Investigation of the anticancer activity of coordination-driven self-assembledtwo-dimensional ruthenium metalla-rectangle

Article abstract of DOI:10.3390/molecules24122284

Coordination-driven self-assembly is an effective synthetic tool for the construction of spatially and electronically tunable supramolecular coordination complexes (SCCs), which are useful in various applications. Herein, we report the synthesis of a two-dimensional discrete metalla-rectangle [(η⁶-p-cymene)₄Ru₄(C₆H₂O₄)₂(2)₂](CF₃SO₃)₄ (3) by the reaction of a dinuclear half-sandwich ruthenium (II) complex [Ru₂(η⁶-p-cymene)₂(C₆H₂O₄)Cl₂] (1) and bis-pyridyl amide linker (2) in the presence of AgO₃SCF₃. This cationic ruthenium metalla-rectangle (3) has been isolated as its triflate salt and characterized by analytical techniques including elemental analysis, Fourier-transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance spectroscopy (¹H-NMR), carbon nuclear magnetic resonance spectroscopy (¹³C-NMR), ¹H-¹H correlation spectroscopy (COSY), ¹H-¹H nuclear Overhauser effect spectroscopy (NOESY), diffusion ordered spectroscopy (DOSY), and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). Significantly, the 2D cationic ruthenium metalla-rectangle showed better anticancer activity towards three different cell lines (A549, Caki-1 and Lovo) as compared with the parent ruthenium complex (1) and the commercially used drug, cisplatin.

Full text of DOI:10.3390/molecules24122284

molecules
Article
Investigation of the Anticancer Activity of
Coordination-Driven
Self-AssembledTwo-Dimensional
Ruthenium Metalla-Rectangle
Harsh Vardhan 1, Ayman Nafady 2,3,*, Abdullah M. Al-Enizi 2, Khalid Khandker 1,
Hussein M. El-Sagher 3, Gaurav Verma 1, Mildred Acevedo-Duncan 1, Tawfiq M. Alotaibi 4
and Shengqian Ma 1,
*
1
Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, USA;
hvardhan@mail.usf.edu (H.V.); kmkhalid@mail.usf.edu (K.K.); gauravv@mail.usf.edu (G.V.);
macevedo@usf.ed (M.A.-D.)
Department of Chemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia;
amenizi@ksu.edu.sa
Chemistry Department, Faculty of Science, Sohag University, Sohag 82524, Egypt; omran1st@yahoo.com
King Abdullah City for Atomic and Renewable Energy, Riyadh 11451, Saudi Arabia; t.otaibi@energy.gov.sa
Correspondence: anafady@ksu.edu.sa (A.N.); sqma@usf.edu (S.M.); Tel.: +966569407110 (A.N.);
+1813-974-5217 (S.M.)
2
3
4
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 11 May 2019; Accepted: 18 June 2019; Published: 19 June 2019
Abstract: Coordination-driven self-assembly is an effective synthetic tool for the construction of
spatially and electronically tunable supramolecular coordination complexes (SCCs), which are useful
in various applications. Herein, we report the synthesis of a two-dimensional discrete metalla-rectangle
[(
ruthenium (II) complex [Ru2(
the presence of AgO3SCF3. This cationic ruthenium metalla-rectangle (
η
6-p-cymene)4Ru4(C6H2O4)2(
2
)2](CF3SO3)4
(
3
) by the reaction of a dinuclear half-sandwich
) and bis-pyridyl amide linker ( ) in
) has been isolated as its
η
6-p-cymene)2(C6H2O4)Cl2] (
1
2
3
triflate salt and characterized by analytical techniques including elemental analysis, Fourier-transform
infrared spectroscopy (FT-IR), proton nuclear magnetic resonance spectroscopy (1H-NMR), carbon
nuclear magnetic resonance spectroscopy (13C-NMR), 1H-1H correlation spectroscopy (COSY), 1H-1H
nuclear Overhauser effect spectroscopy (NOESY), diffusion ordered spectroscopy (DOSY), and
high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). Significantly, the 2D cationic
ruthenium metalla-rectangle showed better anticancer activity towards three different cell lines (A549,
Caki-1 and Lovo) as compared with the parent ruthenium complex (
drug, cisplatin.
1) and the commercially used
Keywords: self-assembly; ruthenium complex; amide linker; anticancer activity; cisplatin
1. Introduction
Self-assembly is a vital synthetic tool for the construction of discrete two-dimensional and
three-dimensional architectures. The design and study of discrete supramolecular coordination
structures is an interesting field of research because of the ease in synthesis of these thermodynamically
favored complex structures [
self-assembled discrete architecture revolves around practical applications such as catalysis [16
biomedicine [23 29], and host–guest systems [30 32]. Due to the potent physiochemical properties,
half-sandwich ruthenium, iridium, and rhodium molecular clips are predominantly employed by
1–
15]. Over the past few decades, the impulse behind the synthesis of
–22],
–
–
Molecules 2019, 24, 2284; doi:10.3390/molecules24122284
www.mdpi.com/journal/molecules

Molecules 2019, 24, 2284
2 of 12
various research groups in the synthesis of discrete architectures for a plethora of applications [33–43].
Moreover, the dynamic imine chemistry is also widely utilized for the preparation of platonic,
Archimedean, stellated, and faceted solids [44]. In particular, sensing of mono-carboxylate or
multi-carboxylate anions is of significant importance owing to their crucial role in chemical, biological,
and environmental systems [45
detection of various diseases and are also essential metabolites in Krebs cycle [49
–
48]. Oxalate, citrate, and tartrate, for instance, are pertinent in the
51]. Furthermore,
–
organic linkers with different bent angle having hydrogen bonding synthons (-C=O and -N-H) are
largely used to synthesize artificial anion receptors. In this context, Stang and Chi research groups
extensively reported a range of discrete 2D and 3D ruthenium structures constructed from the principle
of directional bonding used as promising anticancer agents; many of them have been employed in
in vivo and in vitro studies [52–60].
Considering the significance and usefulness of the coordination-driven self-assembly approach,
herein, a self-assembled arene-Ru derivative has been prepared and screened for its antitumor activity.
This may raise the chance of a potential substitute to cisplatin, which has various drawbacks such as
the lack of selectivity, high nephrotoxicity, neurotoxicity, and ototoxicity together with the inherent
or acquired resistance in various cancer cell lines [61
characterization of a self-assembled 2D metalla-rectangle [(
) prepared by the coordination–driven self-assembly of dinuclear half-sandwich ruthenium (II)
complexes [Ru2( ) and urea functionalized bis-pyridyl amide linker ( ) in
6-p-cymene)2(C6H2O4)Cl2] (
–
63]. In this paper, we report the synthesis, and
η
6-p-cymene)4Ru4(C6H2O4)2(
2
)2](CF3SO3)4
(3
η
1
2
the presence of AgO3SCF3 (Scheme 1). The anticancer activity of this compound toward three different
cell lines (Lovo, Caki-1, A549) was also tested.
Scheme 1. Synthesis of 2D arene ruthenium metalla-rectangle.
2. Results
Half-sandwich ruthenium complex 1 (Figures S1 and S2) is known for the formation of various
discrete architectures based on the symmetry of organic linkers. The reflux reaction of 4-aminopyridine
with 1,10-carbonyldiimidazole in dry tetrahydrofuran (THF) resulted in the formation of dipyridyl
organic linker (2) as evidenced by Fourier-transform infrared spectroscopy (FT-IR), proton and carbon
nuclear magnetic resonance spectroscopy (1H-NMR, 13C-NMR) (Figures S3 and S4). FT-IR spectrum of
1
2
showed NH and CO vibrations stretching peaks at 2917 cm−1 and 1737 cm−1 respectively. H-NMR
spectrum of symmetrical organic linker exhibited one sharp singlet at 9.25 ppm (NH) along with two

