Synthesis of enantiomers of mononuclear Ru(II) complexes with 10,13-diaryl substituted dppz ligands

Article abstract of DOI:10.1016/j.inoche.2013.08.016

An array of enantiomerically pure mononuclcear [Ru(bpy)₂(dppz)] ^{2 +} derivatives with 10,13-diaryl substituted dppz ligand has been synthesized and characterized (bpy = bipyridine, dppz = pyrido-[3,2-a:2′, 3′-c]phenazine). These new complexes exhibit substantially similar absorption spectra, resembling the parent complex [Ru(bpy)₂(dppz)] ^{2 +}, and the enantiomerically pure analogues show the similar CD spectra in buffer solution despite the structural difference.

Full text of DOI:10.1016/j.inoche.2013.08.016

Inorganic Chemistry Communications 36 (2013) 130–132
Contents lists available at ScienceDirect
Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Synthesis of enantiomers of mononuclear Ru(II) complexes with
10,13-diaryl substituted dppz ligands
⁎
Minna Li , Ming Zhao, Shiqi Peng
School of Chemical Biology and Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
a r t i c l e i n f o
a b s t r a c t
An array of enantiomerically pure mononuclcear [Ru(bpy)2(dppz)]2+ derivatives with 10,13-diaryl substituted
dppz ligand has been synthesized and characterized (bpy = bipyridine, dppz = pyrido-[3,2-a:2′,3′-c]phenazine).
These new complexes exhibit substantially similar absorption spectra, resembling the parent complex
[Ru(bpy)2(dppz)]2+, and the enantiomerically pure analogues show the similar CD spectra in buffer solution de-
spite the structural difference.
Article history:
Received 21 June 2013
Accepted 22 August 2013
Available online 4 September 2013
Keywords:
Ruthenium complexes
dppz
Crown Copyright © 2013 Published by Elsevier B.V. All rights reserved.
Enantiomer
10,13-Diaryl
Transition metal complexes that possess selective DNA binding
properties are an attractive and substantial significant subject by virtue
of their potential use as DNA conformational probes, potential drug
leads for chemotherapy, and cellular imaging agents [1–3]. Particularly,
Ru(II) polypyridyl complexes have been intensively synthesized and
studied due to their tuneable photophysical and photochemical prop-
erties by changing the ligands [4,5]. Moreover, complexes (such as
[Ru(bpy)2(dppz)]2+ and its derivatives) that function as excellent
DNA “light switch” i.e., exhibiting nonluminescent in aqueous solution
but intensely luminescent upon binding with DNA [6,7], hold special
potential as DNA-drug or biological imaging agents. Strong DNA affinity
and slow dissociation kinetics are considered to be especially impor-
tant for antitumor application [8], which is proved by the cytotoxic
natural product nogalamycin. The majority of synthetic intercalators
reported in the literature have dissociation rate constants in the order
of 101–10−1 s−1 [9–11]. While an earlier reported semi-rigid dimer
[μ-bidppz(phen)4Ru2]4+ (bidppz = dipyrido-[3,2-a:2′,3′-c]phenazinyl),
in which a single bond connects the two dppz moieties, exhibits even
It thus appears motivated to also study smaller systems to find the
minimal requirements for selective intercalation. As starting minimal
systems, we earlier synthesized several mononuclear ruthenium with
different quaternary ammonium substituents in the 11-position of
the dppz ligand and found dissociation rate to be reduced compared
to the mononuclear unsubstituted complex, even though faster than
[μ-bidppz(phen)4Ru2]4+ [16]. Just as described above, the DNA thread-
ing intercalators about ruthenium complex previously reported were
only the complexes containing a dppz ligand with substituents in the
11-position. How about substitution in the 10-position? We hypothe-
size that introduction of large substituents perpendicular to the dppz
long axis could impair intercalation of the dppz ligand due to steric
interactions with the DNA backbone. Inspired by this idea, we have re-
cently synthesized two new 10,13-diaryl substituted dipyridophenazine
ruthenium complexes and found that small changes in the structure of
the substituents has an extremely intense influence on DNA binding
properties [17]. The di(2-thienyl) substituted complex displays slow
dissociation kinetics characteristic for threading intercalation, while its
diphenyl substituted analogue seems to bind DNA by partial intercala-
tion of one phenyl substituent resulting in faster dissociation. With the
view of developing this area even further, we have set out to generate
novel 10, 13-position substituted dppz ligands that could make us under-
stand deeply how structures affect binding properties of ruthenium com-
plexes. Herein, in this work three new mononuclear [Ru(bpy)2(dppz)]2+
derivatives with 10,13-diaryl substituted dppz ligands and their corre-
sponding enantiomers have been synthesized (Ru-T, Ru-BT and Ru-BF,
Scheme 1). To assess the effect of auxillary ligand on binding property
of complex, the complex [(bpy)2Ru(dppz)]2+ derivative with 10,13-
di(2-thienyl) substituted dppz ligand (Ru-T) was prepared in compari-
son to previously reported [(phen)2Ru(dppz)]2+ analogue. To investi-
gate how the threading intercalation kinetics may depend on the size
slower dissociation with rate constants in the range of 10−3–10−4 s−1
,
which is similar to that observed for nogalamycin [8,12]. In support of
this finding, an array of binuclear ruthenium complexes with varying
auxiliary and bridging ligands has been synthesized to elucidate how
complex structure affects the dissociation kinetics from DNA [13–15].
Although kinetically slow and highly selective for long AT stretches,
the binuclear complex [μ-bidppz(phen)4Ru2]4+ and its congeners
have the drawback of being highly charged molecules with high molec-
ular weights, which are disadvantageous properties for potential drugs.
⁎
Corresponding author. Tel.: +86 10 8391 1870; fax: +86 10 8391 1533.
E-mail address: minnali78@126.com (M. Li).
1387-7003/$ – see front matter. Crown Copyright © 2013 Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.inoche.2013.08.016

