Rhodium(III) Dihalido Complexes: The Effect of Ligand Substitution and Halido Coordination on Increasing Cancer Cell Potency

Article abstract of DOI:10.1021/acs.inorgchem.0c03704

This work presents the synthesis of eight new rhodium(III) dihalido complexes, [RhX2(L)(LH)] (where X = Cl or I), which incorporate two bidentate N-(3-halidophenyl)picolinamide ligands. The ligands have different binding modes in the complexes, whereby one is neutral and bound via N,N (LH) coordination, while the other is anionic and bound via N,O (L) coordination. The solid state and solution studies confirm multiple isomers are present when X = Cl; however, after a halide exchange with potassium iodide (X = I) the complexes exist exclusively as single stable trans isomers. NMR studies reveal the Rh(III) trans diiodido complexes remain stable in aqueous solution with no ligand exchange reported over 96 h. Chemosensitivity data against a range of cancer cell lines show two cytotoxic complexes, where L = N-(3-bromophenyl)picolinamide ligand. The results have been compared to the analogous Ru(III) complexes and overall highlight the Rh(III) trans diiodido complex to be ～78× more cytotoxic than the analogous Rh(III) dichlorido complex, unlike the Ru(III) complexes which are equitoxic against all cell lines. Additionally, the Rh(III) trans diiodido complex is more selective toward cancerous cells, with selectivity index (SI) values >25-fold higher than cisplatin against colorectal carcinoma.

Full text of DOI:10.1021/acs.inorgchem.0c03704

pubs.acs.org/IC
Article
Rhodium(III) Dihalido Complexes: The Effect of Ligand Substitution
and Halido Coordination on Increasing Cancer Cell Potency
Rianne M. Lord,* Markus Zegke, Aida M. Basri, Christopher M. Pask, and Patrick C. McGowan
Cite This: Inorg. Chem. 2021, 60, 2076−2086
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: This work presents the synthesis of eight new rhodium(III) dihalido
complexes, [RhX2(L)(LH)] (where X = Cl or I), which incorporate two bidentate
N-(3-halidophenyl)picolinamide ligands. The ligands have different binding modes in the
complexes, whereby one is neutral and bound via N,N (LH) coordination, while the
other is anionic and bound via N,O (L) coordination. The solid state and solution studies
confirm multiple isomers are present when X = Cl; however, after a halide exchange with
potassium iodide (X = I) the complexes exist exclusively as single stable trans isomers.
NMR studies reveal the Rh(III) trans diiodido complexes remain stable in aqueous
solution with no ligand exchange reported over 96 h. Chemosensitivity data against a
range of cancer cell lines show two cytotoxic complexes, where L = N-(3-
bromophenyl)picolinamide ligand. The results have been compared to the analogous
Ru(III) complexes and overall highlight the Rh(III) trans diiodido complex to be ∼78×
more cytotoxic than the analogous Rh(III) dichlorido complex, unlike the Ru(III)
complexes which are equitoxic against all cell lines. Additionally, the Rh(III) trans diiodido complex is more selective toward
cancerous cells, with selectivity index (SI) values >25-fold higher than cisplatin against colorectal carcinoma.
P388 lymphocytic leukemia but low activity against L1201 and
B16 melanoma.14 A variety of Rh(III) analogues of the well-
known Ru(III) anticancer complexes NAMI-A and KP1019
have shown contrasting activities, whereby mer,cis-
[RhCl3 (Me2 SO)(Im)2 ] (Figure 1B), Na[trans-
[RhCl4(Me2SO)(Im)] (Figure 1C) and (ImH)trans-
[RhCl4(Im)2] (Im = imidazole) (Figure 1D) were all found
to be inactive against human ovarian carcinoma (A2780),15
with half maximal inhibitory concentration (IC50) values of
>200 μM, >100 μM, and >1000 μM, respectively.15 In
contrast, complexes such as mer,cis-[RhCl3(Me2SO)2L] (L =
Im or NH3, Figure 1E), have shown significant cytotoxicity
against A2780 cells with IC50 values of 1.5 0.4 μM (L = Im)
INTRODUCTION
■
Cisplatin, cis-[Pt(NH3)2Cl2] (CDDP), and its platinum
derivatives are still the most frequently used transition metal
complexes in the treatment of various cancer types.1 However,
the corresponding trans isomer, transplatin (trans-
[(NH3)2Cl2Pt]), remains therapeutically inactive.2,3 It has
been suggested that the orientation of the cis chlorides is key
for therapeutic activity, whereby CDDP forms ∼80% of
intrastrand DNA cross-links, while transplatin forms mono-
adducts and interstrand DNA cross-links.4−7 In 2019 Quiroga
et al. reported a series of aliphatic amine Pt(II) complexes and
highlighted the cis dichlorido complexes have similar modes of
action to cisplatin, while the trans diiodido complexes exhibit
different modes of action and activate the cytoplasmic protein
BID, suggesting a pro-apoptotic cascade.8,9 Generally, Pt-based
therapeutics have poor cancer cell selectivity, which is
associated with many adverse side-effects and has led
chemotherapy research toward new non Pt-based alternatives
such as Ru, Os, Rh, and Ir complexes,10−12 in an attempt to
overcome some of these selectivity issues. In particular,
organometallic complexes have been prominent, with many
compounds exhibiting high potency toward cancerous cells,
while remaining nontoxic toward normal cell types, allowing
for a more targeted therapy and reduction in patient side
effects.13
and 15.6
2 μM (L = NH3).15 Such Rh complexes were
shown to inhibit the growth of primary MCa mammary tumors
implanted in metastatic cancer cells in the lungs. Rhodium(III)
complexes of the type mer-[RhCl3(Me2SO)(pp)] (pp = 2,2′-
bipyridine (byp) or benzo[i]dipyrido[3,2-a:2′,3′-c]phenazine
(dppn), Figure 1F) are stable in chloroform in light for 24 h
but exhibit slow isomerization to mer/fac in polar solutions
under the same conditions.16 The rate and extent of
Received: December 18, 2020
Published: January 19, 2021
The antitumor activity of Rh(II) coordination compounds
was explored over 40 years ago, with the dinuclear Rh complex
[Rh2(CH3COO)4(H2O)2] (Figure 1A) showing good anti-
tumor activity against the Ehrlich ascites, sarcoma 180, and
https://dx.doi.org/10.1021/acs.inorgchem.0c03704
© 2021 American Chemical Society
Inorg. Chem. 2021, 60, 2076−2086
2076

Inorganic Chemistry
pubs.acs.org/IC
Article
In 2019, Khan et al. reported Rh(III) isoquinoline
complexes (Figure 1H) which accumulated in the mitochon-
dria and induced apoptosis via mitochondrial membrane
damage25 and highlighted their potentially different modes of
́
action to the Pt(II) based therapeutics. Petrovic et al. reported
new Rh(III) complexes of the type [RhCl3(L)], with the
incorporation of camphor-derived bis(pyrazolylpyridine) li-
gands (Figure 1I) and show their binding to biomolecules,
whereby the binding weakens following this order: guanosine
monophosphate (5′-GMP) > glutathione (GSH) > methio-
nine (L-Me).26 The complexes also had good affinity for calf
thymus-DNA (ct-DNA) and bovine serum albumin (BSA),
again showing potentially different modes of action for Rh(III)
complexes. To date the majority of Rh anticancer research has
been focused on arene-based compounds, and there are
relatively few reports on the anticancer properties of
coordination Rh(III) complexes of the type [RhX2L2].
Alongside other research groups, we have been interested in
answering the question “does geometry matter in the design of
anticancer complexes?”24 Wachter et al. reported that
geometry plays a very important role and showed a Ru(II)
trans complex (Figure 1J) which exhibited higher in vitro
anticancer activity and was significantly superior to that of the
analogous cis complex. Complementary to this work, in 2017
we highlighted Ru(III) dihalido picolinamide complexes
(Figure 1K), which exist as multiple isomers, and are
dependent on the nature of the ancillary halide (X = Cl or
I).27 The Ru(III) dichlorido complexes existed as a range of
different isomers, while the Ru(III) diiodido complexes yielded
single stable trans isomers. In particular, the N-(3-
bromophenyl)picolinamide substituted Ru(III) diiodido com-
plex exhibited nanomolar potency against several cancer cell
lines. Overall, the diiodido complexes were ∼13× more
cytotoxic than the analogous dichlorido complexes, high-
lighting potentially different modes of action, similar to the
Pt(II) work reported by Quiroga et al.8
Since we have already reported the potential of using
picolinamide ligands to increase cytotoxicity of metal
complexes,27−29 we provide further insight into the biological
cytotoxicity and the stability of the cis and trans dihalido
complexes, by reporting eight new N-((3-halidophenyl)-
picolinamide)rhodium(III) dihalido complexes, [RhX2(L)-
(LH)], where X = chlorido (1−4) or iodido (5−8). The
complexes are fully characterized, and we report seven new
crystal structures. Alongside single crystal X-ray diffraction
(SC-XRD), the solid state data from powder X-ray diffraction
(PXRD) measurements indicate a “mixture” of isomers for the
dichlorido complexes 1−4 but single trans isomers for the
diiodido complexes 5−8. The stability of the complexes in
solvent and phosphate buffer solution (PBS) was assessed and
confirms that the trans diiodido complexes remain stable
toward ligand exchange. The library of complexes has been
screened against a range of human cell lines and results show
that the Rh(III) trans diiodido complex (where L/LH = N-(3-
bromophenyl)picolinamide) exhibits high cytotoxicity which is
∼78× more active than the analogous dichlorido complex and
is >25× more selective than cisplatin against human colorectal
cancer.
Figure 1. Selected rhodium and ruthenium complexes which have
been screened for their cytotoxic potential.
isomerization were dependent on the size of the polypyridyl
ligand and highlighted that the presence of multiple isomers
can be problematic. These isomers can have significantly
different cytotoxicity values, and yet determining the active
speciesthough essential for future drug developmenthas
proven difficult.17,18
The majority of Rh(III) coordination complexes are based
on polypyridyl ligands, and this was in part due to their
potential DNA binding properties, redox properties, hydro-
phobic nature, and their conjugated systems, which can be
useful in photoactivate therapy (e.g. PDT) in the treatment of
cancer.19,20 Barton and co-workers have conducted extensive
research on Rh(III) metalloinsertors (e.g., Figure 1G), which
bind DNA mismatches, disrupt DNA synthesis, and have low
micromolar cytotoxicity values. These complexes are more
potent in cells which were unable to repair DNA mismatches,
and this highlights their significance in the treatment of
cancer.21−23 When comparing the work to Ru(II) polypyridyl
complexes, it was shown that complexes with ancillary ligands
in a cis arrangement can form covalent bonds to biomolecules;
however, bioactive Ru(II) trans polypyridyl complexes are not
well explored.24
EXPERIMENTAL SECTION
■
General. All complexes were synthesized using aerobic reaction
conditions. Chemicals were obtained from Sigma-Aldrich Chemical
Co., Acros Organics, Alfa Aesar, and Strem Chemical Co. and, unless
2077
https://dx.doi.org/10.1021/acs.inorgchem.0c03704
Inorg. Chem. 2021, 60, 2076−2086

Inorganic Chemistry
pubs.acs.org/IC
Article
otherwise stated, and were used as supplied. General preparation and
characterization data by nuclear magnetic resonance (NMR)
spectroscopy, Fourier transform infrared (FTIR), ES+MS, and
microanalysis were obtained for complexes 1−8.
