2. LITERATURE SURVEY - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/2273/12/12_chapter...
Transcript of 2. LITERATURE SURVEY - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/2273/12/12_chapter...
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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
complexes containing dicarboxylate ligands (dicarb), namely, malonate
(mal), methylmalonate (mmal), dimethyl-malonate (dmmal), succinate
(suc), and oxalate (ox), and structurally characterized. These
complexes were prepared from the known Ru(II)-Cl-DMSO anticancer
complexes cis, fac-[RuCl2(DMSO-S)3(DMSO-O)] and trans-
[RuCl2(DMSO-S)4] and from the chloride-free precursor fac-[Ru(DMSO-
S)3(DMSO-O)3] [CF3SO3]2, with the aim of assessing how the nature of
the anionic ligands effects the biological activity of these species. All
these complexes were thoroughly characterized by IR spectroscopy in
the solid state, 1–D (1H and 13C) and 2-D (H-H- COSY and HMQC)
NMR spectroscopy in solution. The properties of selected complexes in
aqueous solution were investigated by 1H-NMR spectroscopy. 45
Pongratz et al., have reported the heterocyclic complexes of
ruthenium(III) constitute a relatively new group of potential anticancer
compounds. The general formula for structure of this class is
(HB)[Ru(III)B2Cl4], where B stands for a heterocyclic base, such as
imidazole (Im) or indazole (Ind) (4 and 5 respectively). These
compounds exhibit a high antitumor activity in the autochthonous
colorectal carcinoma model of rats, a model that stimulates the colon
cancer of human very well. The complex (Hind)[Ru(III) Cl4(Ind)2] is
highly active against a colorectal tumor cells both invivo and
invitro46,47 and is completely devoid of side effects and drug incresed
lethality at therapeutically relevant doses.48 It is concluded that
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therapeutic index is better than that (Him)[Ru(III)Cl4(Im)2]. The
complex (Hind)[Ru(III)Cl4(Ind)2] has been reported that efficiently taken
up into the cells probably via interaction with transferrin.49
Ru
N
NH NHNH
NNH
Cl
Cl
Cl
Cl
+
_
NH
N
Ru
N
Cl
Cl
Cl
Cl
NH
NH
NH+
_
(4) (5)
O
N
H
Ru
O
OH
OH
N
(6)
Jayaraju et al.,50 have showed that a salicylaldoxime complex of
cobalt (CoSAL) poisons the activity of topo II by cleavage complex
formation. Molecular analysis implicated the oxime group of the
salicylaldoxime ligands as the topo II interacting moieties in the
molecule. In a similar study, they found that replacement of the cobalt
catalyst with a ruthenium atom (RuSAL), (6) loss of the topo II
poisoning ability. Comparison of these structures no change in the
structure of the molecule by replacement of the central metal atom in
CoSAL or RuSAL was not shown to interact with topo II. From the
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above observations were surprising because the salicylaldoxime
ligands in both compounds are similar, but topo II poisoning were
shown by only those attached to the cobalt atom.
Keppler et al.,51 have reported the anticancer activity of some
ruthenium complexes. They concluded that RuInd was reported to be
more potent anticancer agent compared to RuIm. Both RuIm and
RuInd possess significant antitumor activity against the MAC 15A
colon tumor, Walker 256 carcinosarcoma, solid sarcoma 180 and B16
melanoma. These comlpexes were more superior in their action
against an autochthonous chemically induced colorectal
adenocarcinoma in rats comparison with 5-fluorouracil, which is an
established cytostatic drug against human gastrointestinal
carcinomas.
Fruhauf and Zeller52 (1991) reported that RuInd brings about
antitumor activity by interacting with DNA and inhibiting DNA
synthesis. (HInd)[Ru(III)Cl4(Ind)2] interacts with DNA and forms cross-
links or increases strand breaks.