Molecules 2019, 24, 2284
3 of 12
aromatic protons at 8.35 ppm (CHα), 7.42 (CHβ) ppm and a strong peak at 151.99 ppm in 13C-NMR
further approves the presence of amide functionalities. Self-assembly of and at a 1:1 ratio using
directional bonding approach led to the two-dimensional ruthenium metalla-rectangle ( ) as its triflate
1
2
3
salt (Figure 1). Filtration and precipitation via the addition of diethyl ether yielded an analytically
pure solid. Unfortunately, all attempts to grow single crystals for X-ray structural analysis failed.
Furthermore, the planarity of urea functionalized bis-pyridyl amide linker and the nature of ruthenium
complex
2 further approves the proposed structure of self-assembled metalla-rectangle 3 [64–66]. It is
worth mentioning that the variation in symmetry elements of organic linkers and ligand to metal
complex ratio afford different discrete architectures [67], for instance, self-assembly of pyridine based
trigonal planar linker and half-sandwich ruthenium complex in 2:3 ratio led to ruthenium based
metalla-prisms [68,69].
Figure 1. Proposed structure of 2D ruthenium metalla-rectangle (3).
The synthesis of discrete arene-ruthenium architectures follows a well-established two-step strategy
developed by Süss-Fink [66]. The infrared spectrum of 3 predominantly showed a strong absorption
for C-F, C=O, and weak stretching C-H vibrations at 1254 cm−1, 1733 cm−1, and 3076 cm−1, indicating
the presence of trifluoromethanesulfonate anions, multiple carbonyl groups, and p-cymene moieties,
respectively (Figure S5). Similar arene ruthenium based discrete metalla-rectangles, metalla-bowls
and metalla-prisms exhibited stretching vibrations in a comparable range for C-F, C=O and C-H
functionalities [70
successful synthesis of the ruthenium metalla-rectangle. As can be seen in Figure S7, the 13C-NMR of
exhibited a peak around 184.45 ppm, validating the presence of amide functionality in the discrete
structure. Moreover, the 1H-NMR of
showed proton signal of both ligands and ruthenium complex
,
71]. 1H-NMR and 13C-NMR spectra (Figures S6 and S7) further confirms the
3
3
implying the symmetric coordination driven self-assembly of both precursor units with the NH signal
appears as a singlet at 9.11 ppm, while CHα and CHβ pyridine protons appear as doublets at 8.00
and 7.53 ppm, respectively. The p-cymene groups directly attached to
5.70 ppm along with multiplet, singlet, and doublet in the range 2.90–1.30 ppm, which is somewhat
similar to free ruthenium complex (
). In addition to this, 1H-1H correlation spectroscopy (COSY),
1H-1H nuclear overhauser effect spectroscopy (NOESY) were also performed to further confirm the
3 exhibited doublets at 5.92 and
1
successful synthesis of 2D ruthenium metalla-rectangle (
3
) as shown in Figures S8 and S9. Both 1H-1H
1
COSY and H-1H NOESY spectrum exhibited the resonance cross peaks to NH, pyridine protons,
p-cymene moieties in both NMR at specific shift not only corresponds to the successful preparation of
only one symmetrical structure but, also discard any possibility of unwanted self-assembled units such
as oligomers. The diffusion-ordered NMR (DOSY) spectrum of 3 was also recorded. This technique
provides an estimation of the diffusion coefficient of a compound in a solution, which is directly related
to the size and shape of the compound [72]. The DOSY experiment confirmed the presence of only one

Molecules 2019, 24, 2284
4 of 12
species in solution, with an approximate coefficient and hydrodynamic radius of 4.9 × 10−10 m2s−1
and 0.5 nm respectively (CD3NO2, 25 ◦C) (Figure S10). The presence of single diffusion line suggests
the formation of one discrete structure exclude the formation of any other side products such as
polymers. The peaks are clearly allocated in Figure S10, in general, bigger the assembly, smaller
the diffusion coefficient. Similar observations have been observed for analogous arene ruthenium
architectures [40,73,74].
The successful formation of tetranuclear
ionization mass spectra (HR-ESI-MS), as shown in Figure S11. Dicationic, tricationic, and tetracationic
species corresponding to intact with two, one, and no remaining trifluoromethane sulfonate anions
were detected. The HR-ESI-MS spectrum of displayed peak at m/z 972.1283, 598.3608, and 411.4928,
3 was further supported by high resolution electrospray
3
3
corresponding to [M-2OTf]2+, [M-3OTf]3+, and [M-4OTf]4, respectively. These peaks can be clearly
attributed to the 2D metalla-rectangle. The peaks were isotopically resolved and were in good
agreement with their theoretical distribution, as shown in Figure 2. More importantly, similar
pattern and nature of parent/fragmented ions was also reported by Therrein, Nitschke, Mukherjee,
Cook, Stang and Chi research groups for range of discrete ruthenium metalla-assemblies including
metalla-rectangles [36
ruthenium triflate complex (complex
agreement due to presence of triflate counterions as expected (Table S1). In addition, the conductivity
study showed a linear variation with increase in concentration of metalla-rectangle and a drastic
increase in conductivity of ruthenium triflate complex and metalla-rectangle (168.9 S) as compared
to complex (3.41 S) was observed validate the presence of triflate counterions in specific proportion
,43
,70
,71
,
75,76]. We further conducted elemental analysis comparison between
1
analogous) and complex which in turn, showed good
3
3
3
µ
1
µ
(Figure S12) [77]. It is worth to note that these analytical results strongly favor the successful synthesis
of proposed 2D discrete metalla-rectangle. Moreover, similar ruthenium-based architectures using
amide based organic linker and ruthenium complex were reported with single crystal structure further
approved our proposed structure [37,78,79].
Figure 2. Excerpts of the high-resolution electrospray ionization mass spectrometry (HR-ESI-MS)
of the tetracationic (left), tricationic (center), and dicationic (right) species of
Bottom: theoretical.
3. Top: experimental,

