
2H, 3,8H); 7.55 (m, 10H, PhH); 4.86 (s, 4H, CH COD); 2.64 (d, 4H,
CH2 COD); 2.20 (m, CH2 COD). 13C NMR in CDCl3 (ppm): 152.52
(C–C arom.); 149.45 (C–H arom); 147.68 (C–C arom); 135.28 (C–
C arom); 130.01 (C–H arom); 129.59 (C–H arom); 129.18 (C–H
arom); 128.27 (C–C arom); 126.48 (C–C arom); 125.49 (C–H arom);
2.1.6. [Rh(COD)(dmphen)]BF4ꢁH2O (6)
Yield 71%. Anal. Calc. for C22H26N2BF4ORh: C, 50.41; H, 5.00; N,
5.34. Found: C, 50.08; H, 5.42; N, 4.95%. 1H NMR in DMSO-d6
(ppm): 8.91 (d, 2H, 4,7H, J(4,3/7,8) = 8.4 Hz); 8.24 (s, 2H, 5,6H);
6.08 (d, 2H, 3,8H, J(3,4/8,7) = 8.3 Hz); 4.44 (s, 4H, CH COD); 3.03
(s, 6H, CH3) 2.40 (m, 4H, CH2 COD); 1.98 (m, 4H, CH2 COD). 13C
NMR in DMSO-d6 (ppm): 159.06 (CH); 141.33 (CH); 136.95 (C–
C); 127.69 (C–C); 126.56 (CH); 125.62 (C–C); 87.35 (d, CH COD);
30.18 (CH2 COD); 22.86 (CH3). UV–VIS in DMSO, (k, nm): 388 sh;
353 sh, 323sh. IR (Nujol/KBr, cmꢀ1): 70w; 85m; 90m; 94m;
85.67 (d, CH COD); 30.56 (d, CH2 COD). UV–VIS in CHCl3, (k, nm, (e,
L molꢀ1 cmꢀ1)): 495 (305); 375 (2970); 325 (6570); 299 (12670);
IR (Nujol/KBr, cmꢀ1): 54w; 60m; 65m; 70m; 75m; 80m; 85m;

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U. Sliwinska-Hill et al. / Inorganica Chimica Acta 400 (2013) 26–31
103m; 108m; 112m; 124w; 129w; 135w; 143w; 162w; 174w;
179w; 250m; 258m; 280m; 304w; 377w; 385w; 415w; 472w;
485w; 508w; 518w; 526w; 545m; 570vw; 637w; 678w; 720m;
775w; 808w; 815w; 839w; 860s; 886m; 961m; 989m; 995m;
1008m; 1040s; 1050vs; 1067vs; 1093s; 1160s; 1204m; 1212m;
1228m; 1284m; 1292m; 1299m; 1328m; 1348m; 1380s; 1464s;
1501m; 1535s; 1566m; 1578m; 1605s; 1626s; 1636m; 1973m;
2854vs; 2870vs; 2924vs; 2953vs; 3023s; 3073s; 3139s; 3181s.
2.1.9. [IrCl2(COD)(dmbpy)]BF4 (9)
Yield 21%. Anal. Calc. for C20H24N2Cl2BF4Ir: C, 37.40; H, 3.77; N,
4.36; Cl, 11.04. Found: C, 37.36; H, 3.86; N, 4.24; Cl, 9.78%. 1H NMR
0
0
in DMSO-d6(ppm): 8.75 (s, 2H, 3,3 H); 8.43 (d, 2H, 6,6 H, J(6,5/
0
60,50) = 5.8 Hz); 7.69 (d, 2H, 5,5 H); 6.12 (s, 4H, CH COD); 2.80 (d,
4H, CH2 COD); 2.65 (s, 6H, CH3). 13C NMR in DMSO-d6(ppm):
155.10 (C–H Me2bpy); 154.71 (C–C Me2bpy); 149.04 (CH Me2bpy);
129.45 (CH Me2bpy); 126.30 (CH Me2bpy); 102.84 (CH COD); 28.86
(CH2 COD); 20.90 (CH3 Me2bpy). UV–VIS in DMSO, (kmax, nm, (e,
Mꢀ1 cmꢀ1)): 306 (12471); 318 (12899). IR [Nujol/KBr, cmꢀ1]:
57w; 79m; 100m; 111m; 140w; 153w; 216m; 226m; 249m;
305vs; 318m; 327m; 361m; 393vw; 422m; 439w; 483w; 496w;
524vs; 571s; 575m; 590w; 726w; 742w; 758vw; 766vw; 782w;
832s; 890m; 903w; 927w; 979m; 1033s; 1038s; 1049s; 1066vs;
1083s; 1106s; 1129m; 1150w; 1196w; 1223w; 1251w; 1262w;
1288m; 1311m; 1342m; 1378m; 1456.s; 1490m; 1498m;
1562w; 1619s; 1626m; 1951w; 2854vs; 2923vs; 2953vs; 3030m;
3100m; 3134m.