Kopitza et al53 have concluded that these complexes inducing
formation of H2O2 and DNA-strand breaks in colorectal tumor cells in
a dose dependent way. Na[tras RuCl4DMSO(Im)] (7) ( NAMI; where Im
is imidazole), a ruthenium(III) complex has shown encouraging anti-
tumor and anti-metastatic properties. The imidazolium salt of NAMI,
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i.e. NAMI-A {(H2Im)[trans-Ru(DMSO)Cl4(Im)]} (8) was synthesized with
the aim of improving the solid state stability of the complex.
Rademaker et al., reported that NAMI-A showing a high efficiency
in vivo against lung metastasis and is currently on clinical trial as an
antimetastatic drug.54
N
N
RuCl
Cl
Cl
Cl
SCH
3
CH3
O
Na+
-
H
+
N
N
RuCl
Cl
Cl
Cl
SCH
3
CH3
O
-
NH+
NH
H
+
(7) (8)
Bergamo et al., have concluded that ruthenium complexes with
oxidation state 2+ or 3+ display anticancer activity, especially against
metastatic cancers. In which Ru(III) complex trans-[Na]
[Ru(im)(dmso)Cl4] (7) (Im=imidazole) and its analogue, trans-[ImH]
[Ru(im) (dmso) Cl4], (8) are currently in clinical trial.55
Ruthenium(III) and Ruthenium(II) complexes are presently an
object of great attention in the field of medicinal chemistry, as
anticancer agents with selective antimetastatic properties and low
systemic toxicity. Sava et al., have reported the compounds NAMI (9)
and NAMI-A (10), each having imidazolium as cation, a Ru-terpy
compound (11) and a very active compound (12) of the -isomer of a
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Ru-azpy compound (azpy= 2-phenyl azo pyridine). Out of these, NAMI-
A has been in clinical trials since 2000.56
NH
N
Cl
Cl
Cl
Cl
NH
RU
N
NH
N
Cl
Cl
Cl
ClS
Me
MeO
RU
(9) (10)
N
N
N
N
NN
N
RuCl
Cl
+
+
Cl
Cl
Ru
Cl
N
N
N
(11) (12)
Vilaplana et al57, have reported antitumor properties of
Ruthenium(II) complexes with other derivatives of ethylene diamine.
Grguric-Sipca et al58, have reported a new potential antitumor
soluble drug K[Ru(eddp)Cl2].3H2O, (eddp=ethylene diamine-N,N'-di-3-
propionate). Cytotoxic activity of this complexes against several
human cancer cell lines evidenced that K[Ru(eddp)Cl2] complex had a
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remarkable and selective antiproliferative effect against the cervix
carcinoma, colon adenocarcinoma HT-29, and HeLa.
Tysoe et al28., have showed the tris chelates of the ruthenium
with bidentate ligands show intercalate properties with the DNA and
bind to Fe(III) sites of the proteins lactoferin and transferrin[29] is
thought to be responsible for the delivery of Ru(III) to cancer cells
where it is taken up via receptor mediated endocytosis.
Aird re et al59., have reported thirteen novel ruthenium(II)
organometallic arene complexes. They reported the in vitro and in vivo
anticancer activity of these complexes. IC50 values was obtained (0.5
to > 100M) in A2780 parental cells. Out of thirteen ruthenium
complexes none of the six active ruthenium(II) complexes were cross-
resistant in the A2780 cis cell line, demonstrated to be 10-fold
resistant to cisplatin/carboplatin.
Alessio et al.,60 have established that the rate of loss of DMSO
from NAMI-A type complexes in aqueous solutions are inversely
related to the nitrogen ligand basicity. From this consideration with
the aim of increasing the stability of the ruthenium complexes in
solution, so synthesized new NAMI-A type complexes bearing a weakly
basic heterocyclic nitrogen ligand coordinated to DMSO by trans.