Molecules 2019, 24, 2284
5 of 12
Figure 3 showed the electronic absorption spectra of
The absorption spectrum of
λabs = 310 and 501 nm) was similar to that of
coordination with the pyridine moieties of . These absorption bands are likely to be an amalgamation
1
and
3
in methanol (1
×
10−6 M).
3
exhibited intense band at 287 and 500 nm. The absorption spectrum of
; however, hypsochromic shift was observed after
1
(
3
2
of the intramolecular π → π* transitions and metal-to-ligand charge transfer (MLCT) transitions.
The complex containing hydrogen bonding synthons are able to interact with a range of anions via the
non-covalent interactions. A similar trend has been observed for a range of discrete ruthenium-based
architectures [37].
Figure 3. UV-Vis spectra of ruthenium complex (1) and 2D metalla-rectangle (3) tetracationic
in methanol.
Importantly, the fact that discrete metalla-rectangle
four potential bond donors that can interact, in a specific mode, with multi-carboxylate anions. The
behavior of toward biologically important multi-carboxylate anions such as sodium oxalate is shown
in Figure S13. UV-Vis absorption spectra of changes significantly upon the addition of increasing
3 contains two bis-amide moieties offers
3
3
concentrations of sodium oxalate owing to the cooperative assistance provided by the hydrogen
bonding synthons. As can be seen in Figure S13, metalla-rectangle 3 exhibited two strong absorption
bands close to 287 and 502 nm, in which band at 287 nm underwent a bathochromic shift with
decreasing intensity, along with the disappearance of a weak intensity shoulder at 404 nm, upon the
addition of varying concentrations of sodium oxalate. Moreover, a 1:1 stoichiometry of anion binding
to 3 was evident from Job’s plot (Figure S14). A similar observation was reported by Vardhan et. al,
who showed the formation of discrete 2D and 3D ruthenium based metalla-rectangle, metalla-bowl,
and metalla-prism upon 1:1 binding with multi-carboxylate anions [80,81].
Metal-based drugs are widely used in clinical applications. Due to the existing anticancer activity of
O,O-bridged or N,N-bridged ruthenium supramolecular coordination complexes, the antiproliferative
activity of coordination driven self-assembled 2D metalla-rectangle
cancer cell lines such as A549 (lung cancer), Caki-1 (kidney cancer), and Lovo (colorectal cancer). All
the three cancer cell lines were exposed for a particular time to increasing concentrations of , and their
activities were determined using WST-1 cell proliferative reagent. The activity of is summarized
in Table 1. The IC50 values range from 3 to 4 M for Lovo, Caki-1, A549 cell lines. Fascinatingly,
was observed to inhibit the proliferation of all the three cell lines, even at a very low concentration
(Figure 4). This finding clearly established that metalla-rectangle was profoundly more effective than
cisplatin and ruthenium complex ( ) in inhibiting the growth of different cancer cell lines and could be a
3 was explored against different
3
3
µ
3
3
1
potent candidate as a chemotherapeutic drug against cisplatin-resistant cancer cell lines [27
Notably, the increase in drug concentration led to complete cell kills (Caki-1, Lovo).
,59,66,82,83].

Molecules 2019, 24, 2284
6 of 12
Figure 4. Viability of Caki-1, A549, and Lovo cell lines upon treatment with metalla-bowl (3).
Cell apoptosis is an important phenomenon responsible for destroying undesirable cells during
the development and homeostasis of cellular organisms [84]. We minutely studied three metastatic
cancer cell proliferations and compared them with normal Human Embryonic Kidney cells (HEK 293)
as shown in Figure S15. It was observed that cell proliferation for A549, LoVo, and Caki-1 cells reduced
to 58%, 66%, and 63%, respectively, at 5.0 µM 3. However, at the same concentration of 3, there was
practically no reduction for HEK 293, indicating that this potential anticancer drug has almost no
toxicity for the normal cells at this particular concentration. Experimental details are described in
Materials and methods section. The cancer cells growing rapidly unwind DNA for replication and
thus, leave the DNA strands available for drug binding. The drug-DNA complex inhibits the DNA
replication and DNA repair, leading to cancer cell destruction and apoptosis. Normal cells have slower
growth rate and are less affected by the drug. Therefore, the drug acts only on the rapidly proliferating
cells, i.e., cancer cells and specifically inhibits the growth of cancer cells, leaving the normal cells
unaffected at a certain concentration. The study of DNA ladder assay is very useful because of its easy
availability for the quick screening of apoptotic changes in the cell population. The presence of similar
self-assembled structures such as
drug-DNA complex to inhibit DNA replication and repair [42
incubation with 5.0 µM can severely elevate the apoptotic population of cancer cells.
3
shown DNA ladder assay studies further approve the existence of
,
85 86]. Furthermore, it is expected that
,
Table 1. Cytotoxicity comparison of the metalla-rectangle
different cancer lines.
3 with cisplatin and ruthenium complex 1 in
IC50, µMA
Cell Lines
Cisplatin
Ruthenium Complex (1)
LOVO
CAKI-1
A549
3.2 ± 1.13
3.3 ± 1.21
4.0 ± 1.28
7.1 ± 0.67
>100
>100
>100
>100
a
Drug concentration necessary for 50% inhibition of cell viability.
3. Materials and Methods
All chemicals, solvents, deuterated solvents used in this work were purchased from commercial
sources and used without purification. Starting materials, arene-ruthenium chloride ( ) and bent
organic linker ( ), were prepared according to the methods reported in literature [39 55]. 4-amino
1
2
,
pyridine (98%; Oakwood Chemicals, West Columbia, SC, USA), 1,1-carbonyldiimidazole (97%; Sigma
Aldrich, St. Louis, MI, USA), sodium oxalate (99.9%), dichloro(p-cymene)ruthenium(II)dimer (98%; Alfa