2.1.7. [IrCl2(COD)(phen)]BF4 (7)
A solution of [Ir2Cl2(COD)2] (0.1 mmol), 1,10-phenanthroline
(0.2 mmol) and HBF4 (0.025 ml, 40% water solution) in 5 mL of eth-
anol was stirred at room temperature for 1 h. The orange product
was filtrated off, washed with ethanol and dried under vacuum.
Yield 20%.
Anal. Calc. for C20H20N2Cl2BF4Ir: C, 37.63; H, 3.16; N, 4.39; Cl,
11.11. Found: C, 38.55; H, 2.79; N, 4.55; Cl, 9.67%. 1H NMR in
MeOD-d4 (ppm): 9.00 (dd, 2H, 4,7H, J(4,3/7,8) = 8.2 Hz; J(2,4/
9,7) = 0.8 Hz); 8.95 (d, 2H, 2,9H, J(2,3/9,8) = 5.4 Hz); 8.35 (s, 2H,
5,6H); 8.15 (dd, 2H, 3,8H); 6.31 (s, 4H, CH COD); 3.04 (d, 4H, CH2
COD); 2.58 (m, 4H, CH2 COD). 13C NMR in MeOD-d4(ppm):
170.23 (C–C phen); 151.14 (CH phen); 142.70 (C–H phen);
133.70 (C–C phen); 129.69 (CH phen); 128.27 (CH phen); 103.76
(CH COD); 30.43 (CH2 COD). 13C NMR in DMSO-d6(ppm): 151.00
(C–H phen); 145.70 (C–C phen); 141.76 (CH phen); 131.59 (C–C
phen); 128.53 (CH phen); 127.29 (CH phen); 102.52 (CH COD);
2.2. Cytostatic activity and antibacterial activity in vitro
Human melanoma SK-mel, C-32 and SH-4, human Caucasian
colon adenocarcinoma Caco-2 and human glioblastoma SNB-19
and non-tumor mouse preadipocyte 3T3-L1 cells were used for
the proliferation assay. The experiments were repeated in triplicate
for each tested compound concentration. Statistical significance
was determined using Student’s t-test (p < 0.05 was considered
statistically significant). The cell concentration was 6 ꢂ 103 cells/
well on the 96-well microplate. The basic culture medium for tu-
mor cells consisted of RPMI-1640 medium with 10% fetal calf ser-
um (FCS) and 1% antibiotic–antimycotic solution. The cultured
cells were maintained at 37 °C in humidified air containing 5%
CO2, for 24 h. The next day the media were changed to RPMI with
0.2% FCS and cells were incubated for a further 24 h. The concen-
tration of FCS was changed two times to get synchronized cell cul-
tures. After the preincubation the experimental media composed
with RPMI, 5% FCS and solution of investigated complex was
added. The concentrations of rhodium or iridium compound in
the cultures were 10ꢀ4–10ꢀ6 M. The stock solution of coordination
compound was prepared in DMSO. The tested compound was di-
luted with culture medium to reach the final concentrations of
the complex. The final concentration of DMSO in the cultured cells
was 0.1–1% (v/v). The control cell culture was incubated in the
standard media enriched with 5% FCS and adequate concentration
of DMSO (0.1–1%, v/v). After 72 h of incubation, cell viability was
quantified by a cell proliferation assay (WST-1; Roche, Basel, Swit-
zerland). The amount of WST-1-formazan produced was measured
at 450 nm and appropriate calculations were performed as de-
scribed previously [8,9,33,34]. The results of cytotoxic activity
in vitro were expressed as IC50 – the dose of compound that inhib-
its proliferation rate of the tumor cells by 50% as compared to con-
trol untreated cells. The antibacterial activity was evaluated
in vitro according to the standard methods [9,35,36] on Gram-
negative laboratory strains: Escherichia coli, Klebsiella pneumoniae,
Pseudomonas aeruginosa and Gram-positive strains Staphylococcus
aureus, Micrococcus luteus, Enterococcus faecalis and Staphylococcus
epidermidis. The minimal inhibitory concentrations (MIC) of com-
plexes have been determined for all strains. The experiments were
performed as described earlier [9,35,36].
