Acridine-containing RuII, OsII, RhIII and IrIII Half-Sandwich Complexes: Synthesis, Structure and Antiproliferative Activity

Article abstract of DOI:10.1002/aoc.3852

Research aimed at enhancing the efficacy of organometallic complexes against cancer, has shown that attaching bio-active molecules to (metallo)drugs often enhances their biological properties. New salicylaldimine and 2-pyridylimine ligands (L2 and L3), containing a bio-active acridine scaffold, were synthesized and complexed to Rh(III), Ir(III), Ru(II) and Os(II) metal ion centers. The resulting acridine-containing half-sandwich complexes have been characterized fully by elemental analysis, FT-IR and NMR spectroscopy, HR-ESI mass spectrometry as well as single crystal X-ray diffraction, for the Rh(III) N^N bidentate complex [RhCp*Cl(L3)][BPh₄]. The antiproliferative activity of the ligands (L2 and L3) and complexes (C1 to C9) were evaluated in vitro against human promyelocytic leukemia cells (HL60) and normal skin fibroblast cells (FG0). The compounds exhibit good activities against HL60 cells and are consistently selective towards cancerous cells over non-tumorous cells. This study demonstrates the potential of such hybrid compounds to target cancer cells specifically. The most active complex, [RhCp*Cl(L2)], exhibited binding to DNA model guanosine-5’-monophosphate (5’-GMP) which suggests a mode of action involving interaction of the complex with 5’-GMP found on DNA backbone.

Full text of DOI:10.1002/aoc.3852

Received: 12 January 2017
DOI: 10.1002/aoc.3852
Revised: 16 March 2017
Accepted: 25 March 2017
F U L L PA P E R
II
II
III
III
Acridine‐containing Ru , Os , Rh and Ir Half‐Sandwich
Complexes: Synthesis, Structure and Antiproliferative Activity
1
2
3
3
Asanda C. Matsheku | Marian Y.‐H. Chen | Sandra Jordaan | Sharon Prince |
2
1
Gregory S. Smith | Banothile C.E. Makhubela
1
Department of Chemistry, University of
Research aimed at enhancing the efficacy of organometallic complexes against
cancer, has shown that attaching bio‐active molecules to (metallo)drugs often
enhances their biological properties. New salicylaldimine and 2‐pyridylimine
ligands (L2 and L3), containing a bio‐active acridine scaffold, were synthesized
and complexed to Rh(III), Ir(III), Ru(II) and Os(II) metal ion centers. The resulting
acridine‐containing half‐sandwich complexes have been characterized fully by
elemental analysis, FT‐IR and NMR spectroscopy, HR‐ESI mass spectrometry as
well as single crystal X‐ray diffraction, for the Rh(III) N^N bidentate complex
Johannesburg, PO Box 524, Auckland Park,
2
006, South Africa
2
Department of Chemistry, University of
Cape Town, Rondebosch 7701, Cape Town,
South Africa
3
Department of Human Biology, Division of
Cell Biology, University of the Cape Town,
Cape Town, South Africa
Correspondence
Banothile C.E. Makhubela, Department of
Chemistry, University of Johannesburg, PO
Box 524, Auckland Park, 2006, South
Africa.
[RhCp*Cl(L3)][BPh ]. The antiproliferative activity of the ligands (L2 and L3)
4
and complexes (C1 to C9) were evaluated in vitro against human promyelocytic leu-
kemia cells (HL60) and normal skin fibroblast cells (FG0). The compounds exhibit
good activities against HL60 cells and are consistently selective towards cancerous
cells over non‐tumorous cells. This study demonstrates the potential of such hybrid
compounds to target cancer cells specifically. The most active complex,
Email: bmakhubela@uj.ac.za
Funding information
National Research Foundation of South
Africa, Grant/Award Number: 95517
[
(
RhCp*Cl(L2)], exhibited binding to DNA model guanosine‐5’‐monophosphate
5’‐GMP) which suggests a mode of action involving interaction of the complex
with 5’‐GMP found on DNA backbone.
KEYWORDS
anticancer agents, acridine derivatives, antiproliferative activity, bioorganometallic chemistry, half‐sandwich
complexes
1
| INTRODUCTION
as a single agent or in combination with other anticancer
agents to treat advanced bladder, testicular and ovarian
[
4]
Cancer formation results from the abnormal growth of cells
and their ability to divide in an uncontrolled fashion.
Cancer has become the main cause of mortality and there
cancer. However, there are drawbacks associated with
the clinical use of cisplatin (and I closely related
oxaliplatin and carboplatin) and these include unpleasant
side effects, due to toxicity, acquired and intrinsic drug
resistance as well as a limited broad spectrum cancer tox-
icity. This has led to increased efforts directed towards dis-
[
1,2]
is an urgent need for more effective anticancer drugs.
Rosenberg's discovery of the anticancer properties of
cisplatin (cis‐diamminedichloroplatinum(II)) was followed
by the approval of the first metallodrug, for the treatment
of cancer, by the US Food and Drug Administration
[
4–11]
covering new metal‐based anticancer agents.
To this
end, ruthenium, osmium, iridium and rhodium complexes
have been investigated and found to exhibit promising
[
3]
(FDA) in 1978. Today, cisplatin is one of the most
[
12–20]
widely used therapeutic metallodrugs and is mostly used
cytotoxicity against an array of cancers (Figure 1).
Appl Organometal Chem. 2017;e3852.
wileyonlinelibrary.com/journal/aoc
Copyright © 2017 John Wiley & Sons, Ltd.
1 of 14
https://doi.org/10.1002/aoc.3852

2
of 14
MATSHEKU ET AL.
[26,27]
FIGURE 2 Acridine‐containing anticancer agents
PT‐ACRAMTU (Figure 2) has exhibited promising antican-
FIGURE 1 Selected structures of Ru(II), Os(II), Rh(III) and Ir(III)
complexes that have demonstrated anticancer activity
cer results against leukemia and ovarian cancer cell lines
[
12–20]
[27b]
and has been demonstrated to be superior to cisplatin.
Several other studies have shown that acridine‐containing
metallointercalators exhibit enhanced cytotoxicity by a
unified dual action involving increased DNA affinity, which
is driven by the acridine's intercalating ability, and subse-
quent DNA damage by the vicinal metal through metal‐DNA
[
21]
In particular, two ruthenium complexes, KP1339
H Na[trans‐RuCl (DMSO)(Hind) ] where Hind = indazole)
(
2
4
2
[
22]
and NAMI‐A
(H Im[trans‐RuCl (DMSO)(Him)] where
Him = imidazole), have been found to perform exception-
2
4
[
28–32]
base pair adduct formation.
ally and are currently undergoing clinical trials.
While examples of Pt, Au and Fe complexes conjugated
[
27–33]
An approach aimed at enhancing the efficacy of organo-
metallic complexes against cancer, involves coupling the
complexes with a compound known to have biological activ-
to acridine moieties are known,
there remains an oppor-
tunity to explore the chemical and anticancer properties of
other metal complexes conjugated to acridine. Herein, we
report the synthesis and characterization of a series of new
6,9‐dichloro‐2‐methoxyacridine‐containing ruthenium(II),
osmium(II), rhodium(III) and iridium(III) half‐sandwich
and ferrocenyl complexes. In the former, the metal ions
are coordinated to N^N and N^O bidentate imine ligands.
The antiproliferative activity of the complexes against the
human promyelocytic leukemia cancer cell line (HL60),
and against a normal fibroblast cell line (FG0) were
evaluated in vitro.
[19,23–25]
ity.
The biological and chemical stability of acridine
and its ability to intercalate DNA has rendered this class of
compound useful in the development of targeted anticancer
agents. Examples of acridine‐bearing anticancer agents are
Amsacrine and Nitracrine (Figure 2).
A combination of Amsacrine, Etoposide and Methylpred-
nisolone is used to treat acute lymphoblastic leukemia.
[
26a–b]
Nitracrine has been used to combat various carcinomas such
as breast and lung cancer. However, it has been discontinued
from further clinical application due to its severe side
[
26c–d]
effects.
Organic intercalators such as acridine can be conjugated
to bioactive complexes to afford so‐called metallo‐
intercalators. Ong et al. reported that a ferrocenyl‐acridine
conjugated complex (Figure 2) displayed high toxicity
in vitro as compared to a phenyl‐derived ferrocene complex,
and that the inability of the phenyl‐ferrocene complex to
2
2
| EXPERIMENTAL
.1 | General considerations
1,2,3,4,5‐Pentamethylcyclopentadiene,
2‐pyridine carboxaldehyde, salicylaldehyde, ethylene
diamine, sodium hydride and 9,6‐dichloro‐2‐methoxy
α‐phellandrene,
[
27a]
intercalate DNA resulted in its low cytotoxic activity.