Molecules 2019, 24, 2284
7 of 12
1
Aesar, Heysham, Lancashire, UK), 2,5-dihydroxy-1,4-benzoquinone (98%; Sigma Aldrich). H-NMR,
13C-NMR, 1H-1H COSY, and 1H-1H NOESY spectra were recorded using an Innova 400 MHz NMR
1
spectrometer (Varian Inc., Palo Alto, CA, USA). H-NMR chemical shifts are reported relative to
residual solvent signals. HR mass spectra were recorded in the positive mode on a Waters Synapt G2
tandem mass spectrometer. Elemental analyses were performed using an Elemental GmbH Vario EL
cube (Elementar, Langenselbold, Germany). Absorption spectra were recorded using a JASCO V-670
spectrometer (Jasco Corporation, Hachioji, Tokyo, Japan). Conductivity measurement was performed
using Oakton Con 6 Acorn series conductivity meter (Eutech Instruments, Melrose, MA, USA).
Human cancer cell lines, Lovo, Caki-1, and A549 were purchased from ATCC: The Global
Bioresource Center (Manassa, VA, USA). Cell proliferation reagent, WST-1, was used. Cells (3500
cells) were plated in triplicates on a 96-well microplate in McCoy’s 5A (Logan, UT, USA) and F12K
medium (Manassa, VA, USA). The cells were adhered after 24 h and were treated with different doses.
The treatment was continued for 3 consecutive days, and after treatment on the 4th day, 20
reagent was added to the plates with 180 L of media and mixed well. Three trials were performed for
each cell lines, and IC50 values were calculated. The prepared Ru based metalla-bowl ( ) was tested
µL WST-1
µ
3
for its anti-proliferative effect on three different metastatic cancer cell lines, namely, colorectal cancer
(LoVo), kidney cancer (Caki-1) and lung cancer (A549). Effect on normal HEK 293 cells was also tested.
Using the WST-1 assay, the effect of different drug concentrations on the cell proliferation was found
for each cell line. In the 96-well microplate, 3500 cells were plated in each well, and 200 µL cell culture
media was added. After 24 h, when the cells were adhered to the bottom of the wells, the media
was replaced with fresh media. The cells were then treated with different doses (0.10, 0.25, 0.50, 1.0,
2.5, 5.0, 7.50, and 10.0
of DMSO. After 24 h of treatment, the media was again removed and replaced with 180
media. Additionally, 20
µ
M) of the drug. The control for each cell line was treated with equal volume
L of fresh
L WST-1 reagents were added to the wells and mixed. The microplates were
µ
µ
then incubated in an incubator (37 ◦C, 5% CO2) and read at time t = 0 and t = 2 h. Three trials were
performed for each cell line. Drug solutions were prepared using cell culture grade water from a stock
10 mM solution of the Ru-complex in DMSO.
3.1. Preparation of Ruthenium Complex (1)
A
mixture
of
[Ru2(
η
6-p-cymene)2(
µ-Cl)Cl]2
(184
mg,
0.3
mmol)
and
2,5-dihydroxy-1,4-benzoquinone (42 mg, 0.3 mmol) was suspended in 30 mL MeOH and
stirred for 2 h at room temperature. The blood red precipitate was filtered, washed with diethyl ether,
1
and dried in vacuo. (Yield: 162 mg, 81%). FTIR (cm−1): 1516 (s), 1372 (s), 1257 (s). H-NMR (CDCl3):
δ
(ppm) 5.78 (s, 2H), 5.60 (d, 4H), 5.37 (d, 4H), 2.88 (sept, 2H), 2.27 (s, 6H), 1.30 (d, 12H). Anal. Calcd for
C26H30Cl2O4Ru2: C, 45.90; H, 4,45. Found: C, 45.67; H, 4.55.
4-Aminopyridine (0.941 g, 10 mmol) was dissolved in 25 mL dry THF. To this solution,
1,10-carbonyldiimidazole (0.97 g, 6 mmol) was added. The reaction mixture was refluxed for 12 h
under inert atmosphere, and the mixture was cooled afterwards. The resulting residue was washed
with water several times and dried in vacuo to give a white precipitate. FTIR (cm−1): 2917 (N-H), 1737
(C=O). 1H-NMR (DMSO-d6):
δ
(ppm) 9.25 (s, 2H), 8.35 (d, 4H), 7.42 (d, 4H). 13C-NMR (DMSO-d6):
δ
(ppm) 151.99, 150.63, 146.40, 112.96.
3.2. Synthesis of Metalla-Rectangle (3)
A mixture of [Ru2(
η
6-p-cymene)2(C6H2O4)Cl2] (
1) (1 mmol) and 2 equivalents of AgCF3SO3 (2
mmol) in 25 mL methanol was stirred in the dark for 3 h at room temperature. The white precipitate
was filtered, and the corresponding red filtrate was added to 1,3-di(pyridin-4-yl)urea ( ) (1 mmol) and
2
stirred for 15 h; the solvent was removed under reduced pressure. The crude product thus obtained
was redissolved in nitromethane and subjected to vapor diffusion of diethyl ether, resulting in a red
colored product after several days. Yield (89%). Anal. Calcd for C78H80O22N8S4F12Ru4: C, 41.79; H,
3.60; N, 5.00. Found: C, 40.69; H, 3.19; N, 5.12. FTIR (cm−1): 3076 (CHaryl), 1733 (C=O), 1254 (C-F).

