Phototoxicity of strained Ru(II) complexes: Is it the metal complex or the dissociating ligand?

Article abstract of DOI:10.1039/c7dt02255g

A photochemically dissociating ligand in Ru(bpy)₂(dmphen)Cl₂ [bpy = 2,2′-bipyridine; dmphen = 2,9-dimethyl-1,10-phenanthroline] was found to be more cytotoxic on the ML-2 Acute Myeloid Leukemia cell line than Ru(bpy)₂(H₂O)₂²⁺ and prototypical cisplatin. Our findings illustrate the potential potency of diimine ligands in photoactivatable Ru(ii) complexes.

Full text of DOI:10.1039/c7dt02255g

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DOI: 10.1039/C7DT02255G
Dalton Transactions
COMMUNICATION
Phototoxicity of Strained Ru(II) Complexes: Is it the
Metal Complex or the Dissociating Ligand?
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
a
Daniel Azar, Hassib Audi, Stephanie Farhat, Mirvat El-Sibai, Ralph Abi-Habib and Rony S.
a,*
Khnayzer
DOI: 10.1039/x0xx00000x
www.rsc.org/
[bpy increasingly favored.16-18 In recent studies, attention has been paid
2 2
(dmphen)Cl
A photochemically dissociating ligand in Ru(bpy)
2,2’-bipyridine; dmphen = 2,9-dimethyl-1,10-phenanthroline]
was found to be more cytotoxic on ML-2 cancer cell line than
2
+
to the role of Ru(bpy)
photochemical dissociation of sterically strained diimine ligands.
This photoproduct is believed to mimic cisplatin’s mode of action by
2
(H
2
O)
2
product formed as a result of
=
13
2+
Ru(bpy)
2
(H
O)
2 2
and the prototypical cisplatin. Our findings
20
cross-linking DNA. However, along with the release of these
species, side-products consisting of free ligands are also formed.
Recently, the 2,9-dimethyl-1,10-phenanthroline (dmphen) ligand
was used in an examples of chiral Ru(II) complexes containing a 2,3-
illustrate the potential potency of diimine ligands in
photoactivatable Ru(II) complexes.
Cancer is a disease associated with high mortality rates in the
15
dihydro-1,4-dioxino[2,3-f]-1,10-phenanthroline (dop) ligand or
1
entire world. Limited numbers of metal-based chemotherapeutic
21
hydroxyquinoline ligand . In addition, structurally related
compounds to dmphen were used in conjunction with bipyridine
such as dmdop (2,3-dihydro-1,4-dioxino[2,3-f]-2,9-dimethyl-1,10-
phenanthroline) or dpq (dipyrido[3,2-f:2′,3′-h]-quinoxaline) . All
these examples furnished Ru(II) complexes that demonstrated a
potential application as PACT drugs in cancer therapy. In general, the
biological role of the dissociated ligands is ill-characterized and
mostly assumed to be inert. While this assumption is correct for a
variety of examples tested on a number of cell lines, we found that
the free dmphen is significantly more toxic than Ru(bpy)
product on ML-2 cell lines (non-adherent Acute Myeloid Leukemia
AML) cells). Despite the fact that the utilization of PACT which
produce multiple potentially potent species might complicate the
mechanistic studies in biological media, we believe it has a major
impact on future photosensitizer design and application. In that
perspective, the metal center can be merely used as a carrier for
highly cytotoxic ligands. The latter would be selectively released
inside or in the vicinity of cancer cells upon light activation. Notably,
the photochemistry of caged Ru compounds has been utilized for the
agents are clinically approved, among which is the prototypical drug
2
cisplatin. This Pt(II) complex was associated with side-effects and
3
, 4
drug-resistance problems among patients.
On one hand,
1
5
13
photoactivated chemotherapeutic drugs (PACT)5 rely on the
selective, localized and stoichiometric release of cytotoxic
substances following controlled light irradiation.
6
, 7
Using this
technique, tumor can be targeted with less side effects than
conventional chemotherapy since prodrugs are ideally inert in the
5
, 8
dark at the concentration used. When transition metal complexes
are deployed, the photochemical reactivity can be modulated by
2+
2
(H
2
O)
2
co-
9
virtue of structural modifications. The photophysical tuning of the
(
excited state can be achieved via fine design of the organic ligand
10
framework. On the other hand, photodynamic therapy (PDT) drugs
1
act through the catalytic production of O
2
and subsequently reactive
11
oxygen species (ROS) that will induce cell death. More recently,
research on the photochemical release of cytotoxic agents through
ligand dissociation of PACT is incrementing.
1
2-15
A significant tuning
of photochemical reactivity was afforded by ligand functionalization
9
around metal centers. In sterically congested Ru(II) polypyridyl
2
2
23
release of biologically active molecules such as serotonin, CO,
complexes bearing alkyl or phenyl substituents on the 2,9 positions
of 1,10-phenanthroline or 6,6’ positions of 2,2’-bipyridine,
2
4
NO, etc.