M. Li et al. / Inorganic Chemistry Communications 36 (2013) 130–132
131
Scheme 1. The synthetic routes of Δ-enantiomers of three new [(bpy)2Ru(dppz)]2+ derivatives. Reaction conditions: 1) pyridine, MeOH, H2O, reflux; 2) disodium (+)-O,O′-dibenzoyl-D-
tartrate; 3) (i) 1,10-phenanthroline-5,6-dione, ethylene glycol:H2O (9:1), 120 °C, (ii) H2O, NH4PF6; 4) boric acid analogues, Pd(PPh3)4, K2CO3, dioxane/H2O (4/1), reflux; 5) NaBH4, CoCl2,
EtOH, reflux; 6) CH3CN, HOAc, reflux. Bpy = 2,2′-bipyridine, dppz = pyrido-[3,2-a:2′,3′-c]phenazine, Ph = phenyl.
of the substituent on the dppz ligand, we designed Ru-BT, which has 2-
benzo[b]thienyl substituents in 10, 13-position respectively on the
dppz ligand, and compared to Ru-T. The complex Ru-BF, which corre-
spondingly has 2-benzo[b]furanyl substituents on the dppz ligand,
was synthesized to explore the influence of van der Waals radius of het-
ero atom on the aryl-substituent or the electron distribution on the
binding properties of ruthenium complexes in contrast with Ru-BT.
As shown in Scheme 1, Δ-enantiomer of each new complex was pre-
pared by the condensation reaction of optically pure Δ-[(bpy)2Ru(pq)]·
2PF6 with an excess of the appropriate 3,6-diaryl substituted benzene-
1,2-diamine under boiling water in CH3CN in the presence of a drop
of acetic acid. The latter 3,6-diaryl substituted benzene-1,2-diamines
were derived from reductive removal of the sulfur of 4,7-diaryl-2,1,3-
benzothiadiazoles by NaBH4 in ethanol with CoCl2 as catalyst. It is noting
that in this work 3,6-diaryl substituted benzene-1,2-diamines is utilized
directly in the next reaction without further purification after evapora-
tion of extraction solvent due to their extreme unstability in air. 4,7-
Position substituted benzothiadiazole derivatives (T, BT, BF) were pre-
pared by Suzuki-coupling reaction of 4,7-dibromo-benzothiadiazole
and the corresponding aryl boronic acid analogues in the mixture of
dioxane and water (4:1) in the presence of Pd(PPh3)4 and K2CO3. The op-
tically pure Δ-[(bpy)2Ru(pq)]·2PF6 was achieved by the reaction of 1,10-
phenanthroline-5,6-dione (pq) and Δ-[(bpy)2Ru(py)2][O,O′-dibenzoyl-
D-tartrate]·12H2O, followed by exchanging the tartrate counterions
with PF−6 according to the method of Ji et al. [18], and the latter complex
was prepared by treating the racemic (bpy)2Ru(py)2Cl2 with disodium
(+)[O,O′-dibenzoyl-D-tartrate], followed by crystallization. The complex
(bpy)2Ru(py)2Cl2 was easily prepared by the reaction of Ru(bpy)2Cl2
and pyridine in methanol under reflux. According to a method same to
the preparation of Δ-enantiomer of each new complex, Λ-enantiomer
of analogues was obtained by replacing Δ-[(bpy)2Ru(pq)]·2PF6 with
Λ-[(bpy)2Ru(pq)]·2PF6, and the latter complex was achieved by using
dibenzoyl-L-tartrate instead of dibenzoyl-D-tartrate. Three new com-
plexes were fully characterised by the 1H NMR, TOF-MS and element
analysis (see supporting information).
of π–π* transitions of the two auxiliary bipyridines while the less in-
tense bands at 245 nm and 450 nm were characteristic of MLCT transi-
tions from the Ru (II) center. The transitions at 315 nm are attributed to
π–π* transitions of diaryl dppz. Obviously, for three new complexes, the
band at 375 nm attributed to π–π* transitions of the dppz ligand were
seen to be a slight red shift in comparison to that of the parent complex
[(bpy)2Ru(dppz)]2+, consequently overlapped with MLCT band. The
similar absorption intensity at 315 nm could be found in Ru-T and
Ru-BT. However, it is markedly lower both in Ru-T and Ru-BT in compar-
ison with Ru-BF. The hypochromicity observed for the 315 nm band in
Ru-T and Ru-BT is maybe due to the effect of aggregation, possibly by
π-stacking of the complex in buffer solution [17].
The CD spectra of the enantiomerically pure complexes Δ-Ru-T and
Λ-Ru-T exhibit the intense band at 294 nm, which is typical of π–π* ex-
citon coupling of the two bipyridines, and the expected MLCT band at
Despite the structural difference among three new complexes, the
shapes of their absorption spectra in buffer solution are substantially
similar (Fig. 1), where the intense band at 286 nm was characteristic
Fig. 1. UV–vis absorption spectra of three new [(bpy)2Ru(dppz)]2+ derivatives (38 μM) in
buffer solution (150 mM NaCl, 1 mM cacodylate, pH 7.0).