Molecules 2019, 24, 2284
8 of 12
1H-NMR (CD3NO2):
δ
(ppm) 9.11 (s, 4H; NH), 8.00 (d, 8H, J = 6.8 Hz, CHα; Hb), 7.53 (d, 8H, J = 6.7 Hz,
CHβ; Hc), 5.92 (d, 8H, J = 6.0 Hz; Hcym), 5.77-5.69 (m, 12H; Hcym/Hbenz), 2.89 (sept, 4H; -CH(CH3)2),
2.18 (s, 12H; -CH3), 1.32 (d, 24H, J = 6.9 Hz; -CH(CH3)2). 13C-NMR (CD3NO2):
δ
(ppm) 184.45, 153.00,
150.36, 148.82, 121.60, 119.69, 114.04, 103.39, 101.88, 98.13, 83.77, 81.04, 30.75, 20.89, 17.10. HR-ESI-MS:
m/z = 411.4928 [M-4OTf]4+, 598.3608 [M-3OTf]3+, 971.1283 [M-2OTf]2+
.
3.3. Stability of Metalla-Bowl in DMSO
For the stability analysis, 2D metalla-rectangle was dissolved in DMSO, and the sample was
1
subjected to H NMR spectroscopy immediately after dissolution and after 3 days. No change in
proton NMR was observed, hence confirming the stability of the 2D ruthenium metalla-rectangle.
3.4. UV-Vis Binding Studies
A stock solution of metalla-rectangle (
in water were prepared. The change in absorbance was recorded at room temperature after the addition
3
) in methanol (1
×
10−5 M) and sodium oxalate (1 × 10−3 M)
of increasing concentrations of sodium oxalate to a constant volume of 3. The stoichiometry of the
adduct with 3 (A-Å) was obtained from these spectra (Job’s plot).
4. Conclusions
In conclusion, we have reported the synthesis of coordination driven self-assembled 2D ruthenium
metalla-rectangle ( ) by the reaction of half sandwich ruthenium complex ( ) and bent organic linker ( ).
3
1
2
Wide range of structural and analytical tools such as FTIR and UV-Vis spectroscopy, elemental analysis,
1H NMR, 13C NMR, 1H-1H COSY, 1H-1H NOESY, and DOSY spectroscopy, HR-ESI-MS spectrometry
all confirmed the successful formation of 3. This new metalla-rectangle showed powerful anticancer
activity against three different cell lines (Lovo, Caki-1, A549), as compared with the parent ruthenium
precursor and the commercial available cisplatin drug. Importantly, similar self-assembled discrete
ruthenium architecture exhibit cell apoptosis therefore future studies are conducting in our laboratory
with normal cells and DNA ladder assay provide insights into the cell apoptosis.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/24/12/2284/s1,
Figures S1–S15: showing IR, NMR, MS characterizations, Job’s plot and the effect of
normal cancer lines
3 on difference metastatic and
Author Contributions: Conceptualization: A.N. and S.M.; Data curation, G.V.; Formal analysis, K.K. and G.V.;
Funding acquisition, A.N. and T.M.A.; Investigation, H.V. and H.M.E.-S.; Methodology, H.V. and K.K.; Project
administration, A.M. and M.A.-D.; Resources, A.M.; Software, M.A.-D. and T.M.A.; Supervision, S.M.; Validation,
H.M.E.-S.; Writing—original draft, H.V.; Writing—review & editing, A.N. and S.M.
Funding: The authors acknowledge University of South Florida (USF) for supporting this work. We extend our
sincere appreciation to the Deanship of Scientific Research at King Saud University (KSU) for funding this project
through Research Group (RG #236).
Acknowledgments: We extend our sincere appreciation to the Deanship of Scientific Research at King Saud
University (KSU) for funding this project through Research Group (RG #236) and RSSU for their technical support.
T.M.A. thanks King Abdullah City for Atomic and Renewable Energy for the awarded scholarship.
Conflicts of Interest: The authors declare no conflicts of interest.
References
1.
2.
3.
4.
Whiteside, G.M.; Grzybowski, B. Self-assembly at all scales. Science 2002, 295, 2418–2421. [CrossRef]
[PubMed]
Pedersen, C.J. The discovery of crown ethers (Noble Lecture). Angew. Chem. Int. Ed. 1988, 27, 1021–1027.
[CrossRef]
Lehn, J.M. Supramolecular chemistry: Scope and Perspectives Molecules, supermolecules and molecular
devices. Angew. Chem. Int. Ed. 1988, 27, 89–112. [CrossRef]
Cram, D.J. The design of molecular hosts, guests, and their complexes (Noble Lecture). Angew. Chem. Int.
Ed. 1988, 27, 1009–1020. [CrossRef]