Data Analysis. Statistical analysis of the results was conducted
using Student’s t test, for p < 0.05 being considered as significant, and
p < 0.01 as very significant.
N-(3-X-Phenyl)picolinamide Ligand Preparation (X = F, Cl,
Br, or I). The ligands have been previously reported27,29 and were
prepared using the same synthetic route, which is a modification of
published procedures.37,38 Functionalized aniline (25 mmol, 1 equiv)
was added to a solution of pyridine-2-carboxylic acid (25 mmol, 1
equiv) in pyridine (15 mL) and warmed to 50 °C for 15 min. To this
mixture, triphenylphosphite (25 mmol, 1 equiv) was added and
heated to 110 °C for 18 h, yielding orange solutions. Addition of
water (100 mL) yielded white solids to which dichloromethane (40
mL) was added, and the organic layer was separated. The aqueous
layer was extracted with 1:1 (v/v) aqueous HCl (3 × 100 mL). To
neutralize the extract, sodium bicarbonate was added until pH 7. The
brown solids were isolated by filtration and then washed with distilled
water. After recrystallization from methanol, washing with water, and
drying in vacuo, the ligands were isolated as pale brown solids or
needle-like crystals. 1H NMR was conducted on all ligands to confirm
their successful synthesis.
Rhodium Dichloride Complexes, [(L)(LH)RhCl2]. N-(3-
Halidophenyl)picolinamide ligand (0.80 mmol, 2 equiv) was added
to a solution of RhCl3·3H2O (0.40 mmol, 1 equiv) in ethanol (30
mL), followed by triethylamine (0.40 mmol, 1 equiv). The solution
was heated under reflux for 2 h, yielding a yellow-orange solution.
Pentane was added to precipitate the complexes as yellow solids
which were filtered, washed with pentane, dried in vacuo, and
recrystallized via vapor diffusion in methanol/pentane to yield
analytically pure products. All yields were calculated before
recrystallization.
Instrumentation. All NMR spectra were recorded on a Bruker
DPX 300, Bruker 400 Ultrashield Plus, or a Bruker Ascend 500
spectrometer. Elemental analyses were acquired by Tanya Marinko-
Covell at the Microanalytical Service (University of Leeds) and
Stephen Boyer at the Elemental Analysis Service (London
Metropolitan University). Mass Spectra were recorded on a Bruker
maXis impact mass spectrometer or on a Micromass ZMD
spectrometer with electrospray ionization and photoiodide array
analyzer at the University of Leeds. Infrared spectra were obtained
using a Platinum ATR spectrometer on a crystal plate with samples
analyzed using OPUS software.
X-ray Crystallographic Analysis. A suitable single crystal was
selected and immersed in an inert oil. The crystal was then mounted
on a glass capillary and attached to a goniometer head on a Bruker X8
Apex diffractometer (1, 3Δ, 4a, 4b, 6, and 7) or a XtaLAB Synergy
Dualflex HyPix (3Λ) using graphite monochromated Mo Kα
radiation (λ = 0.71073 Å) or an Agilent SuperNova X-ray
diffractometer fitted with an Atlas area detector and a kappa-geometry
4-circle goniometer, using graphite monochromated Mo Kα radiation
(λ = 0.71073 Å), using 1.0° ϕ-rotation frames. The crystal was cooled
to 100−120 K by an Oxford Cryostream low temperature device.30
The full data set was recorded and the images processed using
APEX231 or CrysAlis Pro software.32 Structure solution by direct
methods was achieved through the use of SHELXS programs33 and
the structural model refined by full matrix least-squares on F2 using
SHELXL.33 Molecular graphics were plotted using Mercury.34 Editing
of CIFs and construction of tables and bond lengths and angles was
achieved using PLATON35 or Olex2 programs.36 Unless otherwise
stated, hydrogen atoms were placed using idealized geometric
positions (with free rotation for methyl groups), allowed to move
in a “riding model” along with the atoms to which they are attached,
and refined isotropically.
Chemosensitivity Assays. Cell viability assays were conducted
using human cell lines: colorectal carcinomas − p53-wildtype and
p53-null (HCT116 p53+/+ and HCT116 p53−/−), lung carcinoma
(A549), melanoma (FM55), pancreatic carcinoma (MIA PaCa-2),
ovarian carcinomas−cisplatin sensitive and cisplatin resistant (A2780
and A2780cisR), breast adenocarcinoma (MCF-7), and normal
epithelial retinal (ARPE-19). All cell lines were routinely maintained
as monolayer cultures in appropriate complete medium and
maintained in either T-25 or T-75 flasks at 37 °C and 5% CO2.
A549, MIA PaCa-2, and ARPE-19 cells were cultured in high glucose
DMEM-F12 medium containing 10% fetal calf serum, while HCT116
p53+/+, HCT116 p53−/−, A2780, A2780cisR, and MCF-7 were
cultured in RPMI-1640 supplemented with 10% fetal calf serum; all
medium was supplemented with sodium pyruvate (1 mM) and L-
glutamine (2 mM). Prior to chemosensitivity studies, cell monolayers
were passaged using Trypsin-EDTA and diluted to a concentration of
1 × 104 cells/mL. All assays were conducted using 96-well plates, in
which 100 μL of the cell suspension was added to each well and
incubated for 24 h at 37 °C and 5% CO2 (column 1 contains just
media to serve as a blank). All complexes were made fresh using stock
solutions of dimethyl sulfoxide (DMSO) at 100 mM. After 24 h, 100
μL of drug dilutions in media were added to the plates in columns 3−
12 (column 2 contains 100% cells to serve as a control) and then
incubated for a further 96 h (24 h or 72 h) at 37 °C and 5% CO2.
After 96 h, 20 μL MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylte-
trazolium bromide, 5 mg/mL) was added to each well and incubated
for 3 h at 37 °C and 5% CO2. All solutions were then removed via
pipet, and 150 μL of DMSO was added. Each well was mixed using a
pipet, and the absorbance of each well was measured at 540 nm using
a ThermoFisher Multiskan FC spectrophotometer microplate reader.
Results were plotted on a logarithmic scale, and the half maximal
inhibitory concentration (IC50) was determined from duplicate of
triplicate repeats and reported as an IC50 Standard Deviation (SD).
[(C12H8FN2O)(C12H9FN2O)RhCl2] (1): Yield: 0.183 g, 0.23 mmol,
49%; ES+MS (CH3OH, m/z): Anal. Calc for C24H17N4O2F2Cl2Rh:
605.2; Anal. Found: 605.0 [M]+; Elemental Analysis: Anal. Calc.: C
47.6; H 2.8; N 9.3; Cl 11.7%; Anal. Found: C 47.3; H 3.0; N 8.9; Cl
11.4%; FTIR (cm−1): 3330 (b), 3079 (w), 1563 (s), 1486 (m), 1475
(m), 1401 (m), 1349 (w), 1305 (w), 1264 (m), 1189 (w), 1120 (w),
1030 (w), 971 (w), 907 (w), 865 (m), 761 (s), 706 (m), 676 (s), 593
1
(w), 518 (m), 457 (m), 448 (w); Major isomer: H NMR (d4-MeOD,
3
300.13 MHz, 300 K): δ 9.81 (d, 1H, J(1H−1H) = 5.9 Hz), 9.38 (d,
3
3
1H, J(1H−1H) = 5.5 Hz), 8.35 (d, 1H, J(1H−1H) = 7.2 Hz), 8.30
(dd, 1H, J(1H−1H) = 7.7 Hz, J(1H−1H) = 1.5 Hz), 8.19 (m, 2H),
3
4
7.90 (ddd, J(1H−1H) = 7.6 Hz, J(1H−1H) = 5.8 Hz, J(1H−1H) =
1.6 Hz), 7.81 (t, 3J(1H−1H) = 6.5 Hz), 7.36 (m, 3H), 7.03 (m, 2H),
6.78 (m, 3H); 13C{1H} NMR (d4-MeOD, 75.47 MHz, 300 K): δ 178.4
(Q, C = O), 174.6 (Q, C = O), 169.7 (CH), 164.4 (Q), 158.8 (Q),
157.3 (Q), 156.1 (Q), 148.9 (CH), 146.2 (CH), 145.0 (CH), 132.9
(CH), 131.5 (CH), 128.4 (CH), 125.2 (CH), 119.2 (CH), 118.8
(CH), 118.3 (CH), 114.8 (CH), 113.8 (CH), 113.4 (CH), 107.2
3
3
4
1
(C−F), 106.7 (CH), 106.0 (C−F), 97.7 (CH); Minor isomer: H
NMR (d4-MeOD, 75.47 MHz, 300 K): δ 9.69 (d, 1H, 3J(1H−1H) = 5
Hz), 9.32 (d, 1H, J(1H−1H) = 5.2 Hz), 8.59 (m, 2H), 7.59 (br. m,
3
9H), 7.19 (d, 2H, J(1H−1H) = 6 Hz), 6.70 (br. m, 1H); 13C{1H}
3
NMR (d4-MeOD, 75.47 MHz, 300 K): δ 195.8 (Q, C = O), 190.3 (Q,
C = O), 187.5 (Q), 180.7 (Q), 180.4 (CH), 177.1 (Q), 172.4 (Q),
170.8 (CH), 166.1 (CH), 165.3 (CH), 159.6 (CH), 155.8 (CH),
151.9 (CH), 146.3 (CH), 141.3 (CH), 139.6 (CH), 129.6 (CH),
124.2 (CH), 117.4 (CH), 111.9 (Q, C−F), 109.2 (Q, C−F), 105.1
(CH), 94.1 (CH), 90.9 (CH).
[(C12H8ClN2O)(C12H9ClN2O)RhCl2] (2): Yield: 0.185 g, 0.29
mmol, 62%. ES+MS (CH3OH, m/z): Anal. Calc for C24H17N4O2Cl4Rh:
638.1; Anal. Found: 636.9 [M − H]+; Elemental Analysis: Anal. Calc.
(with 1 molecule of EtOH): C 45.6; H 3.4; N 8.2; Cl 20.7%. Anal.
