Role of Platinum and Ruthenium Complexes as Anticancer Agents
1.5 Platinum(II) Polypyridyl Complexes
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cyclohexanediamine rigid linkers ( 27), (28), (29), (30) and (31) have been reported in a kinetic and mechanistic study by Jaganyi et al.14a,14d,14f and van Rudi et al.95 However, their DNA binding affinity and cytotoxic activity have not been studied.
N N N Pt H2O
N N
N Pt OH2
N N N Pt H2O
N N
N Pt OH2
N N
N H2O Pt
N N
N Pt
OH2
N N
N Pt OH2 N
N N Pt H2O N
N N Pt OH2 N
N N Pt H2O
R1, R2, R3 = H (21) R1, R2 = CH3 R3 = H (22) R1, R3 = CH3 R2 H (23)
R1, R2, R3 = H (20) R1 = CH3 R2, R3 = H (24) R1, R2 = CH3 R3 H (25) R1, R3 = CH3 R2 = H (26)
(27) (28) (29)
(30) (31)
N N
Pt H3N H3N H2O
R1
Pt NH3 NH3
OH2 R2
R3 2+
N N
Pt H3N H2O H3N
R1
Pt OH2 NH3
NH3 R2
R3 2+
Figure 1.6 Multinuclear Pt(II) complexes with rigid linkers which are used for kinetic and mechanistic study.14a,14d
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hydroxyethanethiol) and CT DNA, which showed interactions of the compound with DNA with a binding constant of 1.2 ± 0.2 x 106 M-1 at a pH of 6.8 in 0.003 M sodium chloride solution.17d The complex was shown to add between the DNA base pairs where it is bound to every other base-pair space in DNA.99
Lippard and co-workers17d,96a further investigated the intercalative property of a variety of Pt(II) terpyridine complexes of the type [Pt(tpy)X]n+ (for n = 1, X = HOˉ, Cl , HET, Cysteine (Cys) and n = 2, X = aminoethanethiol (AET)). Each of these complexes was found to unwind circular DNA. The observed high binding constant for the AET complex was believed to be due to its high charge (Table 1.1).17d Further investigations reported100 for two complexes, [Pt(tpy)(2-CH3py)]2+ (py = pyridine) and [Pt(tpy)(py)]2+
with similar aromatic surfaces when subjected to DNA binding, showed a higher binding constant for the latter complex. The methyl group on the second position of [Pt(tpy)(2-CH3py)]2+ reduces the stacking surface which causes more destabilization of the resulting complex thereby reducing the binding constant. Thus, it has been established17d structural features such as, the planarity and size of the molecule, aromaticity and surface extension of the π system, the charge and the ability of the group on the fourth coordination centre to form hydrogen bonding with DNA base pairs17d,100 influences the DNA binding ability.
Table 1.1 Binding constants of Pt(II) terpyridine complexes reported.17d,101,102,103 Complex DNA medium Binding constant, K (M-1)
[Pt(tpy)Cl]+ ct-DNA; Tris buffer 3.9 x 105
[Pt(tpy)(HET)]+ ct-DNA; pH 7.5, 0.2 M NaCl 1.2 x 105 [Py(tpy)(AET)]2+ ct-DNA; pH 7.5, 0.2 M NaCl 4.3 x 105 [Pt(tpy)Cys]+ ct-DNA; pH 7.5, 0.2 M NaCl 1.0 x 105 [Pt(tpy)(OH)]+ st-DNA; pH 9.0, 0.5 M EPSS buffer 7 x 104
1.5.2 Substitution of Platinum(II) terpyridine Complexes with Biologically Active Nucleophiles
Apart from non-covalent binding, [Pt(Ytpy)X]n+ (where X = a labile group such as chloride, hydroxide, water or pyridine derivatives and Y = H, Cl, OCH3, CH3 and 2- C5H5N), is also capable of undergoing ligand substitution reactions with biological molecules.17d,104 An example of such a reaction is shown in Scheme 1.2 for the reaction of terpyridine with guanosine. Information obtained from such kinetic studies is
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important for understanding the mechanism of action of platinum anticancer drugs with DNA. (Scheme 1.2).
An equilibrium kinetic study reported by Bugarčić et al.14j,105 on [Pt(tpy)Cl]+ at pH 6, and van Eldik and co-workers14j on [Pt(tpy)(OH2)]2+ at pH of 2.5, with some biologically active nucleophiles, glutathione (GSH), inosine (INO), inosine-5´-monophosphate (5´- IMP) and guanisine-5´-monophosphate(5´-GMP) has shown a high reactivity towards all the selected nucleophiles, particularly 5´-GMP and GSH.105,14j In addition, reactions of Pt(II)terpyridine complexes with other DNA bases such as adenosine and 1- methylcytosine (Hmcyt) were found to form di- and tri-cationic complexes depending on the reaction stoichiometry.17d Further kinetic studies of [Pt(tpy)Cl]+ with other bionucleophiles, viz. histidine (His) and cysteine (Cys) at pH 3 under pseudo first-order conditions showed a higher reactivity for Cys (kobs = 1.3 x 10-2 s-1) compared to His ((kobs = 8.5 x 10-5 s-1),106 which was attributed to the stability of the [Pt(tpy)(His)]+ cation in aqueous medium compared to the Cys coordinated cation.17d
The driving force for such reactions depends on both thermodynamic factors such as the stability of the Pt―N bond formed relative to the Pt―X bond, and kinetic factors such as the rate of replacement of X by the incoming ligand.17d In such instances, investigating the reactions under pseudo conditions can force the reaction to go to completion. Studies reported by Lowe et al.104 support the binding of Pt(II) (tpy) to N7 position of guanosine (32).