MATSHEKU ET AL.
3 of 14
acridine, were all purchased from Sigma Aldrich and used as
Aracridine); 7.95‐8.01 (m, 2H, Aracridine); 8.26 (s, 1H,
HC=N); 8.37 (br s, 1H, Aracridine);12.90 (br s, 1H, OH).
.
.
.
received. RuCl 3H O, RhCl 3H O, IrCl 3H O and
3
2
3
2
3
2
13
1
K OsO (OH) were purchased from Heraeus South Africa.
C{ H} NMR (101 MHz, DMSO‐d ): δ (ppm) = 49.9
2
2
4
6
All solvents were of analytical grade and were dried using
MBRAUN SPS‐800 solvent drying system prior to use. All
reactions were carried out in air unless otherwise stated.
(CH ); 54.9 (OMe); 59.5 (CH ); 97.7 (Ar); 116.6 (Ar);
2 2
118.1 (Aracridine); 118.6 (Ar); 118.8 (Aracridine); 123.6‐124.2
(Aracridine); 124.7 (Aracridine); 124.8 (Ar); 128.1 (Aracridine);
131.2 (Aracridine); 131.3(Ar); 132.5 (Aracridine); 134.4
(Aracridine); 146.5 (Aracridine); 147.8 (Aracridine); 148.1
(Aracridine); 156.2 (Aracridine); 160.5 (Ar); 167.3 (HC=N).
[34]
[35]
The precursors, Ru(p‐cym)Cl ]
[Os(p‐cym)Cl ]
2
2,
2 2,
[
36]
[36]
1
[RhCp*Cl2]2,
[IrCp*Cl2]2
and N ‐(6‐chloro‐2‐
[37]
methoxyacridin‐9‐yl)ethane‐1,2‐diamine (L1),
were syn-
1
13
1
‐1
thesized using literature methods. H NMR,
C{ H}
FT‐IR (ATR): ν(cm ) = 3555 (O‐H); 3353 (N‐H); 1630
31
1
NMR and P{ H} NMR spectra were recorded on a
(C=N)imine, 1607 (C=N)acr. imine. HR‐ESI‐MS (+): Calc.
1
13
1
+
Bruker Ultrashield 400 ( H NMR 400.17 MHz, C{ H}
for C H ClN O [M] m/z = 405.1244; Found: m/z =
406.1240 [M+H] .
2
3
20
3 2
1
3
1
+
NMR 101.02 MHz and P{ H} NMR 161.99 MHz)
spectrometer and chemical shifts are reported using
3
1
1
tetramethylsilane and H PO (for P{ H} NMR) spectra
3
4
as the internal standard. Fourier transform infrared (IR)
spectra were obtained using the Perkin Elmer Spectrum
1
2
.3 | Synthesis of N ‐(6‐Chloro‐2‐
2
methoxyacridin‐9‐yl)‐N ‐(pyridin‐2‐
100 FT‐IR spectrometer with an attenuated total reflection
ylmethylene)ethane‐1,2‐diamine (L3)
(ATR) accessory. High resolution (HR) ESI‐mass spectrom-
etry was obtained using Waters API Quattro Micro triple
quadrupole mass spectrometer in the positive ion mode.
Where the ESI probe was injected into a stream of methanol
at a cone voltage of 15 eV. Melting points were determined
using a Buchi B‐540 apparatus and elemental analyses were
performed on a Thermo Scientific FLASH 2000 CHNS‐O
analyzer.
2‐Pyridinecarboxaldehyde (0.330 g, 3.083 mmol) in dichlo-
romethane (20 ml) was added dropwise to a solution of L1
(0.928 g, 3.083 mmol) dissolved in dichloromethane (20
ml). Anhydrous sodium sulfate (approximately 2.00 g) was
added to this mixture, in order to ‘mop‐up’ the water by‐
product in the Schiff‐base condensation reaction and drive
the reaction forward. This reaction mixture was allowed to
stir at room temperature for 48 hours. After 48 hours, sodium
sulfate was removed by filtration. The filtrate was transferred
to a separating funnel and washed with water (3 × 40 ml).
The collected organic layer was then dried with anhydrous
sodium sulfate. The sodium sulfate was then filtered and
the solvent was removed from the filtrate by rotary evapora-
tion to afford L3 as an orange solid (0.901 g, 75% yield).
Melting point: 108–110°C. Elemental Analysis, Calc. for
C H ClN O: C 67.70, H 4.90, N 14.30% Found: C 67.42,
2
.2 | Synthesis of 2‐(((2‐((6‐Chloro‐2‐
methoxyacridin‐9‐yl)amino)ethyl)imino)methyl)
phenol (L2)
Salicylaldehyde (0.142 g, 1.163 mmol) in dichloromethane
(20 ml) was added dropwise to a solution of L1 (0.350 g,
1.166 mmol) in dichloromethane (20 ml). Anhydrous
sodium sulfate (approximately 2.00 g) was added to this mix-
ture, in order to ‘mop‐up’ the water by‐product in the Schiff
base condensation reaction and drive the reaction forward.
This reaction mixture was allowed to stir at room tempera-
ture for 48 hours. After 48 hours, the sodium sulfate was
removed by filtration. The filtrate was transferred to a sepa-
rating funnel and washed with water (3 × 40 ml). Finally,
the organic layer was dried using anhydrous sodium sulfate.
The sodium sulfate was then filtered, and the solvent was
removed from the filtrate by rotary evaporation to afford
L2, as an orange crystalline solid. (0.337 g, 72% yield).
Melting point: 141–143°C. Elemental Analysis, Calc. for
C H ClN O : C 68.11, H 4.97, N 10.30 %; Found: C
22
19
4
1
H 4.66, N 14.41 %. H NMR (400 MHz, DMSO‐d ): δ
6
(ppm) = 3.90 (s, 3H, OMe); 3.97 (t, J = 8.0 Hz, 2H, CH2);
4.05 (t, J = 8.0 Hz, 2H, CH ); 5.41 (br s, 1H, NH); 7.18 (d,
2
J = 4 Hz, 1H, Aracridine); 7.29 (d, J = 4 Hz, 1H, Aracridine);
7.35 – 7.41 (m, 1H, Aracridine); 7.76 (t, J = 16 Hz, 1H, Ar);
7.94‐7.98 (m, , 2H, Ar); 8.00‐ 8.07 (m, 2H, Aracridine); 8.42
(s, 1H, HC=N); 8.45 (s, 1H, Aracridine); 8.67 (d, J = 8.0 Hz,
13
1
1H, Ar). C { H} NMR (101 MHz, DMSO‐d ): δ (ppm) =
6
51.0 (CH ); 55.4 (OMe); 61.1 (CH ); 99.0 (Ar); 116.9 (Ar);
2
2
119.0 (Aracridine); 121.3 (Ar); 124.3 (Aracridine); 124.8
(Aracridine); 124.9 (Aracridine); 125.1 (Ar); 128.4 (Aracridine);
131.6 (Aracridine); 134.7 (Ar); 136.6 (Aracridine); 138.3
(Aracridine); 148.4 (Aracridine); 149.6 (Aracridine); 149.7
2
3
20
3 2
1
6
8.34, H 4.79, N 9.98 %. H NMR (400 MHz, DMSO‐d ):
6
δ(ppm) = 3.71 (t, J = 12 Hz, 2H, CH ); 3.77 (s, 3H,
(Ar
); 156.3 (Aracridine); 164.2 (HC=N). FT‐IR (ATR):
2
acridine
‐
1
OMe); 3.87 (br s, 2H, CH ); 4.10 (br s, 1H, NH); 6.82 (t,
ν (cm ) = 3357 (N‐H); 1647, (C=N)
1605 (C=N)acr.
imine
2
J = 15 Hz, 1H, Ar); 6.96 (d, J = 9 Hz, 1H, Ar); 7.05 (d,
J = 2.4 Hz, 1H, Ar); 7.08 (d, J = 1.6 Hz, 1H, Aracridine);
imine, 1597 (C=N)
. HR‐ESI‐MS (+): Calc. for
pyridylimine
+
C H ClN O [M] m/z = 390.1247 Found: m/z =
22
19
4
+
7.24 (d, J = 6 Hz, 1H, Aracridine); 7.31‐7.42 (m, 2H, Ar and
391.1253 [M+H] .