Found: C 44.9; H 3.0; N 8.0; Cl 20.5%; FTIR (cm−1): 3287 (b), 3086
(w), 1563 (s), 1479 (m), 1428 (w), 1357 (w), 1305 (w), 1297 (w),
1189 (w), 1155 (w), 1098 (w), 1059 (w), 974 (w), 886 (m), 763
(m), 676 (s), 603 (w), 516 (w), 447 (m); Major isomer: 1H NMR (d4-
3
MeOD, 300.13 MHz, 300 K): δ 9.69 (d, 1H, J(1H−1H) = 5.7 Hz),
3
3
9.29 (d, 1H, J(1H−1H) = 5.5 Hz), 8.31 (d, 1H, J(1H−1H) = 7.9
Hz), 8.21 (td, 2H, J(1H−1H) = 7.6 Hz, J(1H−1H) = 1.3 Hz), 8.14
(m, 1H), 8.09 (m, 2H), 7.80 (m, 3H), 7.50 (s, 1H), 7.41 (s, 1H), 6.80
3
4
2078
https://dx.doi.org/10.1021/acs.inorgchem.0c03704
Inorg. Chem. 2021, 60, 2076−2086

Inorganic Chemistry
pubs.acs.org/IC
Article
(m, 3H); 13C{1H} NMR (d4-MeOD, 75.47 MHz, 300 K): δ 195.4 (Q,
C = O), 194.2 (Q, C = O), 190.4 (Q), 185.7 (Q), 185.5 (Q), 179.9
(Q), 178.5 (CH), 173.7 (CH), 167.5 (CH), 157.4 (CH), 154.1
(CH), 151.3 (CH), 141.5 (CH), 137.8 (CH), 135.1 (CH), 131.2
(CH), 128.9 (CH), 128.1 (CH), 126.7 (CH), 124.1 (CH), 119.7 (Q,
C−Cl), 117.5 (Q, C−Cl); Minor isomer: 1H NMR (d4-MeOD, 300.13
3J(1H−1H) = 2.0 Hz), 7.15 (m, 1H), 7.07 (dd, 1H, 3J(1H−1H) = 1.9
Hz, 4J(1H−1H) = 1.1 Hz); 13C{1H} NMR (d6-(CH3)2CO, 75.47 MHz,
300 K): δ 203.2 (Q, CO), 196.5 (Q, CO), 190.4 (CH), 186.6
(CH), 183.6 (Q), 156.1 (Q), 154.0 (CH), 147 (Q), 145.7 (CH),
143.3 (Q), 137.8 (CH), 135.8 (CH), 134.5 (CH), 131.1 (CH), 127.9
(CH), 125.0 (CH), 119.3 (CH), 117.6 (CH), 116.5 (CH), 115.7
(CH), 114.3 (Q, C−Br), 112.8 (CH), 110.9 (Q, C−Br), 109.3 (CH).
[(C12H8IN2O)(C12H9IN2O)RhCl2] (4): Yield: 0.294 g, 0.36 mmol,
73%. ES+MS (CH3OH, m/z): Anal. Calc for C24H17N4O2Cl2I2Rh:
821.0; Anal. Found: 820.8 [M − H]+; Elemental Analysis: Anal. Calc.
(with 0.5 molecules of H2O): C 34.4; H 2.3; N 6.7%. Anal. Found: C
34.0; H 2.2; N 6.3%; FTIR (cm−1): 3236 (b), 3091 (w), 1564 (s),
1469 (m), 1418 (w), 1302 (w), 1270 (w), 1155 (w), 1063 (w), 1028
(w), 995 (w), 860 (w), 764 (m), 681 (s), 601 (w), 515 (w), 437 (w);
Major isomer:1H NMR (d4-MeOD, 300.13 MHz, 300 K): δ 9.83 (d,
3
MHz, 300 K): δ 9.65 (d, 1H, J(1H−1H) = 5.1 Hz), 9.46 (d, 1H,
3J(1H−1H) = 5.6 Hz), 8.66 (d, 1H, 3J(1H−1H) = 7.6 Hz), 8.50 (t, 1H,
3J(1H−1H) = 7.0 Hz), 8.39 (t, 1H, 3J(1H−1H)= 8.4 Hz), 8.01 (d, 1H,
3J(1H−1H) = 7.6 Hz), 7.93 (m, 2H), 7.86 (s, 1H), 7.75 (s, 1H), 7.45
(m, 1H), 7.30 (br. m, 2H), 7.09 (br. m, 2H), 6.97 (br. m, 1H);
13C{1H} NMR (d4-MeOD, 75.47 MHz, 300 K): δ 194.7 (Q, C = O),
193.3 (Q, C = O), 188.9 (CH), 184.3 (Q), 181.7 (Q), 175.1 (Q),
174.1 (Q), 168.3 (CH), 165.5 (CH), 163.5 (CH), 160.0 (CH), 154.8
(CH), 153.2 (CH), 148.2 (CH), 140.2 (CH), 133.2 (CH), 129.7
(CH), 125.9 (CH), 123.9 (CH), 114.7 (Q, C−Cl), 110.7 (Q, C−Cl),
107.3 (CH).
3
3
1H, J(1H−1H) = 5.6 Hz), 9.42 (d, 1H, J(1H−1H) = 5.2 Hz), 8.43
3
3
(d, 1H, J(1H−1H) = 8.7 Hz), 8.35 (d, 1H, J(1H−1H) = 8.7 Hz),
8.28 (td, 1H, J(1H−1H) = 8.0 Hz, J(1H−1H) = 1.0 Hz), 8.01 (dd,
3
4
[(C12H8BrN2O)(C12H9BrN2O)RhCl2] (3): Yield: 0.183 g, 0.25
mmol, 50%. ES+MS (CH3 OH, m/z): Anal. Calc for
C24H17N4O2Br2Cl2Rh: 727.0; Anal. Found: 726.8 [M − H]+; Elemental
Analysis: Anal. Calc.: C 39.7; H 2.4; N 7.7%. Anal. Found: C 39.4; H
2.4; N 7.5%; FTIR (cm−1) 3a: 2997 (w), 2915 (w), 2759 (b), 1543
(s), 1467 (m), 1427 (w), 1338 (m), 1297 (w), 1256 (m), 1146 (m),
1058 (m), 969 (m), 928 (w), 860 (m), 778 (m), 751 (m), 682 (s),
593 (w), 567 (w), 512 (m), 484 (m), 437 (m); 3b: 3189 (w), 3052
(b), 2980 (w), 1618 (m), 1590 (m), 1562 (s), 1469 (m), 1420 (w),
1389 (w), 1344 (w), 1297 (w), 1229 (m), 1153 (w), 1085 (w), 1058
(w), 983 (m), 907 (w), 860 (m), 758 (s), 672 (s), 600 (w), 553 (w),
512 (m), 470 (w), 430 (w); 3c: 3380 (b), 3209 (b), 3066 (w), 1618
(s), 1598 (s), 1568 (s), 1466 (m), 1433 (w), 1413 (w), 1390 (w),
1340 (w), 1311 (w), 1260 (w), 1151 (w), 1062 (w), 1025 (w), 999
(w), 966 (w), 922 (w), 896 (w), 860 (m), 776 (s), 758 (s), 723 (w),
677 (s), 601 (w), 561 (w), 548 (w), 498 (w), 475 (m), 435 (m), 415
2H, J(1H−1H) = 8.4 Hz, J(1H−1H) = 1.5 Hz), 7.94 (m, 1H), 7.79
(m, 1H), 7.71 (m, 2H), 7.37 (s, 1H), 7.19 (m, 3H), 6.83 (s, 1H);
13C{1H} NMR (d4-MeOD, 75.47 MHz, 300 K): δ 192.0 (Q, C = O),
190.2 (CH), 188.50 (Q, C = O), 173.6 (CH), 158.0 (Q), 155.7 (Q),
154.7 (CH), 141.6 (Q), 139.7 (Q), 137.6 (CH), 137.4 (CH), 135.8
(CH), 135.3 (CH), 134.7 (CH), 133.1 (CH), 132.3 (CH), 131.6
(CH), 130.1 (CH), 126.4 (CH), 124.9 (CH), 121.4 (Q, C−I), 118.6
(Q, C−I), 112.9 (CH); Minor isomer:1H NMR (d4-MeOD, 300.13
3
3
MHz, 300 K): δ 9.16 (d, 1H, J(1H−1H) = 5.3 Hz), 9.03 (d, 1H,
3
3J(1H−1H) = 5.2 Hz), 8.29 (dd, 2H, 3J(1H−1H) = 7.8 Hz, 4J(1H−1H)
= 1.6 Hz), 8.08 (d, 1H, 3J(1H−1H) = 8.3 Hz), 7.81 (m, 2H), 7.73 (d,
1H, J(1H−1H) = 6.2 Hz), 7.69 (br. m, 3H), 7.45 (s, 1H), 7.32 (d,
3
3
3
1H, J(1H−1H) = 7.1 Hz), 7.21 (d, 1H, J(1H−1H) = 7.7 Hz), 7.00
(s, 1H), 6.95 (br. m, 1H); 13C{1H} NMR (d4-MeOD, 75.47 MHz, 300
K): δ 178.6 (Q, CO), 178.3 (CH), 177.6 (Q, CO), 176.1 (Q),
174.6 (Q), 157.6 (CH), 144.3 (Q), 143.5 (Q), 140.4 (CH), 139.3
(CH), 139.0 (CH), 136.2 (CH), 136.1 (CH), 135.2 (CH), 133.7
(CH), 132.8 (CH), 127.0 (CH), 126.3 (CH), 125.5 (CH), 122.8
(CH), 122.0 (CH), 117.8 (Q, C−I), 117.6 (CH), 116.0 (Q, C−I).
Rhodium Diiodide Complexes, [(L)(LH)RhI2]. N-(3-
Halidophenyl)picolinamide ligand (1.20 mmol, 2 equiv) was added
to a solution of RhCl3·3H2O (0.60 mmol, 1 equiv) in ethanol (30
mL), followed by triethylamine (0.60 mmol, 1 equiv). The solution
was heated under reflux for 2 h, yielding a yellow-orange solution.
Excess KI (6.0 mmol, 5 equiv) was added to the solution and reflux
continued for 18 h. The dark brown solids were filtered, washed with
ethanol, dried in vacuo, and recrystallized via vapor diffusion in
dimethylformamide/diethyl ether to yield analytically pure products.
All yields were calculated before recrystallization.