28.96 (CH2 COD). UV–VIS in acetone, [kmax, nm, (e
, Mꢀ1 cmꢀ1)]:
368 (714); 352 (1590); 333 (1959). IR [Nujol/KBr, cmꢀ1]: 56w;
64w; 76m; 80m; 88m; 100m; 105m; 112m; 117m; 120m;
126m; 133m; 140m; 150m; 158m; 167m; 170m; 176m; 181m;
188s; 195m; 202m; 215s; 226m; 241s; 244s; 261s; 279m;
289m; 297m; 325vs; 353m; 375w; 398w; 413w; 419m; 435m;
445m; 458m; 479m; 496m; 518s; 521s; 533w; 561w; 619w;
657w; 667vw; 688vw; 717s; 726m; 746w; 779w; 802vw; 815w;
834w; 851s; 879vw; 903vw; 925vw; 967w; 1009m; 1036vs;
1052vs; 1084vs; 1123s; 1150m; 1191w; 1201w; 1228w;
1265vw; 1285w; 1318w; 1347w; 1389w; 1415m; 1431s;
1459w; 1475w; 1486w; 1498w; 1520m; 1588w; 1604m;
1634m; 1817vw; 2011w; 2363w; 2895m; 2927m; 2973m;
2997m; 3063m; 3101m; 3432s.
The complexes 8 and 9 were prepared analogously as com-
pound 7.
2.1.8. [IrCl2(COD)(bpy)]BF4 (8)
Yield 20%. Anal. Calc. for C18H20N2Cl2BF4Ir: C, 35.19; H, 3.28; N,
4.56; Cl, 11.54. Found: C, 35.49; H, 2.30; N, 4.46; Cl, 10.37%. 1H
3,30
NMR in MeOD-d4(ppm): 8.74 (dd, 2H,
H, J(3,4/30,40) = 8.2 Hz;
6,60
J(3,5/30,50) = 0.9 Hz); 8.51 (d, 2H,
H, J(6,5/60,50) = 5.8 Hz); 8.40
0
0
(m, 2H, 4,4 H); 7.84 (m, 2H, 5,5 H); 6.13 (s, 4H, CH COD); 3.01 (m,
4H, CH2 COD); 2.53 (m, 4H, CH2COD). 13C NMR in MeOD-
d4(ppm): 165.30 (C–C bpy); 150.53 (CH bpy); 143.60 (CH bpy);
130.30 (CH bpy); 126.88 (CH bpy); 104.51 (CH COD); 30.34 (CH2
COD); UV–VIS in CH3OH, (kmax, nm, (e
, Mꢀ1 cmꢀ1)): 455 (142);
404 (326); 381 (496); 318 (13846); 305 (13042); 259 (8727). IR
[Nujol/KBr, cmꢀ1]: 56vw; 65w; 84m; 88m; 100w; 105w; 117m;
120m; 132w; 140w; 150w; 158w; 171w; 174w; 182w; 188w;
214m; 227m; 231m; 258s; 280w; 282w; 290w; 306m; 322vs;
342w; 346w; 351w; 370w; 380w; 398w; 421m; 446w; 453w;
457w; 468w; 485m; 522s; 546w; 579m; 585w; 646w; 654w;
670w; 726w; 746w; 774s; 804w; 816w; 832w; 873w; 899w;
1036s; 1057vs; 1084vs; 1123m; 1162m; 1177w; 1193w; 1224w;
1246w; 1285w; 1315m; 1347w; 1386w; 1449s; 1471m; 1500m;
1570w; 1606s; 1635m; 2036w; 2349w; 2850w; 2896w; 2922w;
2976w; 3046w; 3095m; 3103m; 3122m; 3148w; 3215m; 3438s.