Depending on the synthetic procedure, thiazole complex (RuTI) (13)
the pyrazine complex could be obtained either as pyrazinium salt,
RuPYa, (14) or as Zwitterion, RuPYb., (15). They reported that in slightly
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acidic solution the new prepared ruthenium complexes are more
stable than NAMI-A, owing to a lower loss of DMSO.
S
N
Ru
SOMe2
Cl
Cl
Cl
Cl
S
NH+
-
N
N
Ru
SOMe2
Cl
Cl
Cl
Cl
N
NH+
-
(13) (14)
NH+
N
Ru
SOMe2
Cl
Cl
Cl
Cl
-
(15)
Pluim et al61., have reported organic ruthenium anticancer drug
NAMI-A as cytotoxicity and their binding studies in four different
human cancer cell lines.
Kaufhold et al62., have synthesized ruthenium complexes bearing
benzannulated and saturated NH, NH-stabilized N-heterocyclic
carbene ligands. In this they reported reaction of [RuCl2(p-cymene)]2
with 2-azido ethyl isocyanide.
Murakami et al63., have reported Ruthenium complexes with tris
(pyridyl methyl) amine and their application to catalytic alkane
oxidation.
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Song et al64., have reported that certain ruthenium complexes
and their applications in dye sensitized solar cells.
Chandima et al65., have synthesized the new Ru(II) chloroquine
complexes [Ru(n6-p-cymene)(CQ)(en)][PF6]2 en= ethylene diamine, &
[Ru(n6-p-cymene)(n6-CQDP)][BF4]2CQDP = chloroquinediphosphate
showing antimalarial and antitumor activity.
Sengupta et al66., have reported that some of the Ruthenium(II)
complexes of thiosemicarbazones of pyridine 2-aldehyde, thiophene 2-
aldehydes as biological activity.
Scolaro et al67., have reported that antitumor activity of the
organometallic ruthenium-II arene complexes, RuCl2 (n6-arene) (PTA),
(arene= p-cymene, toluene, benzene, 1-ethyl benzene, 2,3-dimethyl
imidazolium tetrafluoroborate, ethylbenzoate, hexamethyl benzene,
PTA= 1,3,5-triaza-7-phosphadamantene).
Das et al68., have synthesized certain half sandwich ruthenium(II)
complexes with strong hydrogen bond acceptor ligands. They reported
the cytotoxic activity of these complexes with their mechanism of
action.
Sahavisit et al69., have synthesized and characterized by spectral
studies of some the Ru(II) complexes bearing bidentate ligands like 5-
chloro-2-(phenylazo) pyridine, 2-(phenylazo) pyridine.
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Sipka et al70., have reported Ru(II) arene complexes with
functionalized pyridines. The complexes revealed low antiproliferative
activity in 6 investigated tumor cell lines. (HeLa, B16, FemX, MDA-
MB-361, MDA-MB-453 & LS-174).
Pakalnis et al71., have synthesized Ru(II) complexes bearing
pyridyl benzimidazole derivatives and characterized.
Mishra et al72., have reported dinuclear Ru(II) complex having
extended conjugation with in the bridging ligand was prepared by
coupling of the Ru(II) polypyridyl complex having a benzoyl
substituted phenazine unit with diamine anthraquinone in one step,
in which emission from the excited Ru(II) center was efficiently
quenched through the anthraquinone unit.
Kratz et al73., have reported the binding properties of the two
Ru(III)complexes. They concluded that the two ruthenium(III)
complexes do not behave as iron(III) complexes, e.g. Fe(EDTA) or
Fe(nitrilotriacetate), which lose their respective ligands when binding
apotransferin, but the N- hetrocycles remain attached to the metal in
the protein bound species.
Grover et al74., have synthesized various polypyridyl ruthenium
complexes. They investigated DNA binding properties and cleavage
properties of all the ruthenium complexes.