1
(w); Major isomer: H NMR (d6-(CH3)2CO, 300.13 MHz, 300 K): δ
3
3
9.85 (d, 1H, J(1H−1H) = 5.6 Hz), 9.39 (d, 1H, J(1H−1H) = 5.6
Hz), 8.57 (d, 1H, 3J(1H−1H) = 7.8 Hz), 8.29 (dtd, 2H, 3J(1H−1H) =
10.4 Hz, J(1H−1H) = 7.8 Hz, J(1H−1H) = 1.5 Hz), 8.14 (m, 1H),
7.95 (ddd, 1H, 3J(1H−1H) = 7.8 Hz, 3J(1H−1H) = 5.5 Hz,
4J(1H−1H) = 1.2 Hz), 7.90 (ddd, 1H, 3J(1H−1H) = 7.6 Hz,
3J(1H−1H) = 5.7 Hz, 4J(1H−1H) = 1.6 Hz), 7.83 (t, 1H, 3J(1H−1H) =
3
4
2.0 Hz), 7.64 (ddd, 1H, J(1H−1H) = 8.1 Hz, J(1H−1H) = 2.1 Hz,
4J(1H−1H) = 0.9 Hz), 7.45 (ddd, 1H, 3J(1H−1H) = 8.0 Hz,
3J(1H−1H) = 1.9 Hz, 4J(1H−1H) = 1.0 Hz), 7.34 (t, 1H, 3J(1H−1H) =
3
3
8.1 Hz), 7.18 (t, 1H, J(1H−1H) = 1.9 Hz), 7.01 (m, 2H), 6.86 (m,
3
1H); 13C{1H} NMR (d6-(CH3)2CO, 75.47 MHz, 300 K): δ 199.2 (Q,
C = O), 197.2 (CH), 194.1 (Q, C = O), 188.6 (Q), 168.7 (Q), 153.3
(CH), 152.7 (Q), 151.7 (Q), 139.6 (CH), 139.4 (CH), 130.8 (CH),
130.5 (CH), 130.1 (CH), 129.9 (CH), 129.6 (CH), 129.2 (CH),
126.9 (CH), 126.3 (CH), 125.5 (CH), 125.3 (CH), 121.5 (CH),
121.2 (Q, C−Br), 120.8 (Q, C−Br); Minor isomer 1:1H NMR (d6-
(CH3)2CO, 300.13 MHz, 300 K): δ 9.46 (d, 1H, 3J(1H−1H)= 5.6 Hz),
[(C12H8FN2O)(C12H9FN2O)RhI2] (5): Yield: 0.124 g, 0.15 mmol,
36%. ES+MS (DMF, m/z): Anal. Calc for C24H17N4O2F2I2Rh: 788.1;
Anal. Found: 788.2 [M]+; Elemental Analysis: Anal. Calc.: C 36.6; H
2.2; N 7.1%. Anal. Found: C 36.3; H 2.4; N 7.3%; FTIR (cm−1): 3066
(b), 2939 (w), 1590 (m), 1579 (s), 1483 (m), 1444 (m), 1405 (m),
1357 (m), 1307 (m), 1265 (m), 1183 (m), 1157 (m), 1125 (m),
1062 (m), 988 (w), 965 (m), 869 (m) 796 (m), 767 (s), 750 (s), 705
3
3
8.91 (d, 1H, J(1H−1H) = 5.2 Hz), 8.04 (dd, 1H, J(1H−1H) = 3.0
Hz, 4J(1H−1H) = 1.4 Hz), 7.8 (d, 1H, 3J(1H−1H) = 1.9 Hz), 7.75 (m,
2H), 7.73 (m, 1H), 7.68 (ddd, 1H, J(1H−1H) = 7.5 Hz, 3J(1H−1H)
3
1
(m), 675 (s); H NMR (d6-acetone, 400.13 MHz, 300 K): δ 9.40 (br.
= 5.7 Hz, J(1H−1H) = 1.5 H), 7.14 (t, 2H, J(1H−1H) = 1.9 Hz),
7.12 (m, 1H), 7.05 (m, 2H), 6.97 (s, 1H), 6.93 (s, 1H), 6.91 (m, 1H);
13C{1H} NMR (d6-(CH3)2CO, 75.47 MHz, 300 K): δ 209.0 (Q, C
O), 201.1 (Q, CO), 195.4 (CH), 192.2 (CH), 161.2 (CH), 159.5
(Q), 156.8 (Q), 155.7 (CH), 149.7 (Q), 146.1 (Q), 143.6 (CH),
141.6 (CH), 138.5 (CH), 136.2 (CH), 134.0 (CH), 133.3 (CH),
132.7 (CH), 131.7 (CH), 127.2 (CH), 123.6 (CH), 120.7 (Q, C−
Br), 120.3 (CH) 118.4 (Q, C−Br), 115.4 (CH); Minor isomer 2:1H
NMR (d6-(CH3)2CO, 300.13 MHz, 300 K): δ 9.70 (d, 1H, 3J(1H−1H)
= 5.4 Hz), 9.50 (d, 1H, 3J(1H−1H) = 5.8 Hz), 8.72 (d, 1H,
3J(1H−1H) = 8.6 Hz), 8.39 (m, 1H), 8.09 (m, 1H), 8.05 (dd, 1H,
3J(1H−1H) = 3.1 Hz, 4J(1H−1H) = 1.4 Hz), 8.02 (dd, 1H, 3J(1H−1H)
4
3
d, 1H, 8.73 3J(1H−1H) = 5.6 Hz), 8.73 (d, 1H, 3J(1H−1H) = 8.4 Hz),
3
3
8.28 (br, t, 1H, J(1H−1H)= 7.6 Hz), 8.08 (d, 1H, J(1H−1H) = 7.8
Hz), 7.89 (m, 1H), 7.71−7.56 (m, 5H), 7.51 (br, s, 1H), 7.50−7.46
(m, 1H), 7.36 (m, 1H), 7.45−7.41 (m, 1H), 7.00 (s, 1H), 7.24 (br. d,
1H, J(1H−1H) = 5.5 Hz), 7.14 (m, 1H); 13C{1H} NMR (d6-acetone,
3
75.47 MHz, 300 K): δ 190.6 (Q, CO), 189.90 (Q, CO), 187.2
(CH), 166.4 (CH), 163.0 (Q), 160.0 (Q), 159.9 (Q), 150.8 (Q),
148.3 (CH), 139.6 (CH), 136.5 (CH), 134.0 (CH), 132.3 (CH),
130.7 (CH), 128.1 (CH), 127.0 (CH), 126.9 (CH), 125.6 (CH),
124.1 (CH), 122.9 (CH), 119.4 (CH), 118.8 (Q, C−Cl), 117.9
(CH).
[(C12H8ClN2O)(C12H9ClN2O)RhI2] (6): Yield: 0.160 g, 0.190 mmol,
45%. ES+MS (DMF, m/z): Anal. Calc for C24H17N4O2Cl2I2Rh: 821.0;
Anal. Found: 820.8 [M − H]+; Elemental Analysis: Anal. Calc. (with
0.33 molecules of DMF and H2O): C 36.2; H 2.9; N 7.8%. Anal. Found:
= 3.1 Hz, J(1H−1H) = 1.4 Hz), 7.99 (d, 1H, J(1H−1H) = 7.3 Hz),
7.86 (m, 1H), 7.78 (d, 1H, 3J(1H−1H) = 1.5 Hz), 7.55 (m, 1H), 7.51
(m, 1H), 7.39 (t, 1H, 3J(1H−1H) = 1.9(x2) Hz), 7.37 (t, 1H,
4
3
2079
https://dx.doi.org/10.1021/acs.inorgchem.0c03704
Inorg. Chem. 2021, 60, 2076−2086

Inorganic Chemistry
pubs.acs.org/IC
Article
C 36.2; H 2.6; N 7.7%; FTIR (cm−1): 3054 (b), 2865 (w), 1567 (s),
1471 (m), 1427 (w), 1343 (m), 1305 (m), 1258 (m), 1155 (m), 1074
(w), 981 (w), 875 (m), 760 (s), 676 (m), 613 (w), 497 (m), 440
(m); 1H NMR (d4-MeOD, 300.13 MHz, 300 K): δ 9.62 (d, 1H,
MeCN:PBS (80:20 v/v). NMR spectra were recorded at various time
points over a period of 96 h.
Ligand Exchange with Complexes 1 and 4 (Water
Exclusion). Each complex (3.6 mg, 4.95 mmol) was treated with
one equivalent of N-(X-phenyl)picolinamide ligand (X = 3-fluoro or
3-iodo) (1.2 mg, 4.95 mmol) and made up to a 7.0 mM concentration
with either 0.7 mL CDCl3 or 0.7 mL d6-DMSO. NMR spectra were
recorded after approximately 10 min.
Ligand Exchange with Complexes 5 and 8 (Water
Exclusion). Each complex (4.5 mg, 4.95 mmol) was treated with
one equivalent of N-(X-phenyl)picolinamide ligand (X = 3-fluoro or
3-iodo) (1.2 mg, 4.95 mmol) and made up to a 7.0 mM concentration
with either 0.7 mL CDCl3 or 0.7 mL d6-DMSO. NMR spectra were
recorded after approximately 10 min.
3
3J(1H−1H) = 5.6 Hz), 8.45 (d, 1H, J(1H−1H) = 4.9 Hz), 7.77 (td,
1H, 3J(1H−1H) = 7.8 Hz), 7.71 (m, 1H), 7.66 (m, 1H), 742 (dd, 1H,
3J(1H−1H) = 8.2 Hz), 7.36 (m, 1H), 7.29 (ddd, 1H, 3J(1H−1H) = 7.4
Hz, 3J(1H−1H) = 5.8 Hz, 4J(1H−1H) = 2.0 Hz), 7.00 (s, 1H), 6.87 (t,
1H, 3J(1H−1H) = 7.1 Hz), 6.70 (m, 5H), 6.60 (s, 1H); 13C{1H} NMR
(d4-MeOD, 75.47 MHz, 300 K): δ 194.2 (Q, CO), 192.5 (Q, C
O), 191.6 (CH), 174.2 (CH), 172.8 (CH), 167.9 (CH), 159.9 (CH),
157.6 (CH), 147.6 (CH), 147.1 (CH), 135.7 (CH), 133.4 (CH),
132.3 (CH), 130.5 (CH), 129.1 (CH), 128.7 (CH), 128.1 (CH),
127.0 (CH), 125.3 (CH), 122.0 (CH), 118.8 (CH), 117.5 (CH),
117.3 (CH), 116.5 (Q, C−Cl).
RESULTS AND DISCUSSION
[(C12H8BrN2O)(C12H9BrN2O)RhI2] (7): Yield: 0.156 g, 0.170
mmol, 36%. ES+MS (DMF, m/z): Anal. Calc for C24H17N4O2Br2I2Rh:
909.9; Anal. Found: 910.7 [MH]+; Elemental Analysis: Anal. Calc. (0.5
molecules of KI): C 27.2; H 1.6; N 5.2%. Anal. Found: C 27.2; H 1.7;
N 5.0%; FTIR (cm−1): 3044 (b), 2919 (w), 1610 (s), 1544 (s), 1468
(m), 1430 (w), 1334 (m), 1298 (m), 1263 (m), 1148 (m), 1059 (w),
996 (w), 924 (w), 862 (m), 783 (m), 778 (m), 678 (s), 600 (w), 562
■
The N-(3-halidophenyl)picolinamide ligands were prepared by
modifications of previously reported methods.27,37,38 The
Rh(III) dichlorido complexes, [RhCl2(L)(LH)] (1−4), were
prepared by heating to reflux RhCl3·3H2O (1 equiv) with a
functionalized N-(3-halidophenyl)picolinamide ligand (2
equiv) and triethylamine (1 equiv), for 2 h in ethanol (Scheme
1A). The Rh(III) diiodido complexes, [RhI2(L)(LH)] (5−8),
were synthesized using a halide-exchange reaction and heating
to reflux the dichlorido complexes 1−4 and excess KI, in
ethanol for 18 h (Scheme 1B).27 All complexes were obtained
as analytically pure compounds in moderate yields (36−73%)
and have been fully characterized using FTIR, NMR,
electrospray mass spectrometry (ES-MS), elemental analysis,
PXRD, and single X-ray diffraction where possible.