3. Results and discussion
The rhodium(I) [Rh(COD)(N–N)]BF4 (1–6) and iridium(III)
[IrCl2(COD)(N–N)]BF4 (7–9) polypyridyl complexes were prepared
by the reactions of dimers [Rh2Cl2(COD)2] and [Ir2Cl2(COD)2],

´
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U. Sliwinska-Hill et al. / Inorganica Chimica Acta 400 (2013) 26–31
Table 2
+
(a)
(b)
+
Cl
Antibacterial activity of [Rh(COD)(N–N)]BF4 (3, 5, 6) and [IrCl2(COD)(N–N)]BF4 (7, 9)
compounds.
N
N
N
N
Rh
Ir
Bacteria line
MIC [lg/ml]
3
5
6
7
9
Cl
E. coli
i
i
i
i
i
i
i
i
i
i
i
i
i
i
Scheme 2. Structures of the rhodium(I) (a) and iridium(III) (b) complexes with N–N
and 1,5-COD ligands.
K. pneumoniae
P. aeruginosa
M. luteus
S. aureus
E. faecalis
50.0
i
12.5
12.5
25.0
12.5
6.25
<3.12
3.12
6.25
6.25
6.25
6.25
6.25
50.0
i
i
i
i
50.0
i
respectively, with 2 equiv. of chelating 1,10-phenanthroline, 2,20-
bypyridyne and their derivatives in the presence of HBF4 solution
in ethanol at room temperature.
S. epidermidis
MIC, minimal inhibitory concentration; i, inactive (MIC > 50.0 [
3 shows also antifungal activity against AD1–9 and FY yeast strains with MIC values
equal to 30–50 mol/L and >100 mol/L.
lg/ml]). Compound
1H and 13C NMR, electronic and IR spectra are in accordance
with the square planar structure of rhodium complexes and the
octahedral structure of iridium complexes containing polypyridyl,
1,5-COD and chloride ligands in trans coordination sites.
The 1H NMR spectra indicate that N–N ligands are symmetri-
cally coordinated to the metal atom and the protons of N–N ligands
are equivalent (Scheme 2). In iridium complexes with Cl atoms in
cis positions, the N–N and COD ligands are coordinated asymmet-
rically. For the [Rh(COD)(N–N)]BF4 complexes (1–6), the CH = CH
(COD) multiplets appeared at d 4.50–4.90 ppm and two CH2
(COD) signals at 2.50 and 2.15 ppm, whereas for the [IrCl2
(COD)(N–N)]BF4 complexes (7–9) the same resonances were found
in the range 6.12–6.31 ppm (olefin protons) and 2.50–3.00 ppm
(methylene protons).
l
l
to the dz2 ? dP(N–N) MLCT spin allowed (singlet–singlet) transi-
tions and internal in N–N ligand transition.