132
M. Li et al. / Inorganic Chemistry Communications 36 (2013) 130–132
Fig. 2. CD spectra of the enantiomerically pure [(bpy)2Ru(dppz)]2+ derivatives (35–38 μM) in buffer solution (150 mM NaCl, 1 mM cacodylate, pH 7.0).
400–500 nm (Fig. 2). These similar absorption bands can also be ob-
served in the other two enantiomerically pure analogues. In comparison
to Ru-T, Ru-BT and Ru-BF show broader MLCT bands above 600 nm,
which is in support of the observation in the MLCT band in UV–vis
spectra of the analogues. The small varying intensity at 310–400 nm
was also found due to the structural slight difference among three
complexes.
In conclusion, the enantiomerically pure mononuclear
[(bpy)2Ru(dppz)]2+ derivatives with 10,13-diaryl substituted dppz li-
gands have been synthesized and characterized. Three new complexes
show the substantially similar UV–vis absorption spectra, which are
characteristic for the parent complex [(bpy)2Ru(dppz)]2+, and the sim-
ilar CD spectra could also been found for the enantiomer of analogues.
Further investigations of the interaction kinetics of new complexes
with DNA are in progress, which will provide a new strategy for devel-
opment of DNA binding drugs with slow dissociation kinetics.
Appendix A. Supplementary material
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.inoche.2013.08.016.
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This work was financially supported by Scientific Research
Common Program of Beijing Municipal Commission of Education
(SQKM201210025006), Funding Project for Academic Human Re-
sources Development in Institutions of Higher Learning under the Juris-
diction of Beijing Municipality (PHR201007114) and the Natural
Science Foundation of Capital Medical University in China (2010ZR06).