1
(w), 516 (m), 514 (m), 437 (m); H NMR (d4-MeOD, 300.13 MHz,
300 K): δ 9.96 (d, 1H, 3J(1H−1H) = 5.3 Hz), 9.62 (d, 1H, 3J(1H−1H)
= 5.0 Hz), 8.41 (d, 1H, 3J(1H−1H) = 7.6 Hz), 8.09 (m, 1H), 7.92 (d,
1H, 3J(1H−1H) = 7.9 Hz), 7.73 (td, 1H, 3J(1H−1H) = 7.6 Hz,
4J(1H−1H) = 1.8 Hz), 7.42 (m, 2H), 7.31 (dd, 1H, 3J(1H−1H) = 6.5
4
3
Hz, J(1H−1H) = 4.8 Hz), 7.18 (t, 1H, J(1H−1H) = 8.5 Hz), 7.01
(m, 2H), 6.91 (d, 1H, J(1H−1H) = 8.3 Hz), 6.87 (m, 2H), 6.76 (s,
3
1H); 13C{1H} NMR (d4-MeOD, 75.47 MHz, 300 K): δ 193.7 (Q, C
O), 192.3 (CH), 192.0 (Q, CO), 188.3 (Q), 179.2 (CH), 173.4
(Q), 163.0 (Q), 147.9 (Q), 142.5 (CH), 138.9 (CH), 138.3 (CH),
136.8 (CH), 130.8 (CH), 130.2 (CH), 129.8 (CH), 128.9 (CH),
128.2 (CH), 126.7 (CH), 124.2 (CH), 123.4 (CH), 122.0 (Q, C−
Br), 117.4 (CH), 116.6 (Q, C−Br).
Scheme 1. Synthesis of (A) Rh(III) Dichlorido Complexes
[RhCl2(L)(LH)] (1−4) and (B) Rh(III) Diiodido
Complexes [RhI2(L)(LH)] (5−8)
[(C12H8IN2O)(C12H9IN2O)RhI2] (8): Yield: 0.234 g, 0.234 mmol,
41%. ES+MS (DMF, m/z): Anal. Calc for C24H17N4O2I4Rh: 1003.9;
Anal. Found: 1004.7 [MH]+; Elemental Analysis: Anal. Calc.: C 28.7; H
1.7; N 5.6%. Anal. Found: C 28.6; H 1.8; N 5.6%; FTIR (cm−1): 2978
(b), 2668 (w), 1614 (s), 1584 (m), 1556 (w), 1465 (m), 1392 (m),
1293 (m), 1261 (m), 1150 (m), 1091 (s), 1055 (s), 1030 (s) 995 (s),
901 (s), 855 (m), 759 (m), 716 (m), 680 (s), 654 (m), 637 (m), 622
1
(s), 598 (s), 554 (s), 508 (s), 459 (s); H NMR (d6-DMSO, 300.13
MHz, 300 K): δ 9.65 (br. d, 1H, 3J(1H−1H) = 5.0 Hz), 7.92 (m, 2H),
3
3
7.89 (d, 2H, J(1H−1H) = 10 Hz), 7.61 (d, 2H, J(1H−1H) = 5 Hz)
7.52 (td, 2H, 3J(1H−1H) = 5 Hz, 4J(1H−1H) = 2.5 Hz), 7.47 (s, 2H),
7.17 (t, 2H, 3J(1H−1H) = 10 Hz), 7.02 (m, 2H), 6.75 (t, 2H);
13C{1H} NMR (d6-DMSO, 75.47 MHz, 300 K): δ 167.9 (Q, CO),
159.3 (Q), 146.9 (Q), 139.3 (CH), 138.2 (CH), 135.6 (CH), 129.6
(CH), 127.2 (CH), 127.1 (CH), 125.2 (CH), 124.9 (CH), 93.9 (Q,
C−I).
Stability Studies of Complex 3 (Water Inclusion). Complex 3
(3.6 mg, 4.95 mmol) was made up to a 7.0 mM concentration with
0.7 mL d6-DMSO:PBS (80:20 v/v), and an NMR was recorded at
various time points over a period of 96 h.
Stability Studies of Complex 7 (Water Inclusion). Complex 7
(4.5 mg, 4.95 mmol) was made up to a 7.0 mM concentration with
0.7 mL d3-MeCN:PBS (80:20 v/v), and an NMR was recorded at
various time points over a period of 96 h.
Ligand Exchange with Complex 3 (Water Inclusion).
Complex 3 (3.6 mg, 4.95 mmol) was treated with one equivalent of
N-(3-chlorophenyl)picolinamide ligand (L′) (1.2 mg, 4.95 mmol)
and made up to a 7.0 mM concentration with 0.7 mL d6-DMSO:PBS
(80:20 v/v). NMR spectra were recorded at various time points over a
period of 96 h.
Ligand Exchange with Complex 7 (Water Inclusion).
Complex 7 (4.5 mg, 4.95 mmol) was treated with one equivalent of
N-(3-chlorophenyl)picolinamide ligand (L′) (1.2 mg, 4.95 mmol)
and made up to a 7.0 mM concentration with 0.7 mL of d3-
Single Crystal X-ray Diffraction (SC-XRD). [RhCl2(L)-
(LH)]. Single crystal X-ray diffraction (SC-XRD) was obtained
for complexes 1, 3Δ, 3Λ, and 4a and 4b (Figure 2) by vapor
diffusion of pentane/methanol. Complex 1 crystallized in an
orthorhombic cell, and structural solution was performed in
space group P212121. Complex 3 crystallized as orange plates;
however, when the reaction was repeated the enantiomer of
complex 3 was obtained (Figure 3). Both structures, 3Δ and
3Λ, crystallized in a monoclinic cell, and structural solutions
were performed in space group Cc. Upon taking the Δ
enantiomer and redissolving it in methanol, the complex
2080
https://dx.doi.org/10.1021/acs.inorgchem.0c03704
Inorg. Chem. 2021, 60, 2076−2086

Inorganic Chemistry
pubs.acs.org/IC
Article
Figure 2. Molecular structures of rhodium dichlorido compounds 1, 3Δ, 3Λ, 4a, and 4b and rhodium diiodido compounds 6 and 7. Hydrogen
atoms and solvent molecules are omitted for clarity, and displacement ellipsoids are at the 50% probability level (shown only for the heteroatoms).
were also observed, red blocks (4a) and orange plates (4b).
SC-XRD was obtained for both of these crystals and confirmed
both to be in a monoclinic cell, and structural solutions were
performed in P21/c and P21/n, respectively. The two crystals of
complex 4 were found to be different structural isomers:
cis(Cl)-trans(N,N)-cis(N,O) (4a) and trans(Cl)-trans(N,N)-
trans(N,O) (4b) (Figure 2). The X-ray crystallographic data
and bond angles are stated in Table S1 and Table S2,
respectively.
[RhI2(L)(LH)]. SC-XRD were obtained for complexes 6 and 7
(Figure 2) by vapor diffusion of diethyl ether/DMF. Both
complexes crystallized in a monoclinic cell, with structural
solutions performed in space group Cc. Only one crystal
morphology was observed for these Rh(III) diiodido
complexes, and both were identified to be the trans(X)-
trans(N,N)-trans(N,O) isomer. The X-ray crystallographic data
and bond angles are stated in Table S3 and Table S4,
respectively.
In all cases, the ligands have different binding modes to the
metal center, whereby one ligand is neutral and bound N,N
(LH) and the other ligand is anionic and bound N,O (L). Both
the dichlorido and diiodido complexes have slightly distorted
Figure 3. Chemical structures (SC-XRD and Chemdraw) of
bond angles suggesting a pseudo octahedral geometry (Table
complexes 3Δ and 3Λ.
S2 and Table S4), with all bond lengths as expected for Rh(III)
compounds (Table 1).
FTIR Spectroscopy. Several of the Rh(III) dichlorido
complexes crystallize in different fractions, with different colors
and morphologies. The first synthetic attempt and recrystal-
lization of complex 3 yielded red needles (cis(Cl)-trans(N,N)-
cis(N,O), 3Δ, Figures 2 and 3), orange blocks 3b, and yellow
microcrystals 3c. The different fractions were well-separated
and collected for further characterization. The FTIR spectra
show the presence of the different fractions (Figure S1),
crystallizes as the Λ enantiomer, showing these structures are
labile and fluxional. Although SC-XRD was only obtained on
the orange plates, three sets of different colored crystal
morphologies were also observed for complex 3; however, on a
second attempted synthesis only two morphologies were
obtained (Figure S5). SC-XRD confirmed complex 3 (Δ and
Λ) to be the cis(Cl)-trans(N,N)-cis(N,O) isomer (Figure 2).
Within the sample vial of complex 4, two different crystal types
2081
https://dx.doi.org/10.1021/acs.inorgchem.0c03704
Inorg. Chem. 2021, 60, 2076−2086

Inorganic Chemistry
pubs.acs.org/IC
Article
Table 1. Selected Bond Lengths (Å) for Compounds 1, 3 (Δ and Λ), 4a, 4b, 6, and 7, with s.u.s Shown in Parentheses
X = Cl
X = I
Bond Lengths (Å)
1
3 (Δ)
3 (Λ)
4a
4b
6
7
Rh(1)−X(1)
Rh(1)−X(2)
Rh(1)−N(1)
Rh(1)−N(2)
Rh(1)−N(3)
Rh(1)−O(2)
2.3168(15)
2.3568(13)
2.017(4)
2.022(4)
2.030(5)
2.043(4)
2.3078(10)
2.3636(10)
2.021(3)
2.011(3)
2.027(3)
2.051(3)
2.3115(9)
2.3665(8)
2.028(3)
2.009(3)
2.034(3)
2.050(2)
2.3134(13)
2.3558(14)
2.030(4)
2.018(4)
2.031(4)
2.050(3)
2.3358(18)
2.3408(17)
2.022(6)
2.021(6)
2.072(6)
2.077(5)
2.6636(12)
2.6631(12)
2.008(10)
2.014(19)
2.035(10)
2.066(9)
2.6776(7)
2.6730(7)
2.040(6)
2.007(5)
2.089(5)
2.073(4)
highlighting a weak NH stretch at 3033 cm−1 (3Δ), 3057 cm−1
(3b), and 3065 cm−1 (3c), and the CO stretch (1613−1543
cm−1) begins to separate into asymmetric and symmetric
stretches; however, this is only observed in fractions 3b and 3c.
Powder X-ray Diffraction (PXRD). PXRD was obtained
for the bulk samples of both complexes 3 and 7 (Figure S2a-b,
respectively) and was compared to the simulated cis and trans
spectra. Complex 3 was also compared to the single crystals of
the cis(X,X)-trans(N,N)-cis(N,O) (3Δ) isomer (Figure 2-3).
We were unable to confirm the major isomer from PXRD
alone, as the PXRD pattern shows a mix of different isomers.
