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

11

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.

12

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

13

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

14

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

15

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

16

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,

17

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

18

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

19

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

20

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.

21

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.

22

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

23

[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

24

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.

25

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

26

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)

27

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.

28

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

31

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

32

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.

34

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.