4
of 14
MATSHEKU ET AL.
1
2
.4 | Synthesis of C1
6.19% Found: C 58.70, H 5.08, N 5.97 %. H NMR (400
MHz, DMSO‐d ): δ (ppm) = 1.64 (s, 15 H, Me‐Cp*); 3.65
6
L1 (0.202 g, 0.671 mmol) was dissolved in 15 mL EtOH.
Ferrocenylcarboxaldehyde (0.170 g, 0.791 mmol) was dis-
solved in 15 ml EtOH and added drop‐wise to the L1 solu-
tion. Molecular sieves (4 Å, 2.00 g) were added. The
reaction mixture was left to stir for 28 hours and followed
by refluxing at 80°C for 20 hours. The molecular sieves
were filtered off and the resulting solution was reduced to
a third of its original volume by rotary evaporation. The
solution was added drop‐wise to cold petroleum ether (100
ml) and a red solid precipitated out. This red solid was
collected by gravity filtration and was later found to be ferro-
cene carboxaldehyde. The filtrate was left at ‐2°C overnight
(
4
(
7
s, 3 H, OMe); 3.98 (br, s 2H, CH ); 4.18 (br, s 1H, CH );
2 2
.33 (br, s, 1H, CH ); 6.30 (t, J = 8 Hz, 1H, Ar); 6.64‐6.88
2
m, , 2H, Ar); 7.05‐7.37 (m, 4H, Ar and Aracridine); 7.68‐
.81 (m, 2H, Aracridine); 7.98 (s, 1 H, HC=N); 8.14 (d, J =
13
1
9
Hz, 1H, Aracridine). C{ H} NMR (101 MHz, DMSO‐d ):
6
δ (ppm) = 9.06 (Me‐ Cp*); 48.2 (CH ); 56.4 (OMe); 65.9
(
1
(
2
CH ); 93.6 (Cp*); 93.8 (Ar); 113.0 (Ar); 114.04 (Aracridine);
2
17.6 (Ar); 119.3 (Aracridine); 123.3 (Aracridine); 124.3
Aracridine); 125.1 (Ar); 125.9 (Aracridine); 126.0 (Aracridine);
31.6 (Ar); 134.9 (Aracridine); 135.3 (Aracridine); 136.2
Aracridine); 150.7 (Aracridine); 152.3‐153.1 (Aracridine); 156.5
1
(
(
(
Ar
acridine
‐1
) 161.9 (Ar); 166.8 (HC=N). FT‐IR (ATR): ν
(
± 18 hours) during which time C1 precipitated from
solution as an orange solid. C1 was collected by filtration
suction) and dried under vacuum for 8 hours. (0.131 g,
9 % yield). Melting point: 63‐65°C. Elemental Analysis,
Calc. for C H ClFeN O: C 65.15, H 4.86, N 8.44%
cm ) = 3309 (N‐H), 1616 (C=N)imine, 1605 (C=N)acr. imine.
+
HR‐ESI‐MS (+): Calc. for C H Cl N O Rh [M] m/z =
6
6
33
34
2 3 2
(
3
+
77.1083 Found: m/z = 678.1156 [M+H] , m/z =
+
42.1393 [M‐Cl] .
2
7
24
3
Complexes C3‐C5 were prepared following the same
1
Found: C 65.43, H 4.83, N 8.60%. H NMR (400 MHz,
procedure as described for C2, using the appropriate
reagents.
DMSO‐d ): δ (ppm) = 3.76 (t, J = 5.5 Hz, 2H, CH ); 3.90
6
2
‐
4.04 (m, 10H, H‐Cp, OMe, CH ); 4.33 (br s, 2H, H‐Cp);
2
4
7
7
.50 (br s, 2H, H‐Cp); 6.77 ‐ 6.86 (br s, 1 H, NH); 7.30 ‐
.46 (m, 2H, Aracridine); 7.70 (d, J = 1.7 Hz, 1H, Aracridine);
.80 ‐ 7.92 (m, 2H, Aracridine); 8.13 (s, 1H, HC=N); 8.51 (d,
2.6 | Synthesis of [IrCp*Cl(L2)] (C3)
1
3
1
J = 9.2 Hz, 1H, Aracridine). C{ H} NMR (101 MHz,
DMSO‐d ): δ (ppm) = 50.6 (CH ); 56.2 (OMe); 61.6
Sodium hydride (0.00590 g, 0.246 mmol) was added to a
stirring solution of L2 (0.100 g, 0.246 mmol). After 15
minutes, [IrCl Cp*] (0.0981 g, 0.123 mmol) was added
6
2
(
CH ); 68.6 (Cp) 69.2 (Cp); 70.5 (Cp); 81.0 (Aracridine);
2
2
2
115.2 (Aracridine); 117.8 (Aracridine); 123.2 (Aracridine); 124.7
and this solution was allowed to continue stirring at room
temperature for 24 hours. C3 was isolated as a mustard yel-
low solid (0.081 g, 86% yield). Melting point: 219–223°C.
Elemental Analysis, Calc. for C H Cl N O Ir: C 51.62,
(
(
(
(
(
Aracridine); 127.3 (Aracridine); 127.7 (Aracridine); 131.3
Aracridine); 133.9 (Aracridine); 136.6 (Aracridine); 148.3
Aracridine); 151.2‐153.2 (Ar
HC=N). FT‐IR (ATR): ν (cm ) = 3425 (N‐H); 1630,
C=N) imine; 1606 (C=N)acr. imine. HR‐ESI‐MS (+): Calc.
); 155.5 (Aracridine); 162.5
acridine
33
34
2 3 2
‐
1
1
H 4.46, N 5.47 % Found: C 51.20, H 4.67, N 5.72 H
NMR (400 MHz, DMSO‐d ): δ (ppm) = 1.49 (s, 15 H,
6
+
for C H ClFeN O [M] m/z = 497.0957 Found: m/z =
27
24
3
+
Me‐Cp*); 3.71 (s, 3H, OMe); 4.07 (br s, 2H, CH ); 4.38
2
498.1036 [M+H] .
(
br s, 1H, CH ); 4.52 (s, 1H, CH ); 6.30 (t, J = 6.9 Hz,
2 2
1
7
H, Ar); 6.65 (d, 1H, Ar); 6.83 (d, J = 6.7 Hz, 1H, Ar);
.19‐7.30 (m, 1H, Aracridine); 7.45 (d, J = 8.8 Hz,1H,
2
.5 | Synthesis of [RhCp*Cl(L2)] (C2)
Aracridine); 7.53 (d, J = 8.4 Hz, 1H, Ar); 7.70 (s, 1H,
Aracridine); 7.85 (d, J = 8.7 Hz, 1H, Aracridine); 7.95 (s, 1H,
Aracridine); 8.04 (s, 1H, HC=N); 8.52 (d, J = 8.8 Hz, 1H,
To a stirring solution of L2 (0.100 g, 0.246 mmol) in dichlo-
romethane (40 ml), Sodium hydride (0.00590 g, 0.246 mmol)
was added and the mixture was allowed to stir at room tem-
13
1
Aracridine). C{ H} NMR (101 MHz, DMSO‐d ): δ (ppm)
6
perature for 15 minutes. After 15 minutes, [RhCl Cp*]2
= 9.16 (Me‐Cp*); 48.4 (CH ); 56.3 (OMe); 68.6 (CH );
2
2
2
(
0.0759 g, 0.123 mmol) in dichloromethane (20 ml) was
95.8 (Cp*); 99.8 (Ar); 110.3 (Ar); 114.3 (Aracridine); 115.1
(Ar); 118.1 (Aracridine); 122.4 (Aracridine); 125.3 (Aracridine);
126.1 (Ar); 126.5 (Aracridine); 127.8 (Aracridine); 130.8 (Ar);
134.3 (Aracridine); 135.2 (Aracridine); 136.1 (Aracridine); 150.2
added and this solution was allowed to continue stirring at
room temperature for 24 hours. After 24 hours, the reaction
mixture was filtered by gravity to remove any unreacted
material. The filtrate was then reduced (to ≈ 5 ml) and cold
diethyl ether (20 ml) was added drop‐wise to the solution to
precipitate C2. C2 was then collected by suction filtration
as an orange solid and dried under vacuum for 3 hours.
(Aracridine); 151.7 (Aracridine
) 152.1 (Aracridine); 156.6
(Ar ); 163.4 (Ar); 165.3; (HC=N). FT‐IR (ATR): ν
acridine
‐
1
(cm ) = 3321 (N‐H); 1617 (C=N)imine, 1602 (C=N)acr. imine.
+
%. HR‐ESI‐MS (+): Calc. for C H Cl N O Ir [M] m/z =
33
34
2 3 2
+
(0.082 g, 98 % yield). Melting point: 149–151°C. Elemental
767.1657 Found: m/z = 768.1721 [M+H] , m/z = 632.1963
+
Analysis, Calc. for C H Cl N O Rh: C 58.42, H 5.05, N
[M‐Cl] .
3
3
34
2 3 2