However, PXRD for complex 7 shows only the expected single
trans isomer which was observed in single crystal XRD and
gives further evidence that the bulk sample consists of one
isomer.
as the protons are almost equivalent. Therefore, we are unable
to confirm if the additional resonances observed are due to the
enantiomer which we have also crystallized out (3Λ) or if it is
the cis(Cl,Cl)-cis(N,N)-trans(N,O) arrangement. The 1H NMR
of complex 3 was also conducted in CDCl3 (Figure S7) so we
could observe the NH resonances, and only two were present
at 11.66 ppm (br. s, major) and 12.06 (br. s, minor). The
major NH resonance is assigned to the cis(Cl,Cl)-cis(N,N)-
cis(N,O) arrangement, while the minor NH resonance cannot
be observed in the NMR of the orange crystals, possibly due to
its poor solubility in CDCl3. These results prove how
unpredictable the isomerization is for the dichlorido complexes
and how difficult it would be to determine the active species.
This reinforces our drive to focus on the single stable trans
diiodido complexes.
The stabilities of the Rh(III) dichlorido complexes were
assessed in DMSO:PBS (phosphate buffer solution) (80:20 v/
v). In these studies we could not use >20% of PBS, as the
complexes have poor solubility at higher water content (Table
S7). Complex 3 (Figure S14) shows very few changes, with
small new resonances at 8.3 ppm and 7.0−7.3 ppm; however,
this species could not be identified and could either be another
isomer or an aqua species. Importantly, the majority of the
complex remains unaffected in these conditions, and the
complex is stable over 96 h. Due to poorer solubility in DMSO,
the stability of the Rh(III) diiodido complexes was assessed in
MeCN:PBS (80:20 v/v), and as with complex 3, complex 7
shows small new resonances appearing over time, but again the
majority of the complex remains unaffected over 96 h (Figure
S15).
NMR Spectroscopy. The 1H NMR spectra of the
complexes do not often show the NH,39 which is usually due
to the use of polar solvents which are required for solubility.
This often highlights the uncertainty of ligand binding in
solution. On the first synthetic attempt of complex 3, several
1
isomers were observed in the H NMR in d3-acetone, which
were proposed to be 3Δ, 3b, and 3c (Figure S3). The different
morphologies were separated out and each 1H NMR obtained,
showing 3c to have additional weak resonances, suggesting yet
another isomer may be present within this solution. The ratio
of the possible isomers determined from the integrals of the 1H
NMR spectra shows 1:0.2 for complex 3Δ and 1:0.2:0.1 for
complex 3c. Variable temperature NMR (213−313 K) was
also conducted on complex 3c and highlighted the appearance
of new resonances at low temperature and provides additional
confirmation for multiple isomers in solution (Figure S4). On
cooling the sample, a shift for the ortho pyridine hydrogens
(Ha and Ha′, see Figure S3) to a higher frequency was
observed, while the remaining pyridine protons shift to lower
frequencies.
A second attempt was made to synthesize and recrystallize
complex 3; however, this gave rise to a dark orange/red
product that on recrystallization from pentane/methanol vapor
diffusion gave orange plates and a yellow microcrystalline
material (Figure S5). The crude 1H NMR has four resonances
for the C−H ortho to py-N, Ha/Ha′, whereby the resonances
at 9.44 pm (d) and 8.66 ppm (d) are attributed to the yellow
microcrystalline material and the resonances at 9.87 pm (d)
and 9.44 ppm (d) are attributed to the orange plates (Figure
S6). The resonances in the yellow material are ∼1 ppm apart,
and we believe this to be from the nonsymmetrical cis(Cl,Cl)-
cis(N,N)-cis(N,O) isomer, which appears to be the major
product and has inequivalent protons. The SC-XRD of the
orange plates confirmed the cis(Cl,Cl)-trans(N,N)-cis(N,O)
arrangement; however, this is not the major product.40 It
should also only have one set of (or two very close
overlapping) resonances for this type of ligand arrangement,
Stability studies with respect to ligand exchange were
1
conducted with complexes 1, 4, 5, and 8, and assessed by H
NMR spectroscopy. A bulk mixture of each complex was
treated with one equivalent of a different meta-substituted
picolinamide ligand L′, and while the NMR for the diiodido
complexes shows only free L′ in CDCl3 and d6-DMSO, the
NMR for the dichlorido complexes shows possible dissociation
of L and a potentially new mixed ligand complex with
incorporation of L′ (Figures S9−S13). This is similar to our
previously reported work on the ligand exchange of titanium
coordination compounds and further suggests these complexes
are fluxional and possible ligand rearrangement occurs in
solution.41
To further assess this exchange, NMR reactions were
conducted with the inclusion of water, and again, due to
poor solubility of all complexes, reactions could only be
conducted in <20% of water (Table S7). Complexes 3 and 7 in
DMSO:PBS (80:20 v/v) and MeCN:PBS (80:20 v/v),
respectively (∼7.0 mM), were treated with one equivalent of
N-(3-chlorophenyl)picolinamide ligand (L′), and the exchange
was monitored over 96 h. The 1H NMR spectra of the
dichlorido complex 3 show the NH resonance for the 3′-ClH
2082
https://dx.doi.org/10.1021/acs.inorgchem.0c03704
Inorg. Chem. 2021, 60, 2076−2086

Inorganic Chemistry
pubs.acs.org/IC
Article
Table 2. IC50 Values/μM ( SD) for Compounds 3, 7, 3-Ru, 7-Ru, and CDDP against a Range of Human Cell Lines, after a 96
a
h Incubation Period
HCT116 p53+/+ HCT116 p53−/−
A549
>100
FM55
>100
MIA PaCa-2
>100
A2780
A2780cisR
9.0 0.6
MCF-7
ARPE-19
>100
3
>100
>100
4.4 0.6
36.5 0.6
(22.9*)
(11.2*)
(2.7*)
7
1.28 0.09
(26.4)
1.53 0.04
(23.9)
4.3 0.3
(7.7)
4.65 0.04
(7.0)
2.3 0.1 (14.2) 6.0 0.4 (5.5) 9.2 0.6 (3.6) 2.2 0.2
(16.3)
33
2
3-Ru
7-Ru
1.96 0.08
1.7 0.1 (0.7)
3.3 0.1
(0.4)
4.8 0.2 (0.2) 2.20 0.09
(0.5)
1.3 0.07
(0.9)
4.4 0.5 (0.3) 1.2 0.2 (1.1)
1.19 0.05
2.43 0.02
1.31 0.08
(1.8)
1.71 0.02
(1.4)
4.1 0.3
(0.6)
4.63 0.04
(0.5)
1.74 0.09
(1.4)
17 1 (0.1)
15 1 (0.2)
1.8 0.4 (1.1)
1.5 0.2 (4.0)
CDDP 1.5 0.1 (4.0) 3.54 0.07
(1.7)
3.0 0.1
(2.0)
6.1 0.3 (1.0) 3.6 0.7(1.7)
1.3 0.1 (4.5) 14 1(0.4)
6
1
a
Selectivity indices (SI) are shown in parentheses. Complexes 1, 2, 4-6, and 8 have IC50 values >100 μM and are eliminated from the table.
denotes the minimum selectivity index (SI), as at least one of the IC50 values is >100 μM.
*
ligand at 10.8 ppm, which over time exchanges to the 3′-BrH
ligand at 10.7 ppm. It is unclear whether this is a mixed ligand
complex or a complete exchange of the 3′-BrH ligands from
complex 3 (Figures S16 and S17); however, it does confirm
the complexes’ instability toward ligand exchange. When
assessing the same ligand exchange with complex 7 in
MeCN:PBS, the NH from the 3′-ClH ligand appears at 10.3
ppm and does not change over the 96 h (Figures S18 and
S19), giving clear evidence that the diiodido complexes are not
only stable with the inclusion of water over 96 h, but they
remain stable toward ligand exchange.
Figure 4. Ruthenium analogues 3-Ru and 7-Ru, which were
synthesized and tested to compare cell results with complexes 3
and 7.
Chemosensitivity Studies. 96 h Incubation. MTT assays
were conducted to determine the in vitro cell viability of
complexes 1−8 and cisplatin (CDDP). Initially, the complexes
were screened against the isogenic human colorectal
carcinomas, HCT116 p53-wildtype (HCT116 p53+/+) and
HCT116 p53-null (HCT116 p53−/−), human lung carcinoma
(A549), human melanoma (FM55) and human pancreas
carcinoma (MIA PaCa-2), and the values are shown in Table
2. After a 96 h incubation period, only the N-(3-
bromophenyl)picolinamide Rh(III) diiodido complex 7
exhibited any cytotoxicity, with values ranging from 1.28
0.09 μM (HCT116 p53+/+) to 4.65 0.04 μM (FM55), and
has similar cytotoxicity to CDDP (p > 0.05). The analogous
Rh dichlorido complex 3 is noncytotoxic against these cell
lines; therefore, cytotoxicity increases by up to 80x (HCT116
p53+/+) when converting from the dichlorido to diiodido
complex. Complexes 1, 2, 4−6, and 8 are nontoxic toward all
cell lines tested at the tested threshold (IC50 > 100 μM);
therefore, the data has been eliminated from Table 2. To the
best of our knowledge, complex 7 is the first reported Rh(III)
trans diiodido coordination compound to have significantly
increased cytotoxicity and remains stable in solution. To
further understand the extent of this reactivity and selectivity
of complexes 3 and 7, the results were compared to the
ruthenium analogues 3-Ru and 7-Ru (Figure 4).27
The results for complexes 3-Ru and 7-Ru (Table 2) show
that both of these Ru(III) complexes are cytotoxic toward all
tested cell lines, and the values are not statistically different (p
> 0.05) between each different cell line. It was previously
highlighted that such Ru complexes increase in cytotoxicity
when switching from the dichlorido to the diiodido.27 The
Ru(III) dichlorido complex (3-Ru) has high cytotoxicity
against all cell lines, whereas the rhodium dichlorido complex 3
is nontoxic in almost all cell lines. When comparing Rh(III) to
Ru(III), a 57-fold increase in cytotoxicity is observed against
HCT116 p53−/−; however, the selectivity of the complexes
decreases. Complexes 3, 7, 3-Ru, and 7-Ru were further
screened against human ovarian carcinomas, cisplatin-sensitive
(A2780) and cisplatin-resistant (A2780cisR), and human
breast adenocarcinoma (MCF-7) (Table 2 and Figure S20).
Due to their lack of cytotoxicity toward the previous cell lines,
the Rh(III) complexes 1, 2, 4−6, and 8 were eliminated from
the additional screening.
Against MCF-7, complexes 7, 3-Ru, and 7-Ru all exhibit
similar potency, and the values are similar to those observed in
the previous cell screening. Complex 3, which was previously
nontoxic (IC50> 100 μM), however, it now exhibits a moderate
IC50 value of 36.5
0.6 μM. When analyzing the results
against the human ovarian cell lines, a reverse in cytotoxicity
was observed, and the diiodido complexes 7 and 7-Ru exhibit
up to an 18-fold decrease in cytotoxicity, when comparing their
cytotoxicity against A2780 with HCT116 p53+/+. Whereas the
dichlorido complexes either remain cytotoxic (3-Ru) or
increase by up to 22-fold (3, A2780 cf. HCT116 p53+/+).