The electronic spectrum of 7 is characterized by absorptions at
kmax = 368 nm
and 333 nm (
charge-transfer Ir ? 1,10-phenanthroline transitions. The spec-
trum of 8 shows the transition at kmax = 455 nm (
= 142 Mꢀ1 cmꢀ1
(e (e )
= 714 Mꢀ1 cmꢀ1), 352 nm = 1590 Mꢀ1 cmꢀ1
e
= 1959 Mꢀ1 cmꢀ1). This bands are assigned to the
e
)
assigned to d-d1A1g ? 1T1g spin allowed transitions. The high en-
ergy shoulder at 404 and 381 nm correspond the Ir ? 2,20-bipyri-
dine MLCT transitions and the bands at 318, 305, 259 nm should
be assigned to the Ir ? COD and Ir ? bpy MLCT and intrinsic tran-
sitions in bipyridine ligand. The electronic spectrum of 9 complex in
DMSO shows two bands at 318 and 306 nm corresponding MLCT
transitions.
The 13C NMR spectra of all complexes exhibit resonances for the
methylene carbons of COD ligands at about 30 ppm. The reso-
nances of olefin carbons for 1–6 complexes appear at about
85 ppm and for 7–9 compounds at higher chemical shifts, at about
104 ppm. The observed 13C NMR shift of the olefinic C atoms in 1–6
complexes – ca. 85 ppm is in good agreement with the values typ-
ical for four-coordinate Rh–COD complexes [37,38].
The resonances of all complexes observed in the range 170–
120 ppm are assigned to the aromatic carbon atoms of the coordi-
nated N-donor ligands. The NMR spectra of 1–6 compounds are
similar to those observed for cationic complexes with 2,20-bipyri-
dine and 1,10-phenanthroline [Rh(COD)(N–N)]+ containing (Z)-
(3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-yli-
dene)(thiophen-2-yl)methanolate counterion [39].
The infrared spectra of all compounds in the region 4000–
400 cmꢀ1 are dominated by absorptions of coordinated N–N and
COD ligands, which are slightly shifted as compared to the free
substrates. The spectra of 1–6 complexes in the range 1050–
1067 cmꢀ1 show strong, broad bands assigned to the mB–F oscilla-
tions. In the case of 7–9 complexes these bands are observed in
the range 1009–1123 cmꢀ1. The
cyclooctadiene and nitrogen ligands are observed in the region
2850–3100 cmꢀ1. The
(Rh–N) and (Ir–N) stretching vibrations
of medium intensity occur at 311–331 cmꢀ1 and 249–290 cmꢀ1
respectively. The (Rh–C) bands appear in the region 359–
371 cmꢀ1 and
m(C–H) stretching bands for the
m
m
,
m
m
(Ir–C) bands in the region 421–445 cmꢀ1. The
The electronic spectra of 1–6 complexes are similar. They show
intensive bands in the range 305–325 cmꢀ1 correspond to
Cl) vibrations.
m(Ir–
absorptions at about kmax = 463–495 nm (
321–381 nm (
= 1320–4990 Mꢀ1 cmꢀ1), 304–363 nm (
15940 Mꢀ1 cmꢀ1) and 266–299 nm ( = 4530–12670 Mꢀ1cmꢀ1).
e
= 250–890 Mꢀ1 cmꢀ1),
e
e = 3740–
In ESI-MS spectra of compounds 7–9 in MeOH very intense are
peaks of molecular cations [IrCl2(COD)(N–N)]+. The stoichiometry
of the analyzed cations was confirmed by the isotopic patterns,
which are very characteristic for compounds [IrCl2(COD)(N–
N)]BF4 because each of Ir and Cl element has two stable isotopes.
Apart of molecular cation, the following cations of high abun-
dances were observed:
e
The transitions around 463–495 nm are assigned to dz2 ? dP(N–
N) MLCT spin forbidden (singlet–triplet) transitions [40,41]. The
more intense bands in the range 381–304 nm correspond the
dz2 ? dP(COD) MLCT spin allowed (singlet–singlet) transitions.
This transition in [Rh2Cl2(COD)2] is observed at 348 nm [40]. The
most intense absorption bands at 278–299 nm should be assigned
Table 1
Cytostatic activity of [Rh(COD)(NN)]BF4 (1–6) and [IrCl2(N–N)(COD)BF4] (7–9) complexes against tumor strains.