MATSHEKU ET AL.
5 of 14
2
.7 | Synthesis of [Ru(p‐cym)Cl(L2)] (C4)
(p‐cymCH); 49.1 (CH
2
); 55.8 (OMe); 65.4 (CH
2
); 76.4‐
9
9.6 (p‐cym ); 100.2 (Ar); 110.7 (Ar); 113.8 (Aracridine);
Ar
L2 (0.0800 g, 0.197 mmol) and sodium hydride (0.00437 g,
1
15.6 (Ar); 118.1 (Aracridine); 120.9 (Aracridine); 124.3
0
1
0
.197 mmol) were allowed to stir at room temperature for
5 minutes. After 15 minutes, [Ru(p‐cym)Cl ] (0.0603 g,
.0985 mmol) was added and this solution was allowed to
(
(
(
(
(
Aracridine); 125.9 (Ar); 126.6 (Aracridine); 131.9 (Ar); 133.8
Aracridine); 134.7 (Aracridine 135.3 (Aracridine); 150.2
Aracridine), 151.5 (Aracridine); 152.6‐153.0 (Aracridine), 157.1
2
2
)
continue stirring at room temperature for 24 hours. C4
was isolated as an orange solid (0.0484 g, 73% yield). Melt-
ing point: 217–219°C. Elemental Analysis, Calc. for
C H Cl N O Ru: C 58.67, H 4.92, N 6.22% Found: C
Ar
acridine
‐1
); 163.8 (Ar); 166.4 (HC=N). FT‐IR (ATR): ν
cm ) = 3313 (N‐H); 1615, (C=N)
1604 (C=N)
imine
acr.
+
imine. HR‐ESI‐MS (+): Calc. for C H Cl N O Os [M]
33
33
2 3 2
3
3
33
2 3 2
+
m/z = 765.1565 Found: m/z = 766.1574 [M+H] , m/z =
1
58.80, H 4.99, N 5.99%. H NMR (400 MHz, DMSO‐d ):
+
6
7
30.1816 [M‐Cl] .
δ (ppm) = 1.03, 1.17 (d, J = 6.6 Hz, 6H, p‐cymCH3);
2
3
4
.11 (s, 3H, p‐cymCH3); 2.64 (m, 1H, p‐cymCH); 3.57 (s,
H, OMe); 4.19 (br s, 2H, CH ); 4.48 (br s, 1H, CH );
2
2
.74 (br s, 1H, CH ); 5.36‐5.79 (m, 4H, p‐cym ); 6.20 (t,
2.9 | Synthesis of [RhCp*Cl(L3)][BPh ] (C6)
4
2
Ar
J = 7.0 Hz, 1H, Ar); 6.49 (s, 1H, Ar); 6.65 (d, J = 8.4
Hz, 1H, Ar); 7.01‐7.15 (m, 1H, Aracridine); 7.31‐7.43 (m,
To a stirring solution of L3 (0.100 g, 0.256 mmol) in chlo-
roform (20 ml), [RhCl Cp*] (0.083 g, 0.128 mmol) in chlo-
2
2
3
9
H, Ar and Aracridine); 7.63 (s, 1H, Aracridine); 7.81 (d, J =
.1 Hz, Aracridine); 7.92 (s, 1H, HC=N); 8.38 (d, J = 9.1
roform (20 ml) was added. This solution was allowed to stir
at room temperature for 24 hours. After 24 hours, the solvent
was removed by rotary evaporation. The remaining solid
was dissolved in methanol (15 ml) and sodium
tetraphenylborate (0.0439 g, 0.128 mmol) was added, and
the mixture was allowed to stir at room temperature for 30
minutes. After 30 minutes, a precipitate formed which was
collected by filtration and washed with methanol (3 x 20
ml) to afford C6 (0.0797 g, 63% yield) as a dark mustard
solid (which was dried under vacuum for 2 hours).
Melting point: 178–180°C. Elemental Analysis, Calc. for
C H BCl N ORh: C 68.38, H 5.53, N 5.70% Found: C
1
3
1
Hz, 1H, Aracridine). C{ H} NMR (101 MHz, DMSO‐d ):
6
δ (ppm) = 18.0, 19.2 (p‐cymCH3); 21.6 (p‐cymCH3); 32.0
(
p‐cymCH); 48.3 (CH ); 56.0 (OMe); 69.9 (CH ); 77.3‐
2
2
9
8.5 (p‐cym ); 99.8 (Ar); 111.2 (Ar); 114.4 (Aracridine);
Ar
116.2 (Ar); 117.6 (Aracridine); 121.8 (Aracridine); 124.0
(
(
(
(
(
Aracridine); 125.8 (Ar); 126.3 (Aracridine); 131.3 (Ar); 134.9
Aracridine); 135.5 (Aracridine 135.7 (Aracridine); 149.8
Aracridine), 151.4 (Aracridine); 152.7‐153.4 (Aracridine), 156.7
Ar ); 164.4 (Ar); 166.3 (HC=N). FT‐IR (ATR): ν
)
acridine
‐
1
cm ) = 3337 (N‐H); 1618, (C=N)
1606 (C=N)acr.
imine
5
6
54
2 4
+
imine. HR‐ESI‐MS (+): Calc. for C H Cl N O Ru [M]
m/z = 675.0993 Found: m/z = 676.1064 [M+H] , m/z =
6
1
33
33
2 3 2
6
8.80, H 5.66, N 5.66 %. H NMR (400 MHz, DMSO‐d ):
6
+
δ (ppm) = 1.65 (s, 15H, Me‐Cp*); 3.50 (s, 3H, OMe);
+
40.1305 [M‐Cl] .
3
.98 ‐ 4.23 (m, 2H, CH ), 4.45 (br s, 1H, CH ), 4.54 (br s,
2
2
1
H, CH ); 6.22 (br s, 1H, NH), 6.70 ‐ 6.86 (m, 4H,
2
‐
‐
BPh ); 6.93‐7.25 (m, 17H, BPh and Ar); 7.39 (t, J = 10
4
4
2
.8 | Synthesis of [Os(p‐cym)Cl(L2)] (C5)
Hz, 1H, Ar); 7.81 ‐ 8.05 (m, 4H, Ar and Aracridine); 8.21 ‐
8.41 (m, 2H, Aracridine); 8.36 (br s, 1H, HC=N); 8.48 (s,
1H, Aracridine); 9.05 (s, J = 5.0 Hz, 1H, Ar). C{ H}
L2 (0.150 g, 0.370 mmol) and sodium hydride (0.0088 g,
13
1
0
1
0
.370 mmol) were allowed to stir at room temperature for
5 minutes. After 15 minutes, [Os(p‐cym)Cl ] (0.146 g,
.185 mmol) was added and this mixture was allowed to
NMR (101 MHz, DMSO‐d ): δ (ppm) = 8.69 (Me‐Cp*);
2
2
6
47.6 (CH ); 55.7 (OMe); 61.8 (CH ); 97.5 (Cp*); 99.5
2
2
continue stirring at room temperature for 24 hours. C5 was
isolated as an orange solid (0.0826 g, 58% yield). Melting
point: 125128°C. Elemental Analysis, Calc. for C H
3 33
(Ar); 112.6 (Ar); 120.4 (Aracridine); 121.6 (Ar); 123.8
(Aracridine); 125.4 (Aracridine); 126.1 (Aracridine); 128.9
(Aracridine); 129.6 (Aracridine); 130.0 (Aracridine); 135.6 (Ar);
136.8 (Aracridine); 140.6 (Aracridine); 145.2 9 (Ar); 151.7
(Aracridine); 152.3‐152.9 (Aracridine); 155.7 (Aracridine); 169.7
3
Cl N O Os: C 51.83, H 4.35, N 5.49 % Found: C 51.98,
2
3 2
1
H 4.76, N 5.04 %. H NMR (400 MHz, DMSO‐d ): δ
6
‐1
(
(
ppm) = 1.02, 1.16 (d, J = 6.7 Hz, 6H, p‐cymCH3); 2.13
s, 3H, p‐cymCH3); 2.59 (m, 1H, p‐cymCH); 3.64 (s, 3H,
(HC=N). FT‐IR (ATR): ν (cm ) = 3329 (N‐H); 1630
(C=N)imine, 1604 (C=N) acr. imine, 1600 (C=N)pyridylimine.
+
OMe); 4.07 (br s, 2H, CH ); 4.38 (br s, 1H, CH ); 4.63
HR‐ESI‐MS (+): Calc. for C H Cl N ORh [M] m/z =
2
2
32 34
2 4
2+
‐
+
(
br. s, 1H, CH ); 5.71‐6.15 (m, , 4H, p‐cym ); 6.30 (t, J
663.1165 Found: m/z = 983.2942 [(M+H) BPh ]
,
2
Ar
4
+
=
7.3 Hz, 1H, Ar); 6.62 (d, J = 8.3 Hz, 1H, Ar); 6.79 (m,
m/z = 663.1174 [M] .
1
H, Ar); 7.10‐7.24 (m, 2H, Aracridine); 7.43‐7.79 m, 4H, Ar
Complexes C7‐C9 were prepared following the same
procedure as described for C6, using the appropriate
reagents. For C8 and C9, the reaction was stirred at room
temperature for 1.5 hours in the first step.
and Aracridine); 7.90 (s, 1H, HC=N); 8.41 (d, J = 9.1 Hz,
13
1
1H, Aracridine). C{ H} NMR (101 MHz, DMSO‐d ):
6
δ (ppm) = 18.7, 19.6 (p‐cymCH3); 22.4 (p‐cymCH3); 31.1

