Role of Platinum and Ruthenium Complexes as Anticancer Agents
1.4 Current Findings on Anticancer Platinum(II) Drugs
Current research on anticancer drugs focuses on the synthesis of structurally different complexes of cisplatin which can exhibit effective antitumour activity with less side effects and tumour resistance. Thus, a number of active mono- and multi-nuclear Pt(II) and other transition metal complexes have been discovered with various structural modifications. This includes complexes with trans configuration, non- H-amine neutral ligands of homometallic and heterometallic supramolecular complexes.23 However, focus here will be only on multinuclear platinum complexes.
1.4.1 Multinuclear Platinum(II) Complexes
Multinuclear platinum complexes contain two or more platinum atoms linked together by a bridging linker. The new approach of designing Pt(II) anticancer drugs allowed the synthesis of various multinuclear Pt(II) compounds having different binding modes with DNA. The complexes vary from cis to trans and from bifunctional to polyfunctional, with varying flexible linkers71 as well as rigid bridges72 (Figure 1.4). Mechanistically, these complexes are expected to interact with DNA in a unique way. Results obtained showed some of these complexes display a very good antitumour activity where some complexes overcome the cisplatin resistance.
1.4.2 Polynuclear Platinum(II) Complexes with Flexible Linkers
The first reported multinuclear platinum complexes were based on cisplatin like (2,2- cis,cis) (6)73 and transplatin like (2,2-trans,trans) (7)73 terminal structures linked by flexible alkyldiamine bridging groups of variable lengths.73-74 The complexes were bifunctional at each metal centre. The complexes were found to cross-link with DNA upon reacting. When tested for anticancer activity, the 2,2-cis,cis complex was reported to be active in cells resistant to cisplatin. Furthermore, DNA binding functions of their monofunctional complexes showed that DNA 1,1/t,t complex cross-links with DNA more efficiently than 2,2/cis,cis complex.75 Furthermore, for the straight chain enjoined
10
complexes, it was reported that 1,6-hexanediamine (n = 6 CH2) was ideal for their optimum activity.73-74,76
However, the most promising within this new class of anticancer compounds is the trinuclear complex, [{trans-PtCl(NH3)2}2{μ-trans-Pt(NH3)2(H2N(CH2)6NH2)2}]4+
(1,0,1/t,t,t), or BBR3464. This complex was found to exhibit cytotoxicity at ten to thousand times lower doze limits77 than cisplatin and has successfully passed through the phase II clinical trials and is currently undergoing some other clinical trials.78 The complex was found to be a very potent cytotoxic agent and is effective against melanoma, pancreatic cancer, lung cancer27c,72,75 and has less neuro and nephro toxicity and less side effects such as nausea and vomiting. This compound can monofunctionally bind to DNA to form long-range interstrand and intrastrand DNA cross-links.72,79 It has a higher cellular uptake due to its high effective positive charge and no cross-resistance to cisplatin resistance cells.27c The cationic inert tetraamine platinum linker enhances water solubility and high DNA affinity.
Meanwhile, a number of other linking ligands have also been used to develop related dinuclear platinum complexes.80 The dinuclear Pt(II) complex, (11) ([ClPt(dtdeg)PtCl]
(where dtdeg = bis[4’-(2,2’:6’,2”-tpyridyl)]-diethyleneglycolether)), was synthesized and characterized.81 DNA interaction study using calf thymas (CT) DNA as a substrate showed a very high activity against all the cancer cell-lines tested, in some cases with a better activity than the well know anticancer drug, cisplatin.81
n = 2 - 6 (11) (10)
H3N Pt Cl
NH2
NH3
(CH2)6 NH2 Pt H3N
NH3
NH2 (CH2)6 NH2 Pt H3N
NH3 Cl 4 Cl
Pt Cl
NH3
NH2 (CH2) NH2 Pt H3N
Cl Cl
(6)
H3N Pt Cl
Cl
NH2 (CH2) NH2 Pt Cl
Cl NH3
(7)
H3N Pt Cl
NH3
NH2 (CH2) NH2 Pt H3N
Cl NH3
(8)
2
n n n
N N
N Pt
Cl O O O N
N N Pt Cl
Cl Pt H3N
NH3
NH2 (CH2) NH2 Pt H3N
NH3 Cl
(9)
2
n
BBR3464 2
Figure 1.4 Some polynuclear Pt(II) complexes which have shown potential anticancer activity.75,78-79,81-82
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1.4.3 Polynuclear Platinum(II) Complexes with Rigid Linkers
A number of other multinuclear platinum complexes, with rigid bridging linkers which include; 4,4’-dipyridyl(sulfide or selenide),83 4,4’-dipyrazolylmethane,84 mesitylene,85 phenyldiamine, azines,14a,25a azoles29b,86 and hydrazines87 have been synthesized and tested for cytotoxicity.
A rigid bridged dinuclear platinum complexe (12) (Figure 1.5) with square planar geometries has been reported by linking two cisplatin like platinum centres through 4,4’-dipyrazolylmethane (dpzm) ligand.84b,c Another dinuclear transplatin like platinum complex, [{trans-Pt(NH3)2Cl}2(μ-dpzm)]Cl2 (13) along with complex (12) were found to have high levels of DNA intrastand cross-linking which was thought to be due to the rigidity of the linker especially, the bifunctional complex, (13) was found to bind preferentially with adenine residues.88 Furthermore, since selenium and sulphur compounds are known to have chemoprotective activity, the dinuclear complexes bridged by either 4,4’-dipyridylselenide or sulfur89 (14a) and (14b) were found to diminish the known toxic side effects of anticancer drugs.90
A series of short pyrazole and hydroxo bridged dinuclear platinum complexes (Figure 1.5) were syntheszed (15a) and (15b) and expected to form 1,2-intrastand adducts without major distortions of the DNA.29b In these complexes the hydroxo group was incorporated both as a linker as well as a leaving group. From the crystal structure obtained for [{cis-Pt(9-EtG2}2(µ-OH)(µ-pyrazolate)](NO3)2, (where EtG = 9- ethylguinine which is a model nucleobase)86a it was reported that the average distance between the platinum atoms is comparable with the distance separating a normal sequential nucleobase in a B- type DNA strand to form stable DNA adducts. The rate of reaction of these complexes with DNA was found to be relatively slower for the first step.91 However, the rate of second step, once the five membered ring is opened, was found to be faster.91
In a related effort, Wheat et al.84a reported an extension of the work on complex (12) to yield a trinuclear Pt(II) complex (19). The dpzm moiety offers moderate rigidity due to the incorporation of the CH2 spacers in the linker. The complex shows anticancer activity in the murine leukaemia cell line L1210.84a This complex is a structural analogue of the well known trinuclear anticancer complex, BBR3464.
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An interesting design of another trinuclear Pt(II) complex with moderate rigidity comes from the mesitylene ligand with three terminus Pt(II) centres linked by three N,N′- bis(2-pyridylmethyl)amine (20).85 This complex shows promising cytotoxicity in human and mouse tumour cells including those which are