Role of Platinum and Ruthenium Complexes as Anticancer Agents
1.7 Heteronuclear Ruthenium(II)-Platinum(II) Polypyridyl Complexes The continuous search for better anticancer drugs has gained interest in The continuous search for better anticancer drugs has gained interest in
heteropolynuclear platinum and ruthenium complexes.34b,180 Since the mechanisms of action of ruthenium and platinum aniticancer complexes are different, it was thought that the combination of the two metals may result into anticancer drugs of improved efficacy. To date, only few heteropolynuclear ruthenium-platinum complexes have been synthesised and reported as potential anticancer agents.113,120,180-181
The first heteronuclear ruthenium-platinum complex reported was [{cis- RuCl2(dmso)3}(H2N(CH2)4NH2){cis-PtCl2(NH3)}] (58) (Figure 1.10) where the two metal
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centres were linked by a long flexible ,-diaminoalkane group.180,182 The compound was found to bind with DNA probably by forming DNA-DNA interstrand cross-link where each metal centre binds to one strand of DNA helix. Another heterometallic Ru(II)-Pt(II) complex having a flexible linker of the form [Cl(tpy)Ru(dtdeg)Ru(tpy)Cl]Cl3 (59) has been reported.120 Reactivity of this complex with DNA using EtG was studied using NMR study. The complex was found to coordinate with EtG via its N7 position.120
Heterometallic Ru(II)-Pt(II) complexes with a short semi-rigid linker, 4’-pyridyl- 2,2’:6’,2”-terpyridine (qpy) has been synthesized and characterized.120 The qpy linking ligand possess two different coordination sites; a tridentate coordination site at the parent terpyridine moiety as well as a monodentate coordination site at the pyridine which is appended at the 4’-position of the terpyridine backbone. Multinuclear Ru(II)- Pt(II) complexes of qpy, [(tpy)Ru(qpy)Pt(en)Cl](NO3)3 (60) and [Cl(en)Pt(qpy)Ru(qpy)Pt(en)Cl](NO3)4 (61) (en = 1,2-ethylenediamine) have been reported. The complexes possess a bis(terpyridyl)-Ru(II) moiety and one or two ethylenediamine centres coordinated to a Pt(II) centre. The complexes were found to react with DNA model base, EtG via the platinum unit which substitutes the labile ligands on the terminal Pt(II) centre(s). Presence of ruthenium was found to increase the water solubility and electrostatic interactions with the DNA base by its high charge.120
Another heterometallic Ru(II)-Pt(II) complex, [(bpy)2Ru(dpb)PtCl2]Cl2 (62) was found to react with DNA at its platinum centre as well as via its planar ligands on the Ru(II) centre.183 Cross- linking interactions of the complex with DNA were found to be higher than that of cisplatin.183 The compounds were also found to have DNA intercalation when different bridging ligands such as 2,3-bis(2-pyridyl)pyrazine and 2,2’- bipyrimidine have been used.
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N N
Pt Cl N
N N
N N N
Ru N
N N
N Pt
Cl N
N N N N N Ru N N
N
Pt Cl
N N
N Ru
N
N N
N
N N
N Pt
Cl Cl N
N Ru N
N
N
O O O N
N N Pt Cl N
3+
3+ 4+
2+
(58) (59)
(62)
(63) (64)
Pt N NH2
Cl NH2
N N N Ru N N
N
N Pt H2N
Cl NH2
4+
(61) Pt
NH2 Cl
Cl H2N
CH3 CH3
Pt S
Cl Cl S S
O
O H3C
H3C H3C
H3C O
NH2(CH2)4
N Pt H2N
Cl NH2 N
N N Ru N N
N
3+
(60)
Figure 1.10 The Ru(II)-Pt(II) with a long and flexible linkers (58) and (59) along with the heterodinuclear Ru(II)-Pt(II) complexes with different linkers.5,113,120,180,172181b
Anions omitted for simplicity.
DNA intercalation of Ru(II)-Pt(II) complexes bridged by back to back planar tridentate ligands such as [(tpy)Ru(tppz)PtPtCl](PF6)3 (63) and [ClPt(tppz)Ru(tppz)PtPtCl](PF6)4
(64) where tppz = 2,3,5,6-tetrakis(2-pyridyl)pyrazine have been reported by Prussin et al.184 The metal complexes (63) and (64) when incubated at different ratios of DNA base pair to metal concentrations at room temperature, results obtained show binding of the complexes to DNA base pairs and the effect was reported to be even greater than the well-known Pt(II) anticancer drug, cisplatin.184 The binding of the complexes with DNA base pairs was also found to be temperature dependent and different from that of cisplatin. This was assumed to be due to the high molecular mass of the complexes and the formal charge of the complexes compared to that of cisplatin.184 Furthermore, photochemical analysis of the complexes showed strong MLCT.185 The planar ligands
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were found to be excellent bridges which enhance the electronic communication between the hetero metal centres.124b,185a Since the complexes are currently under further studies of mechanism of action with DNA184, investigation of their substitution kinetics would bring useful data towards the development of these promising complexes as anticancer drugs.
In the mentioned heterometallic complexes, ruthenium was chosen as the second element180 firstly, due to its antitumour activity186 and secondly, because the octahedral Ru(II) coordination sphere is more sterically demanding compared to that of square planar Pt(II). These properties are thought to improve the kinetic control and the sequence specificity of the types of DNA adducts formed.180 Furthermore, attaching a platinum ion can be useful for imparting the reactivity at the less reactive ruthenium centre in order to facilitate unique cross-linking with specific DNA sequences.180
Heterometallic Ru(II)-Pt(II) complexes are important models for introducing photoinduction of Pt(II) centres with DNA.111g,187 In such complexes, photo reactive light absorbing ruthenium unit is linked with a reactive platinum centre. The molecule can be photoactivated by the light absorbing ruthenium unit which will improve the reactivity of the platinum centre which then coordinates to DNA.120 The positively charged ruthenium centre is thought to increase the solubility of the complexes as well as electrostatic interactions with DNA.120