6
of 14
MATSHEKU ET AL.
2
.10 | Synthesis of [IrCp*Cl(L3)][BPh ] (C7)
18.8, 19.9 (p‐cymCH3); 21.7 (p‐cymCH3); 31.0 (p‐cymCH);
4
4
9.0 (CH ); 56.1 (OMe); 66.9 (CH ); 84.6‐101.4 (p‐cym );
2
2
Ar
L3 (0.096 g, 0.246 mmol) in chloroform (40 ml) and
IrCl Cp*] (0.102 g, 0.123 mmol) were used. After 24 hours
1
03.2 (Ar), 105.3 (Ar), 109.5 (Aracridine); 115.9 (Ar); 118.4
[
2
2
(
(
Aracridine); 122.0 (Aracridine); 125.2 (Aracridine); 126.4
Aracridine); 131.8 (Aracridine); 134.0 (Ar); 136.0 (Aracridine),
of stirring at room temperature, the solvent was removed by
rotary evaporation. The remaining solid was dissolved in
methanol (15 ml) and sodium tetraphenylborate (0.042 g,
1
37.2 (Aracridine), 147.8 (Ar); 150.6 (Aracridine); 151.4‐152.8
(
(
(
Aracridine); 154.4 (Aracridine); 156.2 (Aracridine); 170.4
HC=N). FT‐IR (ATR): ν(cm ) = 3270 (N‐H); 1627
0.123 mmol) was added. The product (C7) precipitated
‐1
out as a dark orange solid. (0.095 g, 72 % yield).
Melting point: 189–191°C. Elemental Analysis, Calc. for
C H BCl N OIr: C 62.68, H 5.07, N 5.22 % Found: C
C=N)imine, 1605 (C=N)acr. imine, 1601(C=N)pyridylimine.
+
HR‐ESI‐MS (+): Calc. for C H Cl N ORu [M] m/z =
6
6
33
36
2 4
5
6
54
2 4
2+
‐ +
61.1075 Found: m/z = 981.2861 [(M+H) BPh ] , m/z =
4
1
62.70, H 5.14, N 5.46 %. H NMR (400 MHz, DMSO‐d ):
+
6
61.1077 [M] .
δ(ppm) = 1.65 (s, 15H, Me‐Cp*); 3.60 (s, 3H, OMe); 4.06
br s, 2H, CH ), 4.35 ‐ 4.67 (m, 2H, CH ); 6.27 (br s, 1H,
(
2
2
‐
NH); 6.73 ‐ 6.82 (m, 4H, BPh ); 6.89‐7.19 (m, 16H,
BPh ); 7.42‐7.55 (m, 2H, Ar); 7.76 ‐ 8.06 (m, 4H, Ar and
2.12 | Synthesis of [Os(p‐cym)Cl(L3)][BPh ]
4
4
‐
(C9)
4
Aracridine); 8.19 ‐ 8.45 (m, 3H, Ar
HC=N); 9.03 (d, J = 5.0 Hz, 1 H, Ar). C{ H} NMR (101
); 8.37 (br s, 1H,
acridine
L3 (0.150 g, 0.384 mmol) in chloroform (40 ml) and
Os(p‐cym)Cl ] (0.0152 g, 0.192 mmol) were used. The
solution was stirred at room temperature for 1 hour 30
minutes. After 1 hour 30 minutes, the solvent was removed
by rotary evaporation. The remaining solid was dissolved
in methanol (15 ml), and sodium tetraphenylborate
1
3
1
[
2
2
MHz, DMSO‐d ): δ(ppm) = 7.70 (Me‐Cp*); 47.2 (CH );
6
2
55.1 (Me‐Cp* and OMe); 62.4 (CH ); 89.4 (Cp*); 99.3
2
(
(
(
Ar); 111.4 (Ar); 117.4 (Aracridine); 121.0 (Ar); 123.3
Aracridine); 124.8 (Aracridine); 128.4 (Aracridine); 129.9
Aracridine); 130.4 (Aracridine); 131.2 (Aracridine); 135.1 (Ar);
(0.0657 g, 0.192 mmol) was added. The product (C7)
138.2 (Aracridine); 140.12 (Aracridine), 146.4 (Ar); 152.9
precipitated out as a brown solid. (0.125 g, 61 % yield).
Melting point: 155–158°C. Elemental Analysis, Calc. for
C H BCl N OOs: C 62.86, H 4.99, N 5.24 % Found: C
(
(
(
Aracridine); 154.3‐154.8 (Aracridin e‐ ); 155.2 (Aracridine); 171.1
1
HC=N). FT‐IR (ATR): ν (cm ) = 3340 (N‐H); 1630
5
6
53
2 4
C=N)imine, 1606 (C=N)acr. imine, 1601(C=N)
.
1
pyridylimine
+
6
2.37, H 4.85, N 5.27 %. H NMR (400 MHz, DMSO‐d ):
6
HR‐ESI‐MS (+): Calc. for C H Cl IrN O [M] m/z =
3
2
34
2
4
δ(ppm) = 0.92, 1.08 (d, J = 8 Hz, 6H, p‐cymCH3); 2.19 (s,
H, p‐cymCH3); 2.63 (m, 1H, p‐cymCH); 3.58 (s, 3H,
OMe); 4.23 (br s, 2H, CH ); 4.36 (br s, 1H, CH ); 4.80
2
+
‐ +
7
=
53.1739. Found: m/z = 1073.3516 [(M+H) BPh ] , m/z
753.1736 [M] .
4
3
+
2
2
(
br s, 1H, CH ); 5.98‐6.19 (m, 5H, Ar and p‐cym );
2
Ar
6
.42 (t, J = 8 Hz, 4H, BPh ); 6.94‐7.14 (m, 16H,
4
2
.11 | Synthesis of [Ru(p‐cym)Cl(L3)][BPh4]
‐
BPh ); 7.17‐7.32 (m, 1H, Ar); 7.82‐8.05 (m, 4H, Ar
and Ar); 8.19‐8.43 (m, 3H, Ar
9.01 (d, J = 8 Hz, 1H, Ar). C{ H} NMR (101 MHz,
4
acridine
(
C8)
); 8.35 (s, 1H, HC=N);
acridine
13
1
L3 (0.124 g, 0.318 mmol) in chloroform (40 ml) and [Ru(p‐
cym)Cl ] (0.0970 g, 0.159 mmol) were used. This solution
DMSO‐d ): δ(ppm) = 19.1, 20.2 (p‐cymCH3); 22.1 (p‐
2
2
6
was allowed to stir at room temperature for 1 hour 30
minutes. After 1 hour 30 minutes, the solvent was removed
by rotary evaporation. The remaining solid was dissolved in
methanol (15 ml), and sodium tetraphenylborate (0.0544 g,
cymCH3); 31.6 (p‐cymCH); 49.4 (CH ); 57.5 (OMe); 67.7
2
(CH ); 86.2‐102.3 (p‐cym ); 104.8 (Ar), 111.3 (Ar),
2
Ar
112.4 (Aracridine); 116.8 (Ar); 117.7 (Aracridine); 121.8
(Aracridine); 124.6 (Aracridine); 126.5 (Aracridine); 130.9
(Aracridine); 135.8 (Ar); 136.4 (Aracridine), 136.7 (Aracridine),
148.1 (Ar); 150.8 (Aracridine); 152.4‐153.1 (Aracridine);
0.159 mmol) was added. The product (C8) precipitated
out as an orange solid. (0.097 g, 62 % yield). Melting
point: 236–239°C. Elemental Analysis, Calc. for
C H BCl N ORu: C 68.57, H 5.45, N 5.71 % Found: C
155.6 (Ar
); 157.0 (Aracridine); 169.2 (HC=N). FT‐IR
acridine
‐
1
(ATR): ν(cm ) = 3277 (N‐H); 1629 (C=N)imine, 1604
(C=N)acr. imine, 1600 (C=N) .. HR‐ESI‐MS (+):
Calc. for C H Cl N OOs [M] m/z = 751.1646 Found:
5
6
53
2 4
1
6
8.20, H 5.17, N 5.47 %. H NMR (400 MHz, DMSO‐d ):
6
pyridylimine
+
δ(ppm) = 0.94, 1.00 (d, J = 8.0 Hz, 6H, p‐cymCH3); 2.21
s, 3H, p‐cymCH3); 2.57 (m, 1H, p‐cymCH); 3.60 (s, 3H,
OMe); 4.21 (br s, 2H, CH ); 4.32 (br s, 1H, CH ); 4.82 (br
32 33 2 4
2+
‐ +
+
(
m/z = 1071.3418 [(M+H) BPh ] , m/z = 751.1634 [M] .
4
2
2
s, 1H, CH ); 5.99‐6.24 (m, 5H, Ar and p‐cym ); 6.55 (t, J
2
Ar
‐
2.13 | X‐ray crystallography
‐
=
8 Hz, 4H, BPh ); 6.90‐7.16 (m, 16H, BPh ); 7.19‐7.28
4
4
(
(
1
m, 1H, Ar); 7.86‐8.01 (m, 4H, Aracridine and Ar); 8.24‐8.46
Single crystals of C6 were obtained by slow diffusion of n‐
heptane (3 mL) into a concentrated solution of C6 (0.005
g) in chloroform (2 ml) at room temperature. Crystal data
m, 3H, Ar ); 8.36 (s, 1H, HC=N); 9.04 (d, J = 8 Hz,
acridine
13
1
H, Ar). C{ H} NMR (101 MHz, DMSO‐d ): δ(ppm) =
6