Complex
Cell line, IC50
SNB-19
[lmol/l]
SK-mel
C-32
Caco-2
SH-4
3T3-L1
1
2
3
4
5
6
7
8
9
10 ( 1.3)
95 ( 19)
10 ( 1.5)
50 ( 7.5)
2.0 ( 0.3)
34 ( 8.7)
2.0 ( 0.15)
0.7 ( 0.12)
0.1 ( 0.02)
72.4 ( 15)
40.9 ( 9.3)
0.22 ( 0.02)
0.12 ( 0.02)
0.1 ( 0.01)
0.12 ( 0.02)
6.0 ( 0.35)
60 ( 9.5)
0.1 ( 0.01)
0.3 ( 0.04)
0.2 ( 0.02)
20 ( 2.1)
>100
10 ( 1.2)
>100
—
—
37.3 ( 7.7)
>100
31.6 ( 6.5)
—
—
—
—
8.0 ( 0.9)
>100
10 ( 1.3)
>100
—
—
39.2 ( 8.3)
43.8 ( 9.2)
7.0 ( 1.6)
30 ( 8.5)
15 ( 2.3)
5.0 ( 0.25)
20 ( 2.6)
3.9 ( 0.20)
45.8 ( 9.5)
28.4 ( 3.5)
12 ( 0.35)
100
—
—
—

´
´
31
U. Sliwinska-Hill et al. / Inorganica Chimica Acta 400 (2013) 26–31
for 7: [IrCl2(COD)(phen)]+ (m/z = 551.06, 77%), [IrCl(COD)-
(phen)(CH3O)]+ (m/z = 547.11, 100%), [Ir(C8H11)(phen)(CH3O)]+
Acknowledgment
(m/z = 511.13,
50%),
[Ir2Cl4(COD)2(phen)2(CH3O)2Na]+
(m/
We thank M.Sc. B. Trombecka for helpful technical assistance in
determination of antibacterial activity.
z = 1187.13, 8%);
for 8: [IrCl2(COD)(bpy)]+ (m/z = 527.05, 69%), [IrCl(COD)-
(bpy)(CH3O)]+ (m/z = 523.10, 100%), [Ir(C8H11)(bpy)(CH3O)]+ (m/
z = 487.13, 50%), [Ir2Cl4(COD)2(bpy)2(CH3O)2Na]+ (m/z = 1139.13,
25%);
References
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Diagnostic Agents, Wiley, Chichester, 2005.
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for 9: [IrCl2(COD)(dmbpy)]+ (m/z = 555.09, 100%), [IrCl(COD)-
(dmbpy)(CH3O)]+ (m/z = 551.14, 100%), [Ir(C8H11)(bpy)(CH3O)]+
(m/z = 515.16,
100%),
[Ir2Cl4(COD)2(bpy)2(CH3O)2Na]+
(m/
z = 1195.19, 17%).
3.1. Biological activity
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cells. They are unusually active against C-32 cells, for which IC50
´
´
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values change in the range 0.1–6.0
compound 6 for which IC50 is 60
these cells are much lower than those against normal 3T3-L1 cells
l
mol/L, with the exception of
l
mol/L. The IC50 values against
(Table 1).
Rhodium compound with dipyrido[3,2-a:20,30-c]-phenazine 5 is
very active against SNB-19, SK-mel and SH-4 strains. Efficient cyto-
static agents are also complexes with 1,10-phenanthroline 1 and 7
and with 4,7-diphenyl-1,10-phananthroline 3. Their activity
against SNB-19, SK-mel and C-32 cells comparable or greater than
that of cisplatin. The complexes with 2,20-bipyridine 2 and 8 and
4,40-dimethyl-2,20-bipyridine 4 and 9 are less active, apart from
C-32 strain. These dependences suggest that cytostatic activity of
the investigated complexes can, in the case of some tumor cells, re-
sult from intercalation of nitrogen ligand between nucleotide
bases, because size of the phen and dppz ligands is greater than
that of bpy and for complex with 4,40-dimethyl-2,20-bipyridine
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