(32) N
N Pt N Cl
2
N NH N
N
NH2 O
O O
H
OH OH H H
H H
N
N N
Pt
N NH N
N
NH2 O
O H
OH OH H H
H H
O
Scheme 1.2 Reaction of Pt(II) (tpy) with guanosine (1:1) showing the N7 binding of guanosine with Pt(II) (tpy) (32).17d,104
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1.5.3 Previous Kinetics and Mechanistic Studies on Platinum(II) terpyridine Complexes with Thiourea and Ionic nucleophiles
Pt(II) terpyridine and its analogues are good anticancer probes and have gained a conciderable research interest in the past few decades. To design more effective anticancer Pt(II) drugs, a clear understanding of kinetic and mechanistic substitution behaviour of such complexes is important in order to elucidate the mechanism of action of the drug in the body.107
van Eldik et al.14k investigated the effect of increasing the π-acceptor of pyridine ligands on the substitution kinetics of aqua Pt(II) with tri(N-donor) non-leaving ligands viz.
[Pt(diethylenetriamine)OH2]2+ (aaa), [Pt(2,6-bis-aminomethylpyridine)OH2]2+ (apa), [Pt(N-(pyridyl-2-methyl)-1,2diamino-ethane)OH2]2+ (aap), [Pt(bis(2- pyridylmethyl)amine) OH2]2+ (pap), [Pt(2,2´-bipyridine)(NH3)(OH2)]2+ (app) and [Pt(tpy)OH2]2+ (ppp) (Figure 1.7) with thiourea (TU), dimethylthiourea (DMTU), trimethylthiourea (TMTU). The rate of substitution reactions showed a general increase by a factor of four orders of magnitude simply by adding pyridine rings within the non-leaving chelate ligand of the complexes. The aqua ligands were substituted in the order aaa < apa < aap < pap < app < ppp. The increase in reactivity was attributed to an increased electronic communication within the chelate ligand due to the increase in the π-acceptance of the pyridine rings.14k It is known that increasing the π- backbonding ability of the ligand system around the platinum centre helps to stabilise the five coordinate transition state through back donation of the electron density onto the aromatic system resulting in an increase in the substitution reaction.14k
Jaganyi et al.14b further extended the investigation to include an understanding of how groups that are attached to the terpyridine ligand (ancilary group) affects its capacity to receive electron density from the platinum metal centre and ultimately the reactivity of the metal centre.107-108 For example, when the ancilliary substituent at the 4’-position is an ortho substituted phenyl ring (39), the reactivity of the complexs depended on the electron donating or electron withdrawing capacity of the substituent groups.108 When electron donating groups (as in 39) are attached, the reactivity is smaller than that of Pttpy and vice versa when electron accepting groups (Cl, CF3 as in 40) are attached.
Furthermore, when the ancilliary is a phenyl ring, extension of π-backbonding towards the ancilliary ring is absent.14b They also studied the cis σ-effect108 by replacing one of the cis pyridine ring on the terpyridine with a phenyl ring. Results obtained further
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support previous studies on cis and trans σ-effect of terpyridine type chelate backbone.109,110
N
N Pt N
OH2 2
N H3N Pt N
OH2
2
N
N Pt N
OH2
2 N
N Pt N
OH2
2 N
N Pt N
OH2
N
N Pt N
OH2 2
2
aaa apa aap
pap
app
ppp
N
N Pt N
Cl L
L L
N
N Pt N
Cl R
L = turt-butyl
R = H, CH3, CF3, Cl
(34) (35) (36)
(37) (38) (39)
(40) (33)
Figure 1.7 Pt(II) complexes studied by van Eldik et al.14k (33-38). Pt(II)terpyridine complexes studied by Jaganyi et al. (38,39) and (40).86-87,90-91
Additionally, the type of substituents on the ortho position of the ancilliary phenyl ring influences the reactivity either by enhancing or reducing the π-backbonding ability of the terpyridine moiety. The presence of electron withdrawing groups such as CF3 group on the 4’-position of terpyridine (40, when R = CF3), the substitution reactivity was moderately enhanced due to the electron withdrawal property of terpyridine which increases the π-backbonding ability of the chelated terpyridine ring. The opposite was observed for the electron donating CH3 group present on the ortho position of the 4’- phenyl ring, which reduces the π-backbonding ability of the terpyridine system.
1.6 Therapeutic Ruthenium Complexes: A Possible Alternative to