MATSHEKU ET AL.
7 of 14
and collection details for C6 are reported in Table 1.
Single‐crystal X‐ray diffraction data were collected on a
Bruker KAPPA APEX II DUO diffractometer using graph-
ite‐monochromated Mo‐Kα radiation (χ = 0.71073 Å).
Data collection was carried out at 173(2) K. Temperature
was controlled by an Oxford Cryostream cooling system
All non‐hydrogen atoms, except those of n‐heptane sol-
vent molecule, were refined anisotropically. Only five out
of seven carbon atoms in n‐heptane could be positioned in
the Fourier maps and were refined isotropically, the other
two carbon atoms and all n‐heptane's hydrogen atoms were
excluded from the final model. The hydrogen atoms on the
water molecule could not be located and were also excluded
from the final model. All other hydrogen atoms, except the
amino hydrogen atom H3N, were placed in idealized posi-
tions and refined in riding models with Uiso assigned 1.2 or
1.5 times Ueq of their parent atoms and the bond distances
were constrained between 0.95 – 0.99 Å. The hydrogen atom
H3N was located in the difference electron density maps and
refined freely. The structure was refined to R factor of
0.0417. The parameters for crystal data collection and struc-
ture refinements, the bond lengths, angles, torsion angles
are contained in file ac20.SUP.
CCDC number 1512942 contains the supplementary
crystallographic data for complex C6. This data can be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre. Copies of this information may be
obtained free of charge from The Director, CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK (fax: +44‐1223/336‐033;
email: deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.
uk/conts/retrieving.html.
(
Oxford Cryostat). Cell refinement and data reduction
[38]
were performed using the program SAINT.
The data
were scaled and absorption correction performed using
[
39]
SADABS.
The structure was solved by direct methods using
[
39]
SHELXS‐97
and refined by full‐matrix least‐squares
2 [39]
methods based on F using SHELXL‐2014
the graphics interface program X‐Seed.
Seed and POV‐Ray
and using
The programs X‐
were both used to prepare molecular
[40]
[
41]
graphic images.
TABLE 1 Crystallographic data for complex C6
.
C6 (C
5
+ O)
Empirical formula
Formula weight
Temperature/K
Crystal system
Space group
C
61
H
54BCl N O Rh
2 4 2
1059.70
173(2)
triclinic
P‐1
Crystal size
0
.130 x 0.100 x 0.050
2.14 | Cell culture
a/Å
b/Å
c/Å
α/°
12.9383(10)
Human promyelocytic leukemia cells (HL60) and skin fibro-
blast cells (FG0) were maintained in RPMI‐1640 medium
13.0568(11))
16.1005(13)
85.570(2)
83.655(2)
87.686(2)
2693.8(4)
2
(Gibco, Paisley, UK) and DMEM medium (Gibco, Paisley,
UK) respectively. All media were supplemented with 10 %
fetal bovine serum (FBS) and antibiotics (100 U/ml penicillin
and 100 μg/ml streptomycin) and cells were cultured at 37°C
β/°
γ/°
in a 5 % CO – 95% air‐humidified incubator.
2
3
Volume/Å
Z
2.15 | Cytotoxicity assay
‐1
μ (mm )
0.463
The compounds (L1‐L3, C1‐C9 and cisplatin) were pre-
pared as DMSO solutions then immediately dissolved in the
culture medium and serially diluted to the appropriate con-
centration, to give a final DMSO concentration of 0.5%.
3
ρcalcg/cm
1.306
F(000)
Radiation
1096.0
MoKα (λ = 0.71073)
1.95< θ < 28.45
70736
Theta range for data collection/°
Reflections collected
For each compound, cells were seeded in 96 well plates at
4
1
.0×10 cells per well and were prepared for treatment as fol-
lows: FG0 were cultured to 50‐60% adherent confluency and
were then treated by replacing normal culture media with
treatment media containing compound or vehicle; whereas
HL60 were grown in suspension for 24 hours and treatment
media were added directly to the normal culture media
already in wells to the desired final concentration. Cells were
thus treated in quadruplicate with a range of concentrations
of compound or vehicle for 48 hours while incubating at
Unique reflections
13606
R
int
0.041
Data/restraints/parameters
13552/0/ 625
1.050
2
Goodness‐of‐fit on F
Final R indices [I > = 2σ (I)]
Final R indices [all data]
Max, Min Δρ/e/ Å‐
R
R
1
1
= 0.0417, wR
= 0.0544, wR
2
2
= 0.1119
= 0.1205
3
1.26, ‐0.66
3
7°C and 5 % CO . Cytotoxicity of the compounds was
2

8
of 14
MATSHEKU ET AL.
evaluated using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphe-
nyltetrazolium bromide (MTT) assay as per manufacturer's
instructions (Roche, Indianapolis, Indiana USA). Briefly,
10 μl of MTT solution was added to each well and incubated
at 37°C for 4 h. This was followed by addition of 100 μl sol-
ubilization buffer (10 % SDS in 0.01 M HCl) and incubation
overnight at 37°C. Absorbance (585 nm) was then determined
for each well and the mean cell viability was calculated as a
percentage of the mean vehicle control. Each compound was
assayed in triplicate (biological repeats) and the half maximal
cytotoxic concentration values (IC ) determined.
5
0
2
.16 | Aqueous media and DMSO stability
studies
Complex C2 was dissolved in DMSO‐d / D O, in a 50:50
6
2
ratio (0.5 ml each), and warmed at 37°C, to mimic physiolog-
1
ical conditions. The sample was monitored by H NMR spec-
troscopy for stability at varying times up to 24 hours. In
another experiment, C2 was dissolved in DMSO‐d and 0.1
6
M NaCl (prepared using D O) (50:50 ratio, 0.5 ml each),
2
1
and the sample was monitored by H NMR spectroscopy
for stability at varying times up to 24 hours.
SCHEME 1 Outline for the synthesis of amino‐ and imino‐acridine
ligands (L1‐L3) and ferrocenyl‐acridine complex C1
2
.17 | 5‘‐GMP model DNA interactions
studies
yields of 72 and 75 % respectively and were fully character-
ized using analytical and spectroscopic techniques.
C2, and an equimolar amount of 5’‐GMP were dissolved in
DMSO‐d / D O, in a 50:50 ratio (0.5 ml each) and warmed
1
The H NMR spectra for ligands L2 and L3 all display
6
2
at 37°C, to mimic physiological conditions. The sample was
characteristic imine singlets in the range of δ = 8.09 to
8.26. The acridinyl and phenyl aromatic protons for L2 and
L3 are observed in the range of δ = 6.82 to 8.37 and δ =
7.18 to 8.45 respectively. In the aliphatic region, signals
1
31
1
monitored by H NMR and P{ H} NMR spectroscopy at
varying times up to 24 hours. In another experiment, C2
and an equimolar amount of 5’‐GMP were dissolved in
DMSO‐d and 0.1 M NaCl (prepared using D O) (50:50
due to the CH groups of the ethylene linker (integrating
6
2
2
1
ratio, 0.5 ml each), and the sample was monitored by H
NMR and P{ H} NMR spectroscopy at varying times up
to 24 hours.
for 2 protons each) and the methoxy (OMe) groups are seen
in the region of δ = 3.71 to 4.05. In addition, the spectrum
for L2 shows a signal due to the phenolic proton at δ =
31
1
13
1
2.90. In the C NMR spectra for L2 and L3, the aliphatic
carbons are observed between δ = 49.9 and δ = 61.1 and
the aromatic carbons between δ = 97.7 and 160.5. The chem-
ical shifts for the signals of the imine carbons resonate at δ =
3
| RESULTS AND DISCUSSION
.1 | Synthesis and characterization of
3
1
67.3 and 164.2 for ligands L2 and L3 respectively. FT‐IR
acridine ligands (L1 –L3 and C1)
spectroscopy also confirms the formation of L2 and L3 by
1
‐1
N ‐(6‐chloro‐2‐methoxyacridin‐9‐yl)ethane‐1,2‐diamine (L1)
was synthesized using the procedure described by Tot
the presence of characteristic imine bands at 1630 cm and
‐
1
1647 cm respectively. The acridinyl imine stretching vibra-
[
37]
‐1
et al.
excess ethylene diamine and refluxed for 20 hours
Scheme 1). L1 was isolated in 75% yield as an orange solid.
6,9‐Dichloro‐2‐methoxyacridine was added to
tion bands are displayed at ca 1600 cm and amino (N‐H)
‐
1
stretching vibration bands are evident at ca 3350 cm . Fur-
ther evidence for the formation of L2 and L3 is shown by
high resolution ESI‐mass spectrometry results, which exhibit
(
Acridinyl imine ligands L2 and L3 were prepared by a
Schiff‐base condensation reaction of L1 with salicylaldehyde
and 2‐pyridine carboxaldehyde in dichloromenthane at room
temperature (Scheme 1). The ligands (L2 and L3) were
obtained as air‐ and moisture‐stable orange solids in good
+
peaks assigned to [M+H] ions at m/z = 406.1240 and m/z =
391. 1253.
The ferrocenyl acridine‐containing complex C1 was
obtained via a Schiff‐base condensation of L1 with a slight