Novakova et al39., have repoted the cytotoxicity of chloro-
polypyridyl ruthenium complexes of structural formulas
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[Ru(II)Cl(bpy)(terpy)]Cl, cis- [Ru(II)(bpy)2Cl2] and mer-[Ru(II)Cl3(terpy)]
(16) (bpy = 2,2'-bipyridyl, terpy = 2,2':6',2''-terpyridine) and have been
demonstrated in murine and human cancer cell lines. Out of these
complexes mer-[Ru(II)Cl3(terpy)] exhibits a remarkably higher
cytotoxicity than the other complexes. Moreover, investigations of
antitumor activity (studied on murine lymphosarcoma LS/BL ascitic
tumor) have revealed the highest efficiency for mer-[Ru(II)Cl3(terpy)].
N
N
N
Ru
ClCl
Cl
(16)
Hotze et al75., have synthesized the three isomeric
dichlororuthenium(II) complexes namely -,-,and -[Ru(II)(azpy)2Cl2]
(azpy = 2-phenylazopyridine). All the complexes were investigated for
cytotoxic studies against series of tumor cell lines. The complex -
Ru(II)(azpy)2Cl2] exhibited a very high cytotoxicity (markedly higher
than cisplatin), which stands in contrast to the much lower
cytotoxicity of the trans dichloro complex -[Ru(II)(azpy)2Cl2] and the
cis-dichloro isomer -[Ru(II)(azpy)2Cl2]. The binding of the complex -
[Ru(II)(azpy)2Cl2] to monomeric 9-ethylguanine and guanosine has
been studied and compared with previously obtained results for the
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binding of these monomers to the bis (bipyridyl) Ru(II) complex.
Tris(ligand)complexes [RuL3](PF6)2 (L = 2-phenylazopyridine or
o-tolylazopyridine) and mixed ligand [Ru(L')2L''](PF6)2 (L' and L'' are
2-phenylazopyridine or bpy) have been synthesized, structurally
characterized and investigated for cytotoxic activity.
Cheng et al76., have synthesized a series of monochloro-
ruthenium complexes, [Ru(II)(terpy)(NN)Cl]+ (NN = bidentate nitrogen
ligand), containing different electron-donating groups. DNA binding
and formation of Ru–DNA adducts were confirmed by gel mobility shift
assay. The preferential DNA binding sites of [Ru(II)(terpy)
(tmephen)Cl]+(tmephen= tetramethylphenanthroline) were purine
residues. Surprisingly, [Ru(II)(terpy)(tmephen) Cl]+ inhibited bacterial
cell growth (wild type E. coli) at less concentrations than cis-
[Ru(II)(bpy)2Cl2]. It was suggested on the basis of these results that
these ruthenium complexes modified with electron-rich groups may
represent a new class of anticancer ruthenium drugs. The interactions
of a metal complex [Ru(II)(phen)2 PMIP]2+ {phen = 1,10-phenanthroline,
PMIP = 2-(4-methylphenyl) imidazo[4,5-f]1,10-phenanthroline} (17)
with yeast transfer RNA and calf thymus DNA have been
investigated.77 Binding modes of these Ru(II) polypyridyl complex to
both nucleic acids involve intercalation.
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NH
NN
N
N
N
Ru
N
N
2+
(17)
Spencer et al78., have reported the ruthenium complexes bearing
4,4'-disubstituted 2,2'-bipyridine ligands. For a series of [Ru(X2bpy)3]2+
complexes, the lowest Ru(III/II) potential was observed with the ligand
4,4'-bis(diethylamino)-2,2'-bipyridine (18).