Ru(bpy)
2
(dmphen)(PF
6
)
2
and
Ru(bpy)
2
(dmphen)Cl
2
were
photochemical ligand ejection follows the population of
a
3*
16-18
synthesized and characterized using a variety of techniques, see
dissociative triplet metal-centered excited state ( MC).
The
25
ESI.
The quantum yield of ligands photoejection from
(dmphen)(PF was measured following 442 nm He/Cd laser
excitation (Fig. S4). A value of 0.32±0.03 % was obtained in
acetonitrile which is comparable to previously reported sterically
latter can be thermally populated from the triplet metal-to-ligand
3
*
19
Ru(bpy)
2
6 2
)
charge transfer state ( MLCT). As the distortions from the regular
octahedral geometry increase, the formation of the 3*MC state was
strained Ru(m-bpy)
one order of magnitude larger than Ru(bpy) (PF ) . Note that these
3 4 2
(BF ) [m-bpy = 6-methyl-2,2′-bipyridine] and
26
a.Department of Natural Sciences, Lebanese American University, Chouran, Beirut
3 6 2
1
102-2801, Lebanon.
quantum yield values are acquired for complexes bearing non-
coordinating counter-ions in acetonitrile as a coordinating solvent.
Electronic Supplementary Information (ESI) available: Experimental section, NMR
spectra, HPLC chromatogram, ESI-MS, UV-vis spectra and cytotoxicity data. See
DOI: 10.1039/x0xx00000x
NMR spectroscopy in CD
3
CN revealed that either bpy or dmphen
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Ple aDs ea l dt oo nn To rt a and sj ua sc tt imo na sr gins
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COMMUNICATION
Journal Name
ligands can dissociate from Ru(bpy) (dmphen)(PF ) forming a ligand, such as bipyridine, dissociate from a stericallyVieewnAcrutimclebOenrleinde
2 6 2
2
7
mixture of solvent-bound Ru(II) products and free ligands in ~ 1:1 ruthenium complex. Sauvage and cowoDrkOeI:rs10.1h0a3v9e/C7pDrTe0v2io2u5s5lGy
(
bpy:dmphen) ratio (Fig. S5).
reported the photochemical dissociation of bipyridine from
27
Ru(bpy)
2 6 2
(dpph)(PF ) [dppH = 2,9-diphenyl-1,10-phenanthroline].
The photochemical ligand dissociation of the water-soluble
Since ligand release likely occurs through a stepwise one nitrogen
2 2
Ru(bpy) (dmphen)Cl was studied in acetonitrile and water under a
28
dissociation of the diimine moiety, the re-coordination of the rigid
phenanthroline based moiety is more efficient than the flexible
bipyridine ligands leading to competitive photo-induced ligand
versatile broadband irradiation (white LED light, see ESI for details).
Under those experimental conditions, the half-life in acetonitrile was
found to be 5 times less in water (~ 5 min) than in acetonitrile (~ 25
min) (Fig. 1). The rate of ligands release was slower in water than in
acetonitrile which is attributed to a larger solubility of the ejected
ligand in the latter as well as the preference of Ru(II) center to
acetonitrile over aquo ligands. It is worth noting that
Ru(bpy) (dmphen)Cl was stable in the dark as evidenced by the lack
2 2
of change in UV-vis spectra after a week of storage in aqueous
solution.
2 2
dissociation of dmphen and bpy ligands from Ru(bpy) (dmphen)Cl .
In addition, steric interactions around the metal can be relieved via
an assymetrical distortion of the octahedral geometry and Ru-N bond
29
elongation labilizing both dmphen and bpy ligands.
cytotoxicities of Ru(bpy) (dmphen)Cl , Ru(bpy) Cl , dmphen, bpy, an
equimolar mixture of Ru(bpy) Cl and dmphen, and cisplatin were
The
2
2
2
2
2
2
measured on ML-2 cancer cell line (Fig. 2 and Table 1).
ML2 (Dark)
(a)
(
a) 0.7
0
0
0
0
.6
.5
.4
.3
1
.0
dmphen
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Ru(bpy)2Cl2
Ru(bpy)2Cl2 + dmphen
2
+
0.5
Ru(bpy) dmphen
2
0.2
0
5
10 15 20 25
Time (min)
0.0
-4
-3
-2
-1
0
1
2
Log 10 [M]
ML2 (LIGHT)
(
b)
300 350 400 450 500 550 600 650 700
1.0
dmphen
Wavelength (nm)
Ru(bpy)2Cl2
Ru(bpy)2Cl2 + dmphen
2
+
Ru(bpy)2dmphen
0.5
(b) 0.7
0.5
0
0
0
0
0
0
0
.6
.5
.4
.3
.2
.1
.0
0.4
0.3
0
.0
-4
-3
-2
-1
0
1
2
Log 10 [M]
0.2
Fig.
Ru(bpy)
dmphen), and a mixture of Rubpy
and upon blue-light (see ESI for more details) excitation (b).