MATSHEKU ET AL.
9 of 14
excess of ferrocene carboxaldehyde (Scheme 1) in ethanol.
C1 precipitated and was collected by filtration as an orange
solid in a yield of 39%. This compound is soluble in most
organic solvents except petroleum ether, n‐hexane and
1
n‐heptane. The H NMR spectrum of C1 displays a charac-
teristic imine signal at δ = 8.13, confirming the formation
of C1. Broad signals at δ = 4.50 and δ = 4.33 represent the
protons on the substituted cyclopentadienyl (Cp) ring. The
broad signal integrating for 10 protons seen at δ = 3.90 to
4.04 is assigned to the methoxy group (OMe), the one CH2
group and the protons on the unsubstituted Cp ring. An imine
1
3
signal at δ = 162.5 is observed in the C NMR spectrum of
C1 while other carbon signals are consistent with the
proposed structure.
In the FT‐IR spectrum of C1, the acridinyl imine
‐
1
absorption band appears at 1606 cm while the imine band
‐
1
is seen at 1630 cm . An N‐H stretching vibration band is
‐1
also observed at 3425 cm . The mass spectrum displays
+
a m/z = 498.1036 peak corresponding to [M+H] , (Fig-
ure S1) thus further confirming the formation of C1.
SCHEME 2 Outline of the synthesis of neutral acridine‐containing
complexes (C2‐C5)
3
.2 | Synthesis and characterization of
acridine‐containing neutral complexes (C2 –C5)
The acridine–containing complexes (C2‐C5) were obtained
by reacting
a
deprotonated L2 in dichloromethane
for L2) to two diastereotopic proton signals in the spectra
with dimeric precursors, [Ru(p‐cym)Cl ] , [Os(p‐cym)
of complexes C2‐C5. For example, in C2 this CH group
2
2
2
Cl ] , [RhCp*Cl ] , and [IrCp*Cl ] (where p‐cym =
gives rise to two distinct signals comprising broad singlets
at δ = 4.18, and δ = 4.33. All other aromatic protons for
the salicylaldimine and acridine moieties (and its substitu-
2
2
2 2
2 2
6
i
5
ɲ ‐p‐ PrC H Me and Cp* = ɲ ‐C Me ) at room temperature
6
4
5
5
over 24 hours (Scheme 2). These new complexes were
obtained as yellow to orange air‐ and moisture‐stable solids
in good yields ranging from 58‐99%.
1
3
ents) were observed in the expected regions. The C NMR
spectra display the most deshielded carbons in the range of
δ = 165.8 to 166.3 assigned to the imine carbons of
complexes C2 – C5. These have shifted from δ = 167.3 in
L2 further confirming coordination of the metal centers to
the imine nitrogen.
Upon complexation of the metals to the acridinyl
salicylaldiminato ligand (L2) a distinct shift of the imine
proton signals (from δ = 8.26 in L2 to δ = 7.98, 8.04, 7.92
and 7.90 in C2, C3, C4 and C5 respectively) is seen in the
1
13
H NMR spectra of the complexes. This confirms coordina-
C NMR spectra of the complexes (C2‐C5) also display
tion of the metals at the imine nitrogen. There is no evidence
of coordination at the acridinyl nitrogen in all the complexes.
The pentamethylcyclopentadienyl (Cp*) protons of the
Rh(III) and Ir(III) complexes (C2 and C3) are observed as
singlets in the range of δ = 1.49 to 1.64 and are similar to
signals in the region of δ = 9.06 to 69.9 assigned to the
aliphatic carbons. Overall, complexes C2‐C5 display chemi-
cal shifts for aromatic carbons in the range of δ = 76.4 to
164.4, inclusive of the signals due to the respective
co‐ligands (Cp* and p‐cym).
[19, 42]
what has been previously reported.
For the Ru(II) and
Further analysis by FT‐IR shows expected N‐H stretch
vibration bands in their characteristic region of 3309 to
Os(II) complexes (C4 and C5), the p‐cym ligands exhibit
1
‐1
expected H NMR signals. Two chemical shifts for the
3321 cm for C2‐C5, and the ν(C=N)imine stretching bands
methyl protons are seen at δ = 1.02 to 1.17 (assigned to the
isopropyl methyl groups) and at ca δ = 2.1 (for the methyl
groups directly bonded to the arene ring). The aromatic
protons of the p‐cym resonate as multiplets between δ =
have shifted to lower absorption frequencies upon complex-
ation. The (C=N)imine bond experiences electron‐withdraw-
ing effects from the aromatic ring and the coordinated
metals which weakens the bond, resulting in a shift to lower
frequencies. Additionally, the absence of the ν(OH)
stretching vibration band gives confirmation of coordination
in a bidentate N^O manner and that L2 acts as anionic
bidentate donor ligand. When analyzed by high resolution
[18,42–45]
5.36 to 6.15 due to metal center induced chirality.
This metal center induced chirality also imparts splitting of
the proton signals assigned to the CH functionalities adja-
2
cent to the imine nitrogens (from one signal in the spectrum

1
0 of 14
MATSHEKU ET AL.
mass spectrometry, these complexes all display peaks
corresponding to the [M+H] and [M‐Cl] ions.
for all complexes (C7‐C9) due to the coordination of the
Ru(II), Os(II), Rh(III) and Ir(III) ions. The coordination
induces diastereotopicity in these complexes as well, and
this is evidenced by splitting of the proton signals assigned
+
+
3
.3 | Synthesis and characterization of
to the CH group directly bonded to the imine nitrogens.
2
acridine‐containing cationic complexes (C6 – C9)
This signal is seen as broad singlets at δ = 4.45 and δ =
4.54 in C6. There are no significant shifts in the acridinyl
proton signals (and its substituent OMe) and this observation
implies that no metal coordination occurs at the acridinyl
imine. All other aromatic protons for the 2‐pyridylimine,
Cp* and p‐cym moieties were observed in the expected
The N^N donor ligand (L3) was reacted with 0.5 equiva-
lents of the appropriate metal precursors, [Ru(p‐cym)Cl ] ,
2
2
[
Os(p‐cym)Cl ] , [RhCp*Cl ] , and [IrCp*Cl ] in chloro-
2
2
2 2
2 2
form (Scheme 3). The ruthenium and osmium analogues
are unstable if left to stir for longer than 90 minutes, after
which decomposition to a black solution is observed.
The acridine‐containing 2‐pyridylimine ligand (L3)
bonds to the metal centers in a bidentate manner via the
pyridyl and imine nitrogen atoms to produce cationic
complexes. These complexes were further treated with
1
regions in the H NMR spectra of complexes C6‐C9.
13
C NMR spectra for C6‐C9 all show the expected
number of signals for the proposed structures, with the imine
carbon signals shifting slightly downfield to δ = 169.7 (C6),
δ = 171.1 (C7), δ = 170.4 (C8) and δ = 169.2 (C9), from
δ = 164.2 in L3. The methyl substituents on the Cp* ligand
resonate between δ = 7.7 and 8.6 while the remaining
carbons of the Cp* ring are seen at δ = 89.4 and 97.5 for
C7 and C6 respectively. The p‐cym ligands in C8 and C9
display aromatic signals in the range of δ = 84.6 to 102.2.
The infrared spectra of complexes (C6‐C9) show the
(C=N)imine stretching frequency band at lower wavenumbers
sodium tetraphenyl borate (Na[BPh ]) in an anion metathesis
4
[
18,23b]
reaction to ensure air‐stability,
thus yielding new
complexes (C6‐C9). The complexes were obtained in yields
ranging from 61 to 72% and are all soluble in warm water
(± 40°C) and in organic solvents such as acetonitrile,
acetone, chloroform, ethanol and dichloromethane.
1
H NMR spectroscopy confirmed coordination of the
‐
1
‐1
metal centers to both the pyridylimine and imine nitrogen
atoms. A notable feature includes a downfield shift in the
imine proton signal from δ = 8.42 in L3 to ca δ = 8.3 in
the complexes. There is also a characteristic downfield shift
in the signals for the proton adjacent to the pyridyl nitrogen
of ca 1630 cm from 1647 cm in L3 while the absorp-
tion bands assigned to the (C=N)pyridylimine stretching fre-
quencies experience slight shifts to higher wavenumbers
‐
1
‐1
of ca 1600 cm from 1597 cm in L3. The former is as
a result of the pyridyl functional groups and the
SCHEME 3 Outline of the synthesis cationic acridine‐containing complexes (C6‐C9)

MATSHEKU ET AL.
11 of 14
coordinated metal centers effectively withdrawing electrons
from to the (C=N)imine bond thereby causing a shift to
lower wavenumbers.
TABLE 2 In vitro IC50 values of compounds L1‐L3 and C1‐C9
determined against the human promyelocytic leukemia (HL60) cancer
cell line and FG0 (normal skin fibroblast) cells, by MTT assay
HR‐ESI mass spectrometry was used for further character-
ization of the complexes and is consistent with the formation
HL60
FG0
SI
a
a
Compound IC50 [μM] ± SD IC50 [μM] ± SD
(FG0/HL60)
2
+
‐ +
of C6‐C9 by displaying [(M+H) BPh ] ion peaks. Interest-
4
L1
2.50 ± 0.66
2.49 ± 0.50
3.76 ± 0.13
2.82 ± 0.01
1.97 ± 0.14
2.34 ± 0.80
2.89 ± 0.18
10.20 ± 0.03
2.51 ± 1.30
3.48 ± 0.01
6.20 ± 0.20
9.16 ± 0.16
6.57 ± 0.11
5.85 ± 1.70
10.02 ± 0.18
7.14 ± 0.60
22.64 ± 3.00
6.50 ± 0.14
5.72 ± 1.90
7.38 ± 0.90
27.80 ± 1.70
3.00 ± 0.01
12.74 ± 0.70
34.35 ± 1.30
29.10 ± 0.30
42.13 ± 1.90
2.34
4.02
1.89
7.94
3.29
2.44
2.55
2.72
1.19
3.28
5.54
3.17
6.41
ingly, though conducted in the positive mode for all the
+
2+
‐ +
L2
complexes, the metal salt plus H ion [(M+H) BPh ]
was detected.
4
[
50]
L3
This may be attributed to the fact that
electron spray is a soft ionization technique and that the anal-
yses were conducted at a low 15V.
C1
C2
C3
C4
3
.4 | X‐ray diffraction studies of complex C6
C5
C6
The molecular structure of complex (C6) was unambiguously
confirmed in the solid state by single crystal X‐ray diffrac-
tion. Orange single crystals suitable for X‐ray diffraction
were obtained by slow diffusion of n‐heptane into a concen-
trated solution of C6 in chloroform at room temperature. The
molecular structure of C6 is depicted in (Figure 3) together
with geometric parameters. Further crystallographic details
are given in Table 1.
Complex C6 crystalizes in the triclinic crystal system and
P‐1 space group. The molecular structure of (C6) shows a
typical piano‐stool geometry with the rhodium center coordi-
nated to the Cp* ligand in an eta‐(5)‐fashion. Other ligands
around the rhodium include a terminal chloride and a chelat-
ing N^N ligand.
C7
C8
C9
cisplatin
a
5
0% inhibitory concentrations as obtained by the MTT assay and the values are
means ± standard deviations obtained from at least three independent experi-
ments. SI is the selectivity index determined as a ratio of the IC50 value of the
FG0 cells over the IC50 value of HL60 cells.
3
.5 | In Vitro anticancer activity of compounds
L1‐L3 and C1‐C9
The antiproliferative activity of the ligands (L1‐L3) and com-
plexes (C1‐C9) were evaluated in vitro against the human
promyelocytic leukemia cell line (HL60) and a non‐cancer-
ous skin fibroblast cell line (FG0). The IC50 values obtained
as an average of three independent determinations are shown
in Table 2.
The Rh‐N bond distances range from 2.118(2) Ȧ to
2
.116(2) Ȧ in C6 and are comparable to those in similar
[42,46]
N^N Rh(III) complexes.
Accordingly, there is no signif-
icant differences in the Rh‐Cl bond lengths of C6 (2.3861(7)
[19,42]
Ȧ as compared to reported values.
FIGURE 3 The ORTEP drawing of the molecular structure of complex (C6), showing atomic labelling. Ellipsoids are at 40 % probability level,
hydrogens omitted for clarity. Selected bond distances (Å) and angles (°): Rh(1)‐N(1), 2.118(2); Rh(1)‐N(2), 2.116(2); Rh(1)‐Cl(1), 2.3861(7);
Cl(1)‐Rh(1)‐N(1), 85.71(6); Cl(1)‐Rh(1)‐N2(1), 88.14(6); N(1)‐Rh(1)‐N(2), 76.63(8)