This highlights the potential of such Rh(III) dichlorido
complexes in targeting ovarian carcinomas.
Selectivity Index (SI). In order to assess the potential of
these compounds to target cancerous cells over normal cells, all
complexes were screened for 96 h against human retinal
epithelial cells (ARPE-19). The results are shown in Table 2
and as with the other screening results, complexes 1−2, 4−6,
and 8 were all nontoxic against this cell line (IC50 > 100 μM)
and so the results have been eliminated from Table 2. Complex
3 shows no cytotoxicity toward this cell line; however, the
diiodido analogue 7 is moderately potent, with an IC50 = 33
1 μM. Complex 7 remains 5.5× less cytotoxic than CDDP
(IC50 = 6 1 μM), highlighting a potentially different mode of
action. The analogous Ru(III) complexes, 3-Ru and 7-Ru,
exhibit high potency toward normal cells, with IC50 values
2.5−5× higher than CDDP.
Using the IC50 values against the normal cell line, divided by
the IC50 value for each cancerous cell line, the selectivity
2083
https://dx.doi.org/10.1021/acs.inorgchem.0c03704
Inorg. Chem. 2021, 60, 2076−2086

Inorganic Chemistry
pubs.acs.org/IC
Article
indices (SI) were calculated. SI values >1 indicate an increase
in selectivity toward cancer cells over normal cells, and these
values are given in the parentheses of Table 2 and are
graphically presented in Figure 5. Complexes 3-Ru and 7-Ru
have high potency toward all cell lines, and they exhibit low to
no selectivity, with SI values ranging between 0.1 and 1.1.
Complex 3 is only cytotoxic toward three of the cell lines and
is nontoxic toward the normal cell line; therefore, it has high
selectivity, specifically against A2780 (SI = 22.7*, see Table 2
footnote). Complex 7 has a moderate cytotoxicity toward
normal cells (IC50 = 33
2 μM) and has an increased
selectivity toward the majority of the cancer cell lines, with
high selectivity toward HCT116 p53+/+ (SI = 25.5), HCT116
p53−/− (SI = 21.4), and MCF-7 (SI = 16.3).
Figure 5. Selectivity indices (SI) for complexes 3, 7, 3-Ru, 7-Ru, and
CDDP. SI > 1 shows selectivity for the cancer cell lines, SI = 1 show
equitoxicity (dotted line), and SI < 1 shows selectivity for the normal
cell line ARPE-19.
Figure 6. (a) IC50 values (μM) complexes 7, 3-Ru, 7-Ru, and CDDP
when screened against HCT116 p53−/−, HCT116 p53+/+, and ARPE-
19, after 24 h, 72 h, and 96 h incubation periods. (b) Selectivity
factors (SF) for complexes 7, 3-Ru, 7-Ru, and CDDP when screened
against HCT116 p53−/− and HCT116 p53+/+
.
24 and 72 h incubation (+ recovery period): Over 50% of
colorectal cancers are well-known to have inactive or mutated
p53 genes.42 The p53-null cell line HCT116 p53−/− can be
considered a more representative example of advanced
colorectal cancers; therefore, identifying compounds which
are selectively active against this cell line could be a significant
step forward toward cancer targeting. In light of this, we
screened complexes 7, 3-Ru, and 7-Ru against the isogenic
colorectal cell lines HCT116 p53+/+ (p53-wildtype) and
HCT116 p53−/− (p53-null) after incubation periods of 24
and 72 h (Figure 6a and Table S5). The results show that the
ruthenium analogues, 3-Ru and 7-Ru, are cytotoxic toward
both cells after short incubation times but remain cytotoxic
toward normal cells (ARPE-19). These complexes are
equitoxic against both HCT116 cell lines, with selectivity
factors (SF) ranging from 0.3−3.2 (Figure 6b and Table S6).
Interestingly, the Rh(III) diiodido complex 7 is nontoxic
against HCT116 p53−/− at 24 and 72 h (IC50 > 100 μM) and
requires the longer incubation periods to become cytotoxic.
After 24 h, complex 7 is cytotoxic against HCT116 p53+/+ and
is >44-fold more active than CDDP, with an IC50 value of 1.7
0.1 μM (IC50 CDDP = 77 2 μM). This complex has no
selectivity toward HCT116 p53−/−, with SF values ranging
from 0.02−0.90 (cf. 0.4−0.8 CDDP). However, it is
significantly selective toward the HCT116 p53+/+, with SF
values >57 and >75, after incubation periods of 24 and 72 h,
respectively (cf. 1.3−1.4 CDDP). Importantly, after 24 h,
complex 7 shows only very moderate cytotoxicity toward
normal cells with an IC50 value of 27
1 μM, meaning it
retains selectivity (SI > 21) even after short incubation periods.
This is contrary to CDDP, which is more cytotoxic toward
normal cells (SI = 0.5). As the results show varying degrees of
cytotoxicity toward both isogenic colorectal cell lines, a
conclusion cannot be drawn on the p53-dependence; however,
we have highlighted that unlike cisplatin, complex 7 is
significantly selective in treating HCT116 p53+/+ after 24 h.
CONCLUSION
■
A library of N-(3-halidophenyl)picolinamide rhodium dihalido
complexes (1−8) is presented, with single crystal X-ray
diffraction for seven new complexes. Solid state and solution
studies confirm the dichlorido complexes (1−4) exist as
multiple isomers, while the diiodido complexes (5−8) exist as
single and stable trans isomers. We report that the Rh(III)
dichlorido complexes are fluxional in solution, with new
resonances appearing when exchange studies are conducted
with a different functionalized ligand. However, the Rh(III)
diiodido complexes remain stable in solution and show no
ligand exchange over a period of 96 h. These results
complement the solid state PXRD studies, which also confirm
the stability of the Rh(III) diiodido complexes. The library of
complexes was screened against a range of cell lines, and the N-
(3-bromophenyl)picolinamide rhodium(III) complexes (3 and
7) exhibit moderate to high in vitro cytotoxicity. The Rh(III)
trans diiodido complex 7 has the highest activity, with IC50
2084
https://dx.doi.org/10.1021/acs.inorgchem.0c03704
Inorg. Chem. 2021, 60, 2076−2086

Inorganic Chemistry
pubs.acs.org/IC
Article
values ranging from 1.28 0.09 μM (HCT116 p53+/+) to 4.65
0.04 μM (FM55), and it has similar cytotoxicity to CDDP
(p > 0.05). In contrast, the analogous Rh(III) dichlorido
complex 3 was not cytotoxic against most cell lines (IC50 > 100
μM); however, it exhibited increased cytotoxicity by up to 22-
fold against the human ovarian carcinoma cell line, A2780.
When comparing these cytotoxicity values with the Ru(III)
analogues (3-Ru and 7-Ru), complex 7 exhibited similar
cytotoxicity but has significantly higher selectivity toward
cancerous cells (SI = 3.6−26.4) when compared to its Ru(III)
analogue (SI = 0.1−1.8). Cytotoxicity screening after 24 and
72 h shows complexes 3-Ru and 7-Ru are cytotoxic toward
cancerous and normal cell lines, whereas complex 7 is nontoxic
against the colon cancer cell line HCT116 p53−/− at both 24
and 72 h and requires longer incubation periods to become
cytotoxic. Complex 7 remains cytotoxic against HCT116
p53+/+ and is 44-fold more active than cisplatin and retains its
high selectivity (SI > 21). As the cytotoxicity values vary
against these isogenic cell lines, a conclusion cannot be drawn
on the p53-dependence. Overall, these results highlight that
Rh(III) trans diiodido complexes have the potential to be
cancer selective and cancer specific, as they outperform
cisplatin; however, ligand modifications are now necessary to
increase the effectiveness of these and other trans drugs. These
complexes exist as single stable isomers, which is crucial for
drug design, as the active species can be more easily
determined. The isomers of these complexes possibly have
different modes of action, and our future work aims to
underpin their cellular uptake and mechanistic pathways.
https://pubs.acs.org/10.1021/acs.inorgchem.0c03704
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank Tanya Marinko-Covell (University of
Leeds) and Stephen Boyer (London Metropolitan University)
for elemental analysis. We would also like to thank Simon
Allison (University of Huddersfield) for providing the ARPE-
19 cell line and the Institute of Cancer Therapeutics
(University of Bradford) for providing the other cell lines
and access to the Cat. II laboratories.
REFERENCES
■
(1) Johnstone, T. C.; Suntharalingam, K.; Lippard, S. J. The Next
Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle
Delivery, and Pt(IV) Prodrugs. Chem. Rev. 2016, 116 (5), 3436−
3486.
(2) Coluccia, M.; Natile, G. Trans-Platinum Complexes in Cancer
Therapy. Anti-Cancer Agents Med. Chem. 2007, 7, 111−123.
(3) Galea, A. M.; Murray, V. The Anti-Tumour Agent, Cisplatin, and
Its Clinically Ineffective Isomer, Transplatin, Produce Unique Gene
Expression Profiles in Human Cells. Cancer Inf. 2008, 6, 315−355.
(4) Fichtinger-Schepman, A. M. J.; Van der Veer, J. L.; Den Hartog,
J. H. J.; Lohman, P. H. M.; Reedijk, J. Adducts of the Antitumor Drug
Cis-Diamminedichloroplatinum(II) with DNA: Formation, Identi-
fication, and Quantitation. Biochemistry 1985, 24 (3), 707−713.
(5) Fichtner, I.; Claffey, J.; Gleeson, B.; Hogan, M.; Wallis, D.;
Weber, H.; Tacke, M. The Interaction of Titanocene Y with Double-
Stranded DNA: A Computational Study. Lett. Drug Des. Discovery
2008, 5 (5), 332−335.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.inorgchem.0c03704.
■
sı
Experimental details, protocols, and single X-ray
diffraction data (PDF)
(6) Eastman, A. Characterization of the Adducts Produced in DNA
by Cis-Diamminedichloroplatinum(II) and Cis-Dichloro-
(Ethylenediamine)Platinum(II). Biochemistry 1983, 22 (16), 3927−
3933.
Accession Codes
CCDC 1978078−1978083 and 2042715 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(7) Brabec, V.; Kasparkova, J. Modifications of DNA by Platinum
Complexes: Relation to Resistance of Tumors to Platinum Antitumor
Drugs. Drug Resist. Updates 2005, 8 (3), 131−146.
́
́
(8) Quiroga, A. G.; Cama, M.; Pajuelo-Lozano, N.; Alvarez-Valdes,
A.; Perez, I. S. New Findings in the Signaling Pathways of Cis and
Trans Platinum Iodido Complexes’ Interaction with DNA of Cancer
Cells. ACS Omega 2019, 4 (26), 21855−21861.
AUTHOR INFORMATION
Corresponding Author
(9) Esposti, M. D. The Roles of Bid. Apoptosis 2002, 7 (5), 433−
440.