2
Cytotoxicity data acquired on ML2 cell line of
dmphenCl , Rubpy Cl , 2,9-dimethyl-1,10-phenanthroline
Cl and dmphen in the dark (a)
0
20 40 60 80 100120
Time (min)
2
2
2
2
(
2
2
Table
1
IC50 on ML2 cell lines expressed in µmol/L of
dmphenCl , Rubpy Cl , 2,9-dimethyl-1,10-phenanthroline
Cl and
Ru(bpy)
2
2
2
2
3
00 350 400 450 500 550 600 650 700
(
dmphen), 2,2’-bipyridine (bpy), and a mixture of Rubpy
dmphen, in the dark and upon light activation. Cisplatin and bpy
controls (Fig. S6) were acquired in the dark.
2
2
Wavelength (nm)
Fig.
Ru(bpy)
1
Absorption spectra of
a
stirred solution of
2
(dmphen)Cl (30 µM) irradiated with white LED light (see ESI
2
for more details) placed 2 cm far from a 1 cm pathlength quartz
cuvette in (a) acetonitrile recorded at 2 min interval and (b) water at
Compound
Dark
Light
Ru(bpy)
2
dmphenCl
2
5.5 µM
> 100 µM
0.02 µM
> 100 µM
0.02 µM
4.0 µM
0.2 µM
>100 µM
0.04 µM
1
0 min intervals. Dashed arrows indicate the progress of the charge
Rubpy
Cl
2 2
transfer absorption peak. The inset represents the change of
absorbance at 450 nm as a function of irradiation time.
dmphen
bpy
Previously reported PACT agents bearing substituted bipyridil
Rubpy Cl +dmphen
0.04 µM
2
2
ligands such as Ru(bpy)
2 2
(dmbpy)Cl [dmbpy = 6,6’-dimethyl-2,2’-
cisplatin
bipyridine] displayed a quantitative photoejection of the dmbpy
13
ligand. However, it is not uncommon to have the non-substituted
2
| J. Name., 2012, 00, 1-3
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Ple aDs ea l dt oo nn To rt a and sj ua sc tt imo na sr gins
Journal Name
The photoresponsive Ru(bpy)
COMMUNICATION
2
+ 32
2
(dmphen)Cl
2
was tested in the dark precursor to Ru(bpy)
2
(H
2
O)
2
,
was found to be minimally potent
View Article Online
and upon photoactivation revealing a phototoxicity index (PI = [IC50 relative to the highly cytotoxic dmphen wheDnOtIe: 1s0te.1d03in9/dCe7pDeTn0d2e2n55tlGy
dark]/[IC50 light]) of 27.5, with IC50 in the dark of 5.5 µM and in the on ML-2 cancer cell line in the dark and upon photoactivation. These
light of 0.2 µM (Fig. 2 and Table 1). A blue LED light source (see ESI experiments clearly indicate that the ruthenium center can act as a
for details) was used to provide metal-to-ligand charge transfer carrier to a cytotoxic diimine ligand. In addition, these findings unveil
(
0
MLCT) photoexcitation. The IC50 of the dmphen ligand was found ~ the potential role of dissociating ligands in the biological mechanism
.02-0.04 µM (difference between light and dark is not significant of action in strained polypyridyl Ru(II) produgs. Finally, this work may
due to plate to plate variability) with and without the presence of aid the development and understanding of new caged PACT drugs
Ru(bpy) Cl indicating that the former is significantly more potent containing cytotoxic phenanthroline or bipyridine derivatives.
2
2
than the latter. Notably, this ligand was also more potent than the
prototypical cisplatin complex which possessed an IC50 of 4.0 µM
when measured under dark conditions, Fig. S6. It is worth noting that Acknowledgements
the bpy ligand was found to have no potency at concentrations lower
than 50 µM on ML-2 cells with IC50 > 100 µM, Fig. S6. In previous
studies, bpy exhibited a moderate cytotoxicity (IC50 ~ 30 µM) on RSK acknowledges financial support from the School Research and
chronic myelogenous leukemia cell line (K562) whereas no potency Development Council at the Lebanese American University and the
30, 31
was detected on MDA-MB-231 and MCF-7 cells.
To further Lebanese National Council for Scientific Research (Ref: 05-06-14).
substantiate our findings, Ru(bpy)
2
Cl
2
, a thermal and photochemical
2+
20, 32
precursor of Ru(bpy)
2
(H
2
O)
2
(Fig. S8),
exhibited marginal
cytotoxicity with and without irradiation (IC50 > 100 µM in the dark References
and upon light activation, Fig. 2 and Table 1). These results are
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+
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2
(H
2
O)
2
was shown to lack DNA
3
3
2+
2 2 2
interstrand cross-linking efficiency. Furthermore, Ru(bpy) (H O)
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and dmphen dissociate in a ratio of ~3:2 (bpy:dmphen) to form the
corresponding polypyridyl Ru(II) aquo species, Fig. S7. In addition,
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Ru(bpy)
in water. Based on these data combined, the
(dmphen)Cl on ML-2 cancer cell
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(H
2
O)
2
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Ru(bpy)
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(H
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2+
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2
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A table of contents entry:
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT02255G
This work exemplifies the potential potency of photochemically ejected ligands from strained Ru(II) polypyridyl complexes
used in photoactivated chemotherapy.
1