1
2 of 14
MATSHEKU ET AL.
All the compounds display higher cytotoxicities when
Importantly, all the compounds proved to be consistently
selective towards the cancer cell line over the normal FG0
cells with C6 being the least selective towards cancer cells
(selectivity index, SI = 1.19).
compared to cisplatin for the HL60 cell line apart from Os(II)
complexes C5 and C9 which had low solubility in the cell
culture medium, and this may have resulted in decreased
uptake into the cells. The ligands (L1‐L3) display good activ-
ities and upon coordination to Rh(III) and Ir(III) (C2, C3, C6
and C7), an increase in antiproliferative activity is demon-
strated. The Fe(II), Ru(II) and Os(II) complexes (C1, C4,
C5, C8 and C9), all exhibit slightly lower activities in com-
parison to the Rh(III) and Ir(III) complexes (C2, C3 and C6).
In general, the neutral complexes (C2‐C4) exhibit better
activity than their cationic (C6‐C8) congeners except for
osmium complexes C5 and C9, where the cationic complex
is slightly more cytotoxic than the neutral complex. The
IC50 values of the ligands and complexes are comparable to
a previously reported platinum complex conjugated with an
acridine moiety (against HL60 cells) although the cytotoxic
3
.6 | Stability and 5’‐GMP binding NMR
studies
An accepted mode of action of metal complexes under phys-
iological conditions involves the substitution of a chloride
ligand with a solvent molecule to form a metal‐aqua species
[47]
which subsequently interacts with DNA base pairs.
NMR studies were employed to assess the stability of
complex C2 (which displayed the best cytotoxicity) in
DMSO‐d /D O (50:50 v/v) over 24 hours at 37°C. This
6
2
solvent solution was used to mimic the preparation solution
prior to conducting the biological assays. In addition, the
same experiments were conducted with C2 using 0.1 M NaCl
solution in D O/DMSO‐d (50:50 v/v) (instead of plain D O)
[
27b]
measurements were not conducted using the same assay.
2
6
2
in order to mimic a chloride concentration similar to that
present in the blood. Complex C2 proved to be stable in both
solutions over 24 hours and there are no signs of aquation or
[
50]
any side product formation (Figure S8).
The binding of metal complexes to DNA and/or proteins
is a significant step in the cytotoxic mechanism of metal‐
based drugs, and studies have shown that metal complexes
[
48,49]
preferentially bind to guanine.
Thus, interaction of C2
with DNA model guanosine‐5’‐monophosphate (5’‐GMP)
1
31
1
was monitored by H and P{ H} NMR spectroscopy in
both DMSO‐d /D O (50:50 v/v) and 0.1 M NaCl in
6
2
D O/DMSO‐d (50:50 v/v) solutions. NMR measurements
2
6
1
were taken after incubation for two hours, where complex
C2 is seen to interact with the DNA model, 5’‐GMP, by
complexing to its N7 atom. This is evidenced by an upfield
shift of the proton signal on the carbon (C8) adjacent to N7
FIGURE 4 (a) H NMR spectrum of the reaction mixture of C2 and
1
5
5
’‐GMP in DMSO‐d
’‐GMP in DMSO‐d
incubation at 37 °C for 2 hours
6
/D
/D
2
O (50:50 v/v) and (b) H NMR spectrum of the
6
2
O (50:50 v/v). Spectra were recorded after
3
1
1
FIGURE 5 31P{1H} NMR spectrum of (a) 5’‐GMP DMSO‐d6/D2O (50:50 v/v) and (b) P{ H} NMR spectrum of C2 and 5’‐GMP in DMSO‐d
O (50:50 v/v). Spectra were recorded after incubation at 37°C for 2 hours
6
/
D
2

MATSHEKU ET AL.
13 of 14
from δ = 8.29 (for free 5‐GMP, Figure 4b) to δ = 7.99 (in the
adduct, Figure 4a). The high stability in solution
demonstrated by C2, suggest that 5’‐GMP binding occurs
via a direct chloride ligand substitution on the metal center.
Additionally, the P{ H} spectra of the free 5’‐GMP and
the mixtures show an upfield shift in the phosphorus
[3] B. Rosenberg, L. Van Camp, J. E. Trosko, V. H. Mansour, Nature
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1
[5] M. Galanski, V. B. Arion, M. A. Jakupec, B. K. Keppler, Curr.
Pharm. Des. 2003, 9, 2078.
(
monophosphate) signal from δ = 1.99 (in free 5’‐GMP) to
[
6] M. A. Jakupec, M. Galanski, B. K. Keppler, Rev. Physiol. Biochem.
Pharmacol. 2003, 146, 1.
δ = ‐1.01 in the adduct (Figure 5(a) and 5(b)). This suggests
that acridine is likely playing the role of a vector, directing
the complex to the DNA. The cytotoxic mechanism may
involve a dual action where DNA intercalation is driven by
the acridine scaffold, and further metal complex interaction
with the DNA base pairs. More specifically, binding to
[7] M. Galanski, M. A. Jakupec, B. K. Keppler, Curr. Med. Chem.
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[
[
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5
’‐GMP nucleotide found in the DNA backbone is a possible
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mode of action for such systems.
[
[
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4
| CONCLUSIONS
Metallomics 2012, 4, 139.
[
13] (a) J. Maksomiska, D. S. Williams, G. E. Atilla‐Gokcumen, K. S.
M. Smalley, P. J. Carroll, R. D. Webster, P. Filippakopoulos, S.
Knapp, M. Herlyn, E. Meggers, Chem.–Eur. J. 2008, 14, 4816;
New acridine‐containing salicylaldimine and 2‐pyridylimine
ligands, ferrocenyl and half‐sandwich Rh(III), Ir(III), Ru(II)
and Os(II) complexes have been successfully prepared and
characterized using an array of spectroscopic and analytical
techniques. The molecular structure of the cationic Rh(III)
complex, C6, has been determined by single crystal X‐ray
diffraction. All the compounds display good in vitro cytotox-
icities against the human promyelocytic leukemia cell line.
The coordination of metal cations to the acridine‐containing
ligands results in slightly improved activity against HL60,
apart from the Os(II) ion. Neutral N^O chelating complexes
(
b) P. Govender, L. C. Sudding, C. M. Clavel, P. J. Dyson, B.
Therrien, G. S. Smith, Dalton Trans. 2013, 42, 1267.
[
14] (a) P. J. Dyson, G. Sava, Dalton Trans. 2006, 16, 1929;
(b) C. Scolaro, A. Bergamo, L. Brescacin, R. Delfino,
M. Cocchietto, G. Laureneczy, T. J. Geldbach, G. Sava, P. J. Dyson,
J. Med. Chem. 2005, 48, 4161.
[
[
[
15] P. Govender, A. K. Renfrew, C. M. Clavel, P. J. Dyson, B. Therrien,
G. S. Smith, Dalton Trans. 2011, 40, 1158.
16] A. A. Nazarov, C. G. Hartinger, P. J. Dyson, J. Organomet. Chem.
2
014, 751, 251.
(
C2‐C5) exhibit better antiproliferative activities over the
17] P. Govender, T. Riedel, P. J. Dyson, G. S. Smith, J. Organomet.
Chem. 2015, 799‐800, 38.
cationic systems, and there is a notable selectivity towards
cancer cells (HL60) in comparison to normal skin fibroblast
cells (FG0). NMR studies show that the most active complex
[18] (a) B. C. E. Makhubela, M. Meyer, G. S. Smith, J. Organomet.
Chem. 2014, 772, 229; (b) P. Govender, F. Edafe, B. C. E.
Makhubela, P. J. Dyson, B. Therrien, G. S. Smith, Inorg. Chim.
Acta 2014, 409, 112.
(
C2) is stable in aqueous solution (including NaCl aqueous
solution) and that this complex binds to 5’‐GMP, thus
suggesting that DNA is an in vitro target.
[
19] (a) A. R. Burgoyne, B. C. E. Makhubela, M. Meyer, G. S. Smith,
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D. J. Schmitz, K. Kräling, K. Harms, C. P. Bagowski, E. Meggers,
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Cutillas, K. G. Samper, M. Capdevila, O. Palacios, A. Espinosa,
Dalton Trans. 2012, 41, 12847.
ACKNOWLEDGMENTS
We would like to thank the University of Johannesburg, the
University of Cape Town the National Research Foundation
of South Africa (NRF) (Grant Number 95517) for financial
support.
[
20] S. H. van Rijt, A. F. A. Peacock, R. D. L. Johnstone, S. Parsons, P.
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