Molecules 2019, 24, 2284
9 of 12
5.
6.
Cook, T.R.; Stang, P.J. Recent developments in the preparation and chemistry of metallacycles and metallacages
via coordination. Chem. Rev. 2015, 115, 7001–7045. [CrossRef] [PubMed]
Cook, T.R.; Zheng, Y.-R.; Stang, P.J. Metal-organic frameworks and self-assembled supramolecular
coordination complexes: Comparing and contrasting the design, synthesis, and functionality of metal-organic
materials. Chem. Rev. 2013, 113, 734–777. [CrossRef]
7.
8.
9.
Chakrabarty, R.; Mukherjee, P.S.; Stang, P.J. Supramolecular coordination: Self-assembly of finite two-and
three-dimensional ensembles. Chem. Rev. 2011, 111, 6810–6918. [CrossRef]
Oliveri, C.G.; Ulmann, P.A.; Wiester, M.J.; Mirkin, C.A. Heteroligated supramolecular coordination complexes
formed via the halide-induced ligand rearrangement reaction. Acc. Chem. Res. 2008, 41, 1618–1629. [CrossRef]
Harris, K.; Fujita, D.; Fujita, M. Giant hollow MnL2n spherical complexes: Structure, functionalization and
applications. Chem. Comm. 2013, 49, 6703–6712. [CrossRef]
10. Lindoy, L.F.; Park, K.-M.; Lee, S.S. Metal, macrocycles and molecular assemblies-macrocyclic complexes in
metallo-supramolecular chemistry. Chem. Soc. Rev. 2013, 42, 1713–1727. [CrossRef]
11. Smulders, M.M.J.; Riddell, I.A.; Browne, C.; Nitschke, J.R. Building on architectural principles for
three-dimensional metallosupramolecular construction. Chem. Soc. Rev. 2013, 42, 1728–1754. [CrossRef]
[PubMed]
12. Ward, M.D. Polynuclear coordination cages. Chem. Commun. 2009, 30, 4487–4499. [CrossRef] [PubMed]
13. Tranchemontagne, D.J.; Ni, Z.; O’Keeffe, M.; Yaghi, O.M. Reticular chemistry of metal-organic polyhedra.
Angew. Chem. Int. Ed. 2008, 47, 5136–5147. [CrossRef] [PubMed]
14. Mishra, A.; Gupta, R. Supramolecular architectures with pyridine-amide based ligands: Discrete molecular
assemblies and their application. Dalton Trans. 2014, 43, 7668–7682. [CrossRef] [PubMed]
15. Saalfrank, R.W.; Maid, H.; Scheurer, A. Supramolecular coordination chemistry: The synergistic effect of
serendipity and rational design. Angew. Chem. Int. Ed. 2008, 47, 8794–8824. [CrossRef] [PubMed]
16. Catti, L.; Zhang, Q.; Tiefenbacher, K. Advantages of Catalysis in Self-assembled molecular capsules.
Chem.-Eur. J. 2016, 22, 9060–9066. [CrossRef] [PubMed]
17. Koblenz, T.S.; Wassenaar, J.; Reek, J.N.H. Reactivity within a confined self-assembled nanospace.
Chem. Soc. Rev. 2008, 37, 247–262. [CrossRef]
18. Meeuwissen, J.; Reek, J.N.H. Supramolecular catalysis beyond enzyme mimics. Nat. Chem. 2010, 2, 615–621.
[CrossRef]
19. Howlader, P.; Das, P.; Zangrando, E.; Mukherjee, P.S. Urea functionalized self-assembled molecular prism for
heterogeneous catalysis in water. J. Am. Chem. Soc. 2016, 138, 1668–1676. [CrossRef]
20. Vardhan, H.; Yusubov, M.; Verpoort, F. Self-assembled metal-organic polyhedra: An overview of various
applications. Coord. Chem. Rev. 2016, 306, 171–194. [CrossRef]
21. Vardhan, H.; Verpoort, F. Metal-organic polyhedra: Catalysis and reactive intermediates. Adv. Synth. Catal.
2015, 357, 1351–1368. [CrossRef]
22. Pluth, M.D.; Bergman, R.G.; Raymond, K.N. Proton-mediated chemistry and catalysis in a self-assembled
supramolecular host. Acc. Chem. Res. 2009, 42, 1650–1659. [CrossRef] [PubMed]
23. Zheng, Y.-R.; Suntharalingam, K.; Johnstone, T.C.; Lippard, S.J. Encapsulation of Pt(IV) prodrugs within a
Pt(II) cage for drug delivery. Chem. Sci. 2015, 6, 1189–1193. [CrossRef] [PubMed]
24. Zheng, Y.-R.; Suntharalingam, K.; Bruno, P.M.; Lin, W.; Wang, W.; Hemann, M.T.; Lippard, S.J. Mechanistic
studies of the anticancer activity of an octahedral hexanuclear Pt(II) cage. Inorg. Chim. Acta 2016, 452,
125–129. [CrossRef] [PubMed]
25. Therrein, B. Transporting and shielding photosensitizers by using water-soluble organometallic cages: A‘new
strategy in drug delivery and photodynamic therapy. Chem.-Eur. J. 2013, 19, 8378–8386. [CrossRef] [PubMed]
26. Therrein, B. Biologically relevant arene ruthenium metalla-assemblies. CrystEngComm 2015, 17, 484–491.
[CrossRef]
27. Cook, T.R.; Vajpayee, V.; Lee, M.H.; Stang, P.J.; Chi, K.-W. Biomedical and biochemical applications of
self-assembled metallacycles and metallacages. Acc. Chem. Res. 2013, 46, 2464–2474. [CrossRef]
28. Therrien, B. Drug delivery by water-soluble organometallic cages. Top. Curr. Chem. 2011, 319, 35–55.
29. Barry, N.P.E.; Zava, O.; Dyson, P.J.; Therrien, B. Synthesis, Characterization and Anticancer activity of
porphyrin-containing organometallic cubes. Aust. J. Chem. 2010, 63, 1529–1537. [CrossRef]
30. Therrien, B. Arene ruthenium cages: Boxes full of surprise. Eur. J. Inorg. Chem. 2009, 2009, 2445–2453.
[CrossRef]

Molecules 2019, 24, 2284
10 of 12
31. Nakamura, T.; Ube, H.; Shionoya, M. Silver-mediated formation of a cofacial porphyrin dimer with the
ability to intercalate aromatic molecules. Angew. Chem. Int. Ed. 2013, 52, 12096–12100. [CrossRef] [PubMed]
32. Rousseaux, S.A.L.; Gong, J.Q.; Haver, R.; Odell, B.; Claridge, T.D.W.; Herz, L.M.; Anderson, H.L. Self-assembly
of Russian doll concentric porphyrin nanorings. J. Am. Chem. Soc. 2015, 137, 12713–12718. [CrossRef]
[PubMed]
33. Zhang, W.-Z.; Han, Y.-F.; Lin, Y.-J.; Jin, G.-X. Synthesis and characterization of molecular rectangles of
half-sandwich p-cymene ruthenium complexes bearing oxamidato ligands. Dalton Trans. 2009, 39, 8426–8431.
[CrossRef] [PubMed]
34. Han, Y.-F.; Fei, Y.; Jin, G.-X. Self-assembled half-sandwich Ir, Rh-based organometallic molecular boxes for
reversible trapping of halocarbon molecules. Dalton Trans. 2010, 39, 3976–3984. [CrossRef] [PubMed]
35. Vajpayee, V.; Song, Y.H.; Lee, M.H.; Kim, H.; Wang, M.; Stang, P.J.; Chi, K.-W. Self-assembled
arene-ruthenium-based rectangles for the selective sensing of multi-carboxylate anions. Chem. Eur. J.
2011, 17, 7837–7844. [CrossRef] [PubMed]
36. Furrer, M.A.; Furrer, J.; Therrien, B. Physical and physicochemical stimuli-responsive arene ruthenium
metallaprisms. Organometallics 2012, 31, 3149–3154. [CrossRef]
37. Mishra, A.; Vajpayee, V.; Kim, H.; Lee, M.H.; Jung, H.; Wang, M.; Stang, P.; Chi, K.-W. Self-assembled
metalla-bowls for selective sensing of multi-carboxylate anions. Dalton Trans. 2012, 41, 1195–1201. [CrossRef]
38. Wang, M.; Vajpayee, V.; Shanmugaraju, S.; Zheng, Y.R.; Zhao, Z.; Kim, H.; Mukherjee, P.S.; Chi, K.-W.;
Stang, P.J. Coordination-driven self-assembly of M3L2 trigonal cages from preorganized metalloligands
incorporating octahedral metal centers and fluorescent detection of nitroaromatics. Inorg. Chem. 2011, 50,
1506–1512. [CrossRef]
39. Tehrani, A.A.; Esrafili, L.; Abedi, S.; Morsalim, A.; Carlucci, L.; Proserpio, D.M.; Wang, J.; Junk, O.C.; Liu, T.
Urea Metal-organic frameworks for nitro-substituted compounds sensing. Inorg. Chem. 2017, 56, 1446–1454.
[CrossRef]
40. Barry, N.P.E.; Furrer, J.; Freudenreich, J.; Süss-Fink, G.; Therrien, B. Designing the host-guest properties of
tetranuclear arene ruthenium metalla-rectangles to accommodate pyrene molecule. Eur. J. Inorg. Chem. 2010
,
2010, 725–728. [CrossRef]
41. Govender, P.; Renfrew, A.K.; Clavel, C.M.; Dyson, P.J.; Therrien, B.; Smith, G.S. Antiproliferative activity
of chelating N,O- and N,N-ruthenium (II) arene functionalized poly(propyleneimine) dendrimer scaffolds.
Dalton Trans. 2011, 40, 1158–1167. [CrossRef] [PubMed]
42. Vajpayee, V.; Lee, S.; Kim, S.-H.; Kang, S.C.; Cook, T.R.; Kim, H.; Kim, D.W.; Verma, S.; Lah, M.S.; Kim, I.S.;
et al. Self-assembled metalla-rectangles bearing azodipyridyl ligands: Synthesis, characterization and
antitumor activity. Dalton Trans. 2013, 42, 466–475. [CrossRef] [PubMed]
43. Oldacre, A.N.; Friedman, A.E.; Cook, T.R. A self-assembled cofacial cobalt porphyrin prism for oxygen
reduction catalysis. J. Am. Chem. Soc. 2017, 139, 1424–1427. [CrossRef] [PubMed]
44. Vardhan, H.; Mehta, A.; Nath, I.; Verpoort, F. Dynamic imine chemistry in metal-organic polyhedra. RSC Adv.
2015, 5, 67011–67030. [CrossRef]
45. Caltagirone, C.; Gale, P.A. Anion receptor chemistry: Highlights from 2007. Chem. Soc. Rev. 2009, 38, 520–563.
[CrossRef]
46. Gale, P.A.; Quesada, R. Anion coordination and anion-templated assembly: Highlights from 2002 to 2004.
Coord. Chem. Rev. 2006, 250, 3219–3244. [CrossRef]
47. Oshovsky, G.V.; Reinhoudt, D.N.; Verboom, W. Supramolecular chemistry in water. Angew. Chem. Int. Ed.
2007, 46, 2366–2393. [CrossRef]
48. Gales, P.A.; Garcia-Garrido, S.E.; Garric, J. Anion receptor based on organic frameworks: Highlights from
2005 and 2006. Chem. Soc. Rev. 2008, 37, 151–190. [CrossRef]
49. Morakot, N.; Rakrai, W.; Keawwangchai, S.; Kaewtong, C.; Wanno, B. Design and synthesis of thiourea based
receptor containing naphthalene as oxalate selective sensor. J. Mol. Model. 2009, 16, 129–136. [CrossRef]
50. Pal, R.; Parker, D.; Costello, L.C. A europium luminescence assay of lactate and citrate in biological fluid.
Org. Biomol. Chem. 2009, 7, 1525–1528. [CrossRef]
51. Costello, L.C.; Franklin, R.B. Prostatic fluid electrolyte composition for the screening of prostate cancer:
A potential solution to a major problem. Prostate Cancer Prostatic Dis. 2008, 12, 17–24. [CrossRef] [PubMed]