NN
XX
(18) X= N(CH2CH3)2
Certain ruthenium complexes exist as chiral molecule capable of
enantioselective recognition of DNA. Thus, DNA binding and cleavage
properties of various polypyridyl ruthenium compounds have been
intensively investigated since they have been proposed as possibly
useful probes of DNA conformation (Barton et al 79., 1986; Erikson et
al80., 1994; Grover et al81., 1992; Satyanarayana et al82., 1993) or DNA
cleavage agents (Grover et al74., 1994; Gupta et al83., 1993. The
analogues of these ruthenium complexes containing, besides
polypyridyl ligands, chloro or aqua groups have been also prepared
and were found to bind DNA covalently in cell-free media. The chloro
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or aqua ligands in these complexes represent leaving ligands in
contrast to the kinetically more stable pyridyl groups.[61]
N
N
N
Ru Cl
Cl
Cl
mer-[Ru(terpy)Cl3]
(19)
The compound mer-[Ru(terpy)Cl3] [19] Terpy = 2,2':6',2''-terpyridine
shows a significant cytotoxicity in both human and murine tumor cell
lines and antitumor activity in a standard tumor screen. In contrast
[Ru(terpy)(bpy)Cl]Cl (20) or both isomers of cis-[Ru(bpy)2Cl2] (21, 22)
terpy=2,2':6',2''-terpyridine, bpy=2,2'-bipyridyl, i.e. the complexes with
only one or two leaving chloride ligands, respectively, show markedly
lower cytotoxic activities in the same tumor models.
N
N
N
RuN
NCl
N
N
RuN
NCl
Cl
[Ru(terpy)(bpy)Cl] cis-[Ru(bpy)2Cl2]
(20) (21)
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N
N
Ru N
N
ClCl
cis-[Ru(bpy)2Cl2]
(22)
Morris et al84., have synthesized the organometallic ruthenium(II)
complexes with arene ligands. They reported the monodentate
ruthenium (II) arene complexes of the type [(η6-arene)Ru(II)(en)Cl][PF6]
(en = ethylenediamine). They concluded that all the complexes were
inhibiting the cancer cell growth.
Wang et al85., have synthesized ethylene diamine Ru(II) arene
complexes in which arene=biphenyl (23), dihydroanthracene,
tetrahydroanthracene (24), p-cymene (25), or benzene, bind
preferentially to guanine residues in natural double-helical DNA. DNA
may be a favored reaction site for these ruthenium anticancer
complexes since a recent study demonstrates that the presence of
cytochrome c or l-histidine had little effect on the course of the reaction
with the short DNA fragment.
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Ru
NH2
NHCl2
+
Ru
NH2
NHCl2
+
(23) (24)
Ru
NH2
NHCl2
+
(25)
Novakova et al86., have reported the two Ru(II) arene complexes
bearing the tetrahydro-anthracene or p-cymene ligand. They examined
that these two complexes in two tumor cell lines HT29 and A2780.
Abraha et al87., have reported Ru(II) complexes of the[η6-
arene)Ru-(XY)Cl]Z where XY is an N,N-(diamine), N,O-(e.g. amino
acidate), or O,O- (e.g.,β-diketonate) chelating ligand, the arene ranges
from benzene derivatives to fused polycyclic hydrocarbon, and Z is
usually PF6. They concluded that some of these complexes most active
toward A2780 human ovarian cancer cells contained XY =
ethylenediamine (en) and extended polycyclic arenes. Complexes with
polar substitutes on the arene or XY = bipyridyl derivatives exhibited
reduced activity.
29
Brabec et al88., have reported certain polynuclear metal based
complexes represent a novel class of antitumor agents.
Messori et al89, have studied the reaction of Na [trans-
RuCl4(DMSO)(Im)] NAMI and ImH[trans-RuCl4(Im)] ICR, complexes
with BSA (bovine serum albumin) by various physico-chemical
techniques. They have shown that NAMI, following chloride hydrolysis,
binds to BSA tightly.
Messori et al90, have reported the effect of RAP and NAMI on
thermal denaturation profiles of calf thymus DNA. They have shown
that, both the complexes slightly stabilized the CT DNA in the
concentration range of 0.01>r<0.1.
Mazumder et al91, have prepared some Ruthenium complexes and
studied for their antitumor activity.
