10 2. LITERATURE SURVEY Ruthenium complexes have attracted much attention as building blocks for new transition metal based anticancer agents. Ruthenium complexes offer a potential role as antitumor agents over platinum(II) complexes and are in currently clinical trials, with the properties of a novel mechanism of action, the prospect of non-cross-resistance 30,31,32 reduced toxicity and a different spectrum of activity. 33,34 In cisplatin-resistance cancer cells, with wide spectrum of anticancer activity Ru complexes exerts antitumor action which is in part due to the ability of ruthenium complexes to mimic the binding of iron to certain biological molecules, exploiting the mechanism that the body has evolved for non-toxic transport of iron is a particularly attractive nature of ruthenium complexes. [35] Ability of ruthenium to mimic iron in binding to certain biological molecules make these complexes well suited for medicinal importance and as an alternative drugs for the platinum anticancer drugs in the treatment of cancer cells resistance to cisplatin and its analogues. There are number of reviews have appeared that summarize the different properties of ruthenium complexes including their unique DNA binding modes and antitumor effects of ruthenium complexes. Several reports concerning mononuclear Ru(II)complexes aiming to provide different medicinal and pharmacological activities. Ruthenium complexes are potential metal-based drugs that show
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2. LITERATURE SURVEY
Ruthenium complexes have attracted much attention as building
blocks for new transition metal based anticancer agents. Ruthenium
complexes offer a potential role as antitumor agents over platinum(II)
complexes and are in currently clinical trials, with the properties of a
novel mechanism of action, the prospect of non-cross-resistance
30,31,32 reduced toxicity and a different spectrum of activity.33,34 In
cisplatin-resistance cancer cells, with wide spectrum of anticancer
activity Ru complexes exerts antitumor action which is in part due to
the ability of ruthenium complexes to mimic the binding of iron to
certain biological molecules, exploiting the mechanism that the body
has evolved for non-toxic transport of iron is a particularly attractive
nature of ruthenium complexes.[35] Ability of ruthenium to mimic iron
in binding to certain biological molecules make these complexes well
suited for medicinal importance and as an alternative drugs for the
platinum anticancer drugs in the treatment of cancer cells resistance
to cisplatin and its analogues. There are number of reviews have
appeared that summarize the different properties of ruthenium
complexes including their unique DNA binding modes and antitumor
effects of ruthenium complexes.
Several reports concerning mononuclear Ru(II)complexes aiming
to provide different medicinal and pharmacological activities.
Ruthenium complexes are potential metal-based drugs that show
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potential cytotoxicity against various human cancer cell lines.
Researchers are focused on the searching for the potential antitumor-
active metal complexes, several ruthenium complexes have been
reported to be as promising as anticancer drug.36
Pieper et al have reported ruthenium complexes like “ruthenium
red”, [(NH3)5Ru-O-(NH3)4Ru-O-Ru(NH3)5]Cl6, cis-[Ru(NH3)4Cl2]Cl and
ruthenium DMSO complexes, like cis-and trans-[RuCl2(DMSO)4],
which have shown in vivo antitumor activity in several murine models
along with the reduction in the formation of metastasis. In particular,
complexes of the general formula trans-[RuL4Cl2], in which L is a N-
heterocycle like imidazole(im) or indazole (ind) which are active in
different antitumor screening methods.37
Ruthenium complexes such as mer-[Ru-(chd-H2)Cl2] (chd=1,2-
cyclohexane diamine tetraacetate), and mer-[Ru-(terpy)Cl3] (terpy=
2,2': 6'.6'' terpyridine) have been reported to be highly antitumor-
active complexes.38,39 Dimethyl sulfoxide (DMSO) complexes of both
Ru(II) and Ru(III) exhibit anticancer activity comparable to cisplatin at
equitoxic dosage in animal models of metastasizing tumor, but with
less severe draw backs and prolongation of survival times in the host.
A small series of ruthenium complexes whose parent compounds are
cis-and trans-[Ru(II)(DMSO)4Cl2](1, 2) constitute one class of DMSO
ruthenium compounds. Anticancer effects of cis- and trans-
[Ru(II)(DMSO)4Cl2] have revealed by comparison of these two.
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Ru
SO(CH3)2
SO(CH3)2
SO(CH3)2
SO(CH3)2
Cl
Cl
Ru
Cl
Cl
SO(CH3)2
SO(CH3)2
SO(CH3)2
SO(CH3)2
(1) (2)
The structure of cis- and trans-[Ru(II)(DMSO)4Cl2] contain two
chlorides in the octahedral form. Observation of the structure cis-
[Ru(II)(DMSO)4Cl2] in which the three DMSO molecules are bonded
with S, in a facial configuration and the fourth is bonded with O.
Where as in trans-[Ru(II)(DMSO)4Cl2] all the DMSOs bonded with S.
These complexes when dissolved in water, the cis isomer immediately
undergoes loss of the O-bonded DMSO ligand whereas the trans
compound rapidly loses two S-bonded DMSO ligands yielding cis-
diaqua species. Both these hydrolyzed isomers then undergo slow
reversible chloride dissociation forming cationic compound. After
finishing this step, the trans compound contains three reactive group
while the cis isomer only two.40 The presence of the three remaining
DMSO ligands in the cis isomer represent a considerable steric
hindrance, which makes the cis aqua species inert relative to the trans
isomer. This difference between these two correlates with a higher
potency of the trans isomer as an anticancer agent.41
The photocytotoxicity and cytotoxicity of cis- and trans-
[Ru(II)(DMSO)4Cl2] complexes were tested in two melanoma cell lines,
human and mouse. Trans isomer was found to be more effective for
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inhibition of cell growth than its cis analogue. However, the
antiproliferative activity of both isomers was significantly increased
after irradiation with UV light in comparison with their activity in the
dark.[42] Interesting results have been also obtained in studies of the
mechanism of antitumor activity of Ru(II)(C6H6)(DMSO)Cl2 complex (3).
This complex exhibits a strong DNA-binding affinity, but binding does
not alter substantially DNA conformation but binding does not alter
substantially strong DNA-binding affinity. On the other hand, it could
completely inhibit DNA relaxation activity of topoisomerase II by
trapping it into a ternary complex with DNA. 43
RuCl
Cl
SO(CH3)2
(3)
Turel et al., have synthesized two new complexes of Ru(III) with
purine base derivatives, [mer-RuCl3(acv)(DMSO)(C2H5OH].(acv=
acyclovir, DMSO=dimethyl sulfoxide) and [trans-RuCl4(guah) (DMSO-
S)]2H202 (guaH=protonated molecule of guanine) both these complexes
were also characterized by various physico-chemical methods in the
solution and in the solid state. Both complexess are only poorly active
on proliferation of tumor cell but showed an interesting pro-adhesive
effect that suggest possible activity on tumor malignancy.44
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Bratsos et al., have reported a series of new Ru(II)-DMSO