Molecules 2019, 24, 2284
11 of 12
52. Vajpayee, V.; Yang, Y.J.; Kang, S.C.; Kim, H.; Kim, I.S.; Wang, M.; Stang, P.J.; Chi, K.-W. Hexanuclear
self-assembled arene-ruthenium nanoprismatic cages: Potential anticancer agents. Chem. Commun. 2011, 47,
5184–5186. [CrossRef] [PubMed]
53. Barry, N.P.E.; Edafe, F.; Therrien, B. Anticancer activity of tetracationic arene ruthenium metalla-cycles.
Dalton Trans. 2011, 40, 7172–7180. [CrossRef] [PubMed]
54. Barry, N.P.E.; Zava, P.; Furrer, J.; Dyson, P.J.; Therrien, B. Anticancer activity of opened arene ruthenium
metalla-assemblies. Dalton Trans. 2010, 39, 5272–5277. [CrossRef] [PubMed]
55. Therrien, B.; Süss-Fink, G.; Govindaswamy, P.; Renfrew, A.K.; Dyson, P.J. The “complex-in-a-complex” cations
[(acac)2M
47, 3773–3776. [CrossRef] [PubMed]
⊂
Ru6(p-iPrC6H4Me)6(tpt)2(dhbq)3]6+: A Trojan Horse for cancer cells. Angew. Chem. Int. Ed. 2008
,
56. Zava, O.; Mattsson, J.; Therrien, B.; Dyson, P.J. Evidence for drug release from a metalla-cage delivery vector
following cellular internalization. Chem. Eur. J. 2010, 16, 1428–1431. [CrossRef] [PubMed]
57. Barry, N.P.E.; Abd Karim, N.H.; Vilar, R.; Therrien, B. Interactions of ruthenium coordination cubes with
DNA. Dalton Trans. 2009, 10717–10719. [CrossRef]
58. Vajpayee, V.; Song, Y.H.; Yang, Y.J.; Kang, S.C.; Cook, T.R.; Kim, D.W.; Lah, M.S.; Kim, I.S.; Wang, M.;
Stang, P.J.; et al. Self-assembly of cationic, hetero-or homonuclear ruthenium (II) macrocyclic rectangles and
their photophysical, electrochemical, and biological studies. Organometallics 2011, 30, 6482–6489. [CrossRef]
59. Mishra, A.; Jung, H.; Park, J.W.; Kim, H.K.; Kim, H.; Stang, P.J.; Chi, K.-W. Anticancer activity of Self-assembled
molecular rectangles via arene-ruthenium acceptors and a new unsymmetrical amide ligand. Organometallics
2012, 31, 3519–3526. [CrossRef]
60. Zhou, J.; Yu, G.; Huang, F. Supramolecular chemotherapy based on host-guest molecular recognition: A novel
strategy in the battle against cancer with a bright future. Chem. Soc. Rev. 2017, 46, 7021–7053. [CrossRef]
61. Linares, F.; Galindo, M.A.; Galli, S.; Romero, M.A.; Navarro, J.A.R.; Barea, E. Tetranuclear coordination
assemblies based on half-sandwich ruthenium (II) complexes: Noncovalent binding to DNA and cytotoxicity.
Inorg. Chem. 2009, 48, 7413–7420. [CrossRef] [PubMed]
62. Linares, F.; Procopio, E.Q.; Galindo, M.A.; Romero, M.A.; Navarro, J.A.R.; Barea, E. Molecular architecture of
redox-active half-sandwich Ru(II) cyclic assemblies. Interaction with biomolecules and anticancer activity.
CrystEngComm 2010, 12, 2343–2346. [CrossRef]
63. Dubey, A.; Jeong, Y.J.; Jo, J.H.; Woo, S.; Kim, D.H.; Kim, H.; Kang, S.C.; Stang, P.J.; Chi, K.-W. Anticancer
activity and autophagy involvement of self-assembled arene-ruthenium metallacycles. Organometallics 2015
34, 4507–4514. [CrossRef]
,
64. Keller, W.E. Evidence for the planar structure of the urea molecule. J. Chem. Phys. 1948, 16, 1003. [CrossRef]
65. Platts, J.A.; Maarof, H.; Harris, K.D.M.; Lim, G.K.; Willock, D.J. The effect of intermolecular hydrogen
bonding on the planarity of amides. Phys. Chem. Chem. Phys. 2012, 14, 11944–11952. [CrossRef] [PubMed]
66. Yan, H.; Süss-Fink, G.; Neels, A.; Stoeckli-Evans, H. Mono-, di- and tetra-nuclear p-cymene ruthenium
complexes containing oxalate ligands. J. Chem. Soc. Dalton Trans. 1997, 22, 4345–4350.
67. Vardhan, H.; Verpoort, F. Ligand constraints and synthesis of metal-organic polyhedra. Aust. J. Chem. 2015
68, 707–730. [CrossRef]
,
68. Paul, L.E.H.; Therrien, B.; Furrer, J. Interactions of arene ruthenium metallaprisms with human proteins.
Org. Biomol. Chem. 2015, 13, 946–953. [CrossRef]
69. Vajpayee, V.; Lee, S.M.; Park, J.W.; Dubey, A.; Kim, H.; Cook, T.R.; Stang, P.J.; Chi, K.-W. Growth inhibitory
activity of a bis-benzimidazole-bridged arene ruthenium metalla-rectangle and -prims. Organometallics 2013
32, 1563–1566. [CrossRef]
,
70. Orhan, E.; Garci, A.; Therrien, B. Coordination-driven self-assembly of arene ruthenium metalla-rectangles.
Inorg. Chim. Acta 2017, 461, 78–83. [CrossRef]
71. Orhan, R.; Garci, A.; Therrien, B. Flexible arene ruthenium metalla-prisms. Inorg. Chim. Acta 2015, 438, 5–9.
[CrossRef]
72. Johnson, C.S., Jr. Diffusion ordered nuclear magnetic resonance spectroscopy: Principles and applications.
Prog. Nucl. Magn. Reson. Spectrosc. 1999, 34, 203–256. [CrossRef]
73. Pitto-Barry, A.; Barry, N.P.E.; Zava, O.; Deschenaux, R.; Dyson, P.J.; Therrien, B. Double targeting of tumours
with pyrenyl-modified dendrimers encapsulated in an arene-ruthenium metalla-prism. Chem. Eur. J. 2011
,
17, 1966–1971. [CrossRef] [PubMed]