Barea et al92, have investigated the molecular interactions in
isolated mammalian nuclei of three Ru complexes. i.e., Na[trans-
RuCl4(DMSO)(Imidazole)]NAMI, Na[trans-RuCl4 (TMSO)(Isoquinoline)]
(TEQU) and Na[trans-RuCl4(DMSO)(Oxazole)] NAOX. Which are
putative antineoplastic chemotherapeutic agents effective in reducing
metastatic tumors in vivo, have been investigated and compared with
the well-known antitumor drug cisplatin.
30
Keppler et al93, have compared the nephrotoxic effect of antitu
mor active Pt(CPL,KP734,KP735) and Ru(KP418, KP1019, KP6 92)
complexes in rats.
Keppler et al94, have studied the mode of action for the following
two complexes trans-HIm[RuCl4(Im)2] and trans-HInd[RuCl4(Ind)2].
These complexes show promising antitumor activity in different tumor
models, especially colon carcinomas. They have studied the mode of
action for these complexes by the aquation chemical as well as the
reactions with serum proteins and polynucleotides have been
investigated. They bind to polynucleotides showing selectivity in their
binding towards poly (dG)Xpoly (dc) and poly (dA)Xpoly (dT).
Sava et al95, have reported ImH[trans-(Im)(DMSO)Cl4Ru] NAMI-A
and Na[trans-RuCl4(DMSO)Im] NAMI for the antimetastasis effects in
models of solid metastasizing tumors of the mouse examined. Their
study shows that NAMI-A behaves similar to the NAMI on several
parameters.
Keppler et al96, have concluded two of six newly synthesized
ruthenium complexes possess anti-proliferative activity against a
panel of human colon carcinoma cell lines. The most effective
compounds are trans-IndH[Cl4(2H-Ind)Ru] and trans--IndH[Cl4(1H-
Ind)Ru].
Van Vliet et al97, shown that [Ru(terpy)Cl3] forms interstrand
cross links in DNA and binds to guanine derivatives in trans
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configuration. The above complex was active as a cytostatic in L1210
leukemia cells with an activity in between cisplatin and carboplatin.
Keppler et al98, have studied the efficacy of (ImH)Ru(Im)2Cl4],
(BzImH)2[Ru(BzIm)Cl5] and (InH)Ru(Ind)2Cl4] complexes against
chemically induced autochronous colorectal carcinoma in rats.
Morris et al99, have shown that, inhibition of cancer cell growth
by ruthenium(II) arene complexes.
Dembek et al100, have reported the polyhaloaromatic ruthenium
complexes. Novel ruthenium arene complexes could react with
phenoxides or thiophenoxides to form polyfunctional ruthenium
complexes. Finally they concluded that these complexes were useful
as crosslinking agents in polymerizations.
Gossens et al101, performed in vacuo density functional theory
(DFT) calculations, classical MD, and mixed QM/MM Carparrinello
MD explicit solvent simulations to rationalize the binding mode of two
series of anticancer ruthenium(II)- arene complexes to double-
stranded DNA.
Chen et al102, have investigated the recognition of nucleic acid
derivatives by organometallic ruthenium(II) arene anticancer
complexes of the type (6-arene) Ru(II)(en)X] where en= ethylene
diamine, arene=biphenyl, tetrahydroanthracene, dihydroanthracene
,p-cymene (Cym) or benzene (Ben), X= Cl- or H2O using NMR
spectroscopy. For mononucleosides, (6-Bip) Ru(en)]2+ bound only to
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N7 of guanosine, to N7 and N1 of inosine, and to N3 of thymidine.
Binding to N3 of cytidine was weak, and almost no binding to
adenosine was observed.
Fernandez et al103, reported that the chelating ligand XY in Ru(II)
anticancer complexes of the type [Ru (6-arene) (XY)Cl]n+ had a major
influence on the rate and extent of aquation, the pKa of the aqua
adduct, and the rate and selectivity of binding to nucleobases.