■
́
(10) Markowska, A.; Kasprzak, B.; Jaszczynska-Nowinka, K.; Lubin,
Rianne M. Lord − School of Chemistry, University of East
Anglia, Norwich NR4 7JT, U.K.; School of Chemistry and
Biosciences, University of Bradford, Bradford BD7 1DP,
U.K.; orcid.org/0000-0001-9981-129X; Email: r.lord@
uea.ac.uk
J.; Markowska, J. Noble Metals in Oncology. Contemp Oncol (Pozn)
2015, 19 (4), 271−275.
(11) Gasser, G.; Ott, I.; Metzler-Nolte, N. Organometallic
Anticancer Compounds. J. Med. Chem. 2011, 54 (1), 3−25.
(12) Medici, S.; Peana, M.; Nurchi, V. M.; Lachowicz, J. I.; Crisponi,
G.; Zoroddu, M. A. Noble Metals in Medicine: Latest Advances.
Coord. Chem. Rev. 2015, 284, 329−350.
Authors
Markus Zegke − School of Chemistry and Biosciences,
University of Bradford, Bradford BD7 1DP, U.K.
Aida M. Basri − School of Chemistry, University of Leeds,
Leeds LS2 9JT, U.K.
Christopher M. Pask − School of Chemistry, University of
Leeds, Leeds LS2 9JT, U.K.
(13) Ndagi, U.; Mhlongo, N.; Soliman, M. E. Metal Complexes in
Cancer Therapy − an Update from Drug Design Perspective. Drug
Des., Dev. Ther. 2017, 11, 599−616.
(14) Bear, J. L.; Gray, H. B., Jr.; Rainen, L.; Chang, I. M.; Howard,
R.; Serio, G.; Kimball, A. P. Interaction of Rhodium (II) Carboxylates
with Molecules of Biologic Importance. Cancer Chemotherapy Reports
1975, 59 (3), 611−620.
Patrick C. McGowan − School of Chemistry, University of
Leeds, Leeds LS2 9JT, U.K.
(15) Mestroni, G.; Alessio, E.; Sessanta o Santi, A.; Geremia, S.;
Bergamo, A.; Sava, G.; Boccarelli, A.; Schettino, A.; Coluccia, M.
Rhodium(III) Analogues of Antitumour-Active Ruthenium(III)
Complete contact information is available at:
2085
https://dx.doi.org/10.1021/acs.inorgchem.0c03704
Inorg. Chem. 2021, 60, 2076−2086

Inorganic Chemistry
pubs.acs.org/IC
Article
Compounds: The Crystal Structure of [ImH][Trans-RhCl4(Im)2]
(34) Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.;
McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de
Streek, J.; Wood, P. A. Mercury CSD 2.0 - New Features for the
Visualization and Investigation of Crystal Structures. J. Appl.
Crystallogr. 2008, 41 (2), 466−470.
(Im = imidazole). Inorg. Chim. Acta 1998, 273 (1−2), 62−71.
̈
(16) Harlos, M.; Ott, I.; Gust, R.; Alborzinia, H.; Wolfl, S.; Kromm,
A.; Sheldrick, W. S. Synthesis, Biological Activity, and Structure-
Activity Relationships for Potent Cytotoxic Rhodium(III) Polypyridyl
Complexes. J. Med. Chem. 2008, 51 (13), 3924−3933.
(35) Spek, A. Single-Crystal Structure Validation with the Program
PLATON. J. Appl. Crystallogr. 2003, 36 (1), 7−13.
(17) Chen, J. C.; Li, J.; Qian, L.; Zheng, K. C. Electronic Structures
and SARs of the Isomeric Complexes α-, β-, γ- [Ru(Mazpy)2Cl2] with
Different Antitumor Activities. J. Mol. Struct.: THEOCHEM 2005, 728
(1), 93−101.
(36) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A.
K.; Puschmann, H. It OLEX2: A Complete Structure Solution,
Refinement and Analysis Program. J. Appl. Crystallogr. 2009, 42 (2),
339−341.
(37) Das, A.; Peng, S.-M.; Lee, G.-H.; Bhattacharya, S. Synthesis,
Structure and Electrochemical Properties of a Group of Ruthenium-
(III) Complexes of N-(Aryl)Picolinamide. New J. Chem. 2004, 28 (6),
712−717.
(38) Bhattacharya, I.; Dasgupta, M.; Drew, M. G. B.; Bhattacharya,
S. N-(Aryl)Picolinamide Complexes of Rhodium: Synthesis, Structure
and, Spectral and Electrochemical Properties. J. Indian Chem. Soc.
2012, 89 (2), 205−216.
(39) Bhattacharya, P. K.; Dutta, S. Synthesis and Substitution
Reactions on Dicholoro[2-(N-(2-Hydroxyphenyl)-Carbamoyl)-
Pyridine] Bis(Dimethyl Sulfoxide)-Ruthenium(II). Indian J. Chem.
2003, 42A, 268−274.
(40) Dubler, E.; Buschmann, R.; Schmalle, H. W. Isomer Abundance
of Bis(β-Diketonato) Complexes of Titanium(IV). Crystal Structures
of the Antitumor Compound Budotitane [TiIV(Bzac)2(OEt)2] and of
Its Dichloro-Derivative [TiIV(Bzac)2Cl2] (Bzac = 1-Phenylbutane-1,3-
Dionate). J. Inorg. Biochem. 2003, 95 (2−3), 97−104.
(41) Lord, R. M.; Mannion, J. J.; Hebden, A. J.; Nako, A. E.;
Crossley, B. D.; McMullon, M. W.; Janeway, F. D.; Phillips, R. M.;
McGowan, P. C. Mechanistic and Cytotoxicity Studies of Group IV B-
Diketonate Complexes. ChemMedChem 2014, 9 (6), 1136−1139.
(42) Kaeser, M. D.; Pebernard, S.; Iggo, R. D. Regulation of P53
Stability and Function in HCT116 Colon Cancer Cells. J. Biol. Chem.
2004, 279 (9), 7598−7605.
(18) Hotze, A. C. G.; Caspers, S. E.; de Vos, D.; Kooijman, H.; Spek,
A. L.; Flamigni, A.; Bacac, M.; Sava, G.; Haasnoot, J. G.; Reedijk, J.
Structure-Dependent in Vitro Cytotoxicity of the Isomeric Complexes
[Ru(L)2Cl2] (L= o-Tolylazopyridine and 4-Methyl-2-Phenylazopyr-
idine) in Comparison to [Ru(Azpy)2Cl2]. J. Biol. Inorg. Chem. 2004, 9
(3), 354−364.
(19) Basava Punna Rao A, B.; Uma, A.; Chiranjeevi, T.; Bethu, M.
S.; Venkateswara Rao, J.; Deb, D. K.; Sarkar, B.; Kaminsky, W.;
Kollipara, M. R. The in Vitro Antitumor Activity of Oligonuclear
Polypyridyl Rhodium and Iridium Complexes against Cancer Cells
and Human Pathogens. J. Organomet. Chem. 2016, 824, 131−139.
(20) Knoll, J. D.; Turro, C. Control and Utilization of Ruthenium
and Rhodium Metal Complex Excited States for Photoactivated
Cancer Therapy. Coord. Chem. Rev. 2015, 282−283, 110−126.
(21) Junicke, H.; Hart, J. R.; Kisko, J.; Glebov, O.; Kirsch, I. R.;
Barton, J. K. A Rhodium(III) Complex for High-Affinity DNA Base-
Pair Mismatch Recognition. Proc. Natl. Acad. Sci. U. S. A. 2003, 100
(7), 3737−3742.
(22) Boyle, K. M.; Barton, J. K. Targeting DNA Mismatches with
Rhodium Metalloinsertors. Inorg. Chim. Acta 2016, 452, 3−11.
(23) Boyle, K. M.; Barton, J. K. A Family of Rhodium Complexes
with Selective Toxicity toward Mismatch Repair-Deficient Cancers. J.
Am. Chem. Soc. 2018, 140 (16), 5612−5624.
(24) Wachter, E.; Zamora, A.; Heidary, D. K.; Ruiz, J.; Glazer, E. C.
Geometry Matters: Inverse Cytotoxic Relationship for Cis/Trans-
Ru(II) Polypyridyl Complexes from Cis/Trans-[PtCl2(NH3)2]. Chem.
Commun. (Cambridge, U. K.) 2016, 52 (66), 10121−10124.
(25) Khan, T.-M.; Gul, N. S.; Lu, X.; Kumar, R.; Choudhary, M. I.;
Liang, H.; Chen, Z.-F. Rhodium(III) Complexes with Isoquinoline
Derivatives as Potential Anticancer Agents: In Vitro and in Vivo
Activity Studies. Dalton Trans. 2019, 48 (30), 11469−11479.
̌
́
́
́
(26) Petrovic, A.; Milutinovic, M. M.; Petri, E. T.; Zivanovic, M.;
́
́
Milivojevic, N.; Puchta, R.; Scheurer, A.; Korzekwa, J.; Klisuric, O. R.;
Bogojeski, J. Synthesis of Camphor-Derived Bis(Pyrazolylpyridine)
Rhodium(III) Complexes: Structure−Reactivity Relationships and
Biological Activity. Inorg. Chem. 2019, 58 (1), 307−319.
́
(27) Basri, A. M.; Lord, R. M.; Allison, S. J.; Rodríguez-Barzano, A.;
Lucas, S. J.; Janeway, F. D.; Shepherd, H. J.; Pask, C. M.; Phillips, R.
M.; McGowan, P. C. Bis-Picolinamide Ruthenium(III) Dihalide
Complexes: Dichloride-to-Diiodide Exchange Generates Single Trans
Isomers with High Potency and Cancer Cell Selectivity. Chem. - Eur. J.
2017, 23 (26), 6341−6356.
(28) Lucas, S. J.; Lord, R. M.; Wilson, R. L.; Phillips, R. M.;
Sridharan, V.; McGowan, P. C. Synthesis of Iridium and Ruthenium
Complexes with (N,N), (N,O) and (O,O) Coordinating Bidentate
Ligands as Potential Anti-Cancer Agents. Dalton Trans. 2012, 41
(45), 13800−13802.
(29) Almodares, Z.; Lucas, S. J.; Crossley, B. D.; Basri, A. M.; Pask,
C. M.; Hebden, A. J.; Phillips, R. M.; McGowan, P. C. Rhodium,
Iridium, and Ruthenium Half-Sandwich Picolinamide Complexes as
Anticancer Agents. Inorg. Chem. 2014, 53, 727−736.
(30) Cryosystems, O. New Cryostream Cooler. J. Appl. Crystallogr.
2000, 33 (1), 190.
(31) Bruker-AXS, APEX2; Bruker AXS Inc.: Madison, Wisconsin,
USA, 2014.
(32) Agilent. CrysAlis Pro; Agilent Technologies Ltd: Yarnton,
Oxfordshire, England, 2014.
(33) Sheldrick, G. M. Crystal Structure Refinement with SHELXL.
Acta Crystallogr. C Struct Chem. 2015, 71 (Pt 1), 3−8.
2086
https://dx.doi.org/10.1021/acs.inorgchem.0c03704
Inorg. Chem. 2021, 60, 2076−2086