Molecules 2019, 24, 2284
12 of 12
74. Lee, H.; Elumalai, P.; Singh, N.; Kim, H.; Lee, S.U.; Chi, K.-W. Selective synthesis of ruthenium
(II)metalla[2]catenane via solvent and guest-dependent self-assembly. J. Am. Chem. Soc. 2015, 137,
4674–4677. [CrossRef] [PubMed]
75. Percástegui, E.G.; Mosquera, J.; Nitschke, J.R. Anion exchange renders hydrophobic capsule and cargoes
water-soluble. Angew. Chem. Int. Ed. 2017, 56, 9136–9140. [CrossRef] [PubMed]
76. Kumar, A.; Zangrando, E.; Mukherjee, P.S. Self-assembled Pd3L2 cages having flexible tri-imidazole donors.
Polyhedron 2019. [CrossRef]
77. Okan, S.E.; Champeney, D.C. Molar conductance of aqueous solutions of sodium, potassium, and nickel
trifluoromethanesulfonate at 25 ◦C. J. Solut. Chem. 1997, 26, 405–414. [CrossRef]
78. Mishra, A.; Jeong, Y.J.; Jo, J.-H.; Kang, S.C.; Lah, M.S.; Chi, K.-W. Anticancer potency studies of coordination
driven self-assembled arene-Ru-based metalla-bowls. ChemBioChem 2014, 15, 695–700. [CrossRef]
79. Mishra, A.; Lee, S.C.; Kaushik, N.; Cook, T.R.; Choi, E.H.; Kaushik, N.K.; Stang, P.J.; Chi, K.-W. Self-assembled
supramolecular hetero-bimetallacycles for anticancer potency by intracellular release. Chem. Eur. J. 2014, 20,
14410–14420. [CrossRef]
80. Vardhan, H.; Mehta, A.; Ezugwu, C.I.; Verpoort, F. Self-assembled arene ruthenium metalla-assemblies.
Polyhedron 2016, 112, 104–108. [CrossRef]
81. Vardhan, H.; Verpoort, F. UV-Vis absorption studies of coordination-driven self-assembled 2D
metalla-rectangle towards multi-carboxylation anions. Polyhedron 2019, 157, 262–266. [CrossRef]
82. Vajpayee, V.; Song, Y.H.; Jung, Y.J.; Kang, S.C.; Kim, H.; Kim, I.S.; Wang, M.; Cook, T.R.; Stang, P.J.; Chi, K.-W.
Coordination-driven self-assembly of ruthenium-based molecular-rectangles: Synthesis, characterization,
photophysical and anticancer potency studies. Dalton Trans. 2012, 41, 3046–3052. [CrossRef] [PubMed]
83. Therrein, B. The role of the second coordination sphere in the biological activity of arene ruthenium
metalla-assemblies. Front. Chem. 2018, 6, 602. [CrossRef] [PubMed]
84. Kaufmann, S.H.; Hengartner, M.O. Programmed cell death: Alive and well in the new millennium.
Trends Cell Biol. 2001, 11, 526–534. [CrossRef]
85. Jing, H.; Dubey, A.; Koo, H.J.; Vajpayee, V.; Cook, T.R.; Kim, H.; Kang, S.C.; Stang, P.J.; Chi, K.-W. Self-assembly
of ambidentate pyridyl-carboxylate ligands with octahedral ruthenium metal centers: Self-selection for
a single-linkage isomer and anticancer-potency studies. Chem. Eur. J. 2013, 19, 6709–6717. [CrossRef]
[PubMed]
86. Dubey, A.; Min, J.W.; Koo, H.J.; Kim, H.; Cook, T.R.; Kang, S.C.; Stang, P.J.; Chi, K.-W. Anticancer potency
and multidrug-resistant studies of self-assembled arene-ruthenium metallarectangles. Chem. Eur. J. 2013, 19,
11622–11628. [CrossRef] [PubMed]
Sample Availability: Samples of the compounds 1,2 and 3 are available from the authors.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).