Mazumder et al., [104] have reported Anticancer and Antibacterial
activity of the type [Ru(R)2(L)]2+ (R=1,10 phenanthroline/2,2'-bipyridine
and L= N-methyl isatin–3-thiosemicarbazone, isatin-3-(4-cl-phenyl
thiosemicarbazone acetazolamide and 4-substituted thiosemi-
carbazides etc.
Mazumder et al., [105] have reported Antineoplastic and
Antibacterial activity of the type [Ru(R)2(L)]2+ (R=1,10
phenanthroline/2,2’-bipyridine and L= 7-iodo-8-hydroxy quinoline 5-
sulphonic acid, 3-hydroxy coumarin etc. They concluded that
treatment with these complexes prolonged the life span of EAC
bearing mice as well as decreased their tumor volume and viable
ascitic cell count. Some of the complexes exhibited mild to moderate
antibacterial activity.
Mazumder et al106, have reported [Ru(M)2(U)]2+ Where M=2,2'-
bipyridine, 1,10-phenanthroline and U=thiopicolinanilide, 2-phenyl-
azo-imidazole and their pharmacological activities. They tested all the
33
complexes towards in vivo anticancer activity against a transplantable
murine tumor cell line, Ehrlich’s ascitic carcinoma (EAC) and in vitro
antibacterial activity against Gram positive and Gram-negative
microorganisms. They concluded that these complexes increase the
life span of the tumor hosts by 19-52%, and decrease tumor volume
and viable ascitic cell count. They reported that antibacterial activity
of the certain complexes significant against microorganisms like Vibrio
cholera 865, Staphylococcus aureus 6571, and Shigella flexneri as
compared to that of standard drug chloramphenicol.
Rathinasamy et al107, have reported ruthenium(II) complexes
containing 1-thiocarbamoyl-3,5-diphenyl-2-pyrazoline, 2-(3,5-
diphenyl-4,5-dihydropyrazol-1-yl)-4-phenylthiazole, 2-hydroxy phenyl
benzimidazoles and benzoin thiosemicarbazone and their anticancer
activities. They reported that all these complexes increased the life
span of the EAC-bearing mice, decreased their tumor volume and
viable ascitic cell count as well as improved Hb, RBC, WBC counts.
Ruthenium complexes bearing 2-hydroxy-1-naphthaldehyde
thiosemicarbazone as a ligand have been studied for their antifungal
and antimicrobial activities.
Sulu et al108, have reported the ruthenium complexes for in vitro
antifungal activity with a range of values, between 16 and 250
g/ml.
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Reedijl et al109, have reported water soluble complexes of the type
-[Ru(azpy)2(L)] (azpy=2-phenylazopyridine and L=1,1-cyclobutane
dicarboxylic acid, oxalic acid and malonic acid) as cytotoxic against
A2780 human ovarian carcinoma.
Anticancer and cytotoxic activites of the type [Ru(S)2(K)]2+ (S=1,10
phenanthroline/2,2'-bipyridine and K= isatin thio semicarbazone, 2-
{3-chloro-4-fluoro-phenyl imino] methyl}phenol etc., are reported110.
They tested all the complexes towards in vivo anticancer activity
against a transplantable murine tumor cell line, Ehrlich’s ascitic
carcinoma (EAC) and in vitro cytotoxic activity against a human cancer
cell line Molt 4/C8, CEM, and murine tumor cell line L1210. They
concluded that these complexes prolonged the life span of mice
bearing EAC tumor by 10-43%, in vitro evaluation of these complexes
revealed cytotoxic activity from 0.24 to 27 M against Molt 4/C8, 0.27
to 48 M against CEM, and 0.94 to 248 M against L1210.
In view of these above facts, it was thought worthwhile to
synthesize some mononuclear Ru(II) complexes bearing N, S, and
oxygen heteroatoms.
The present thesis deals with the synthesis, characterization and
in vitro cytotoxic activities of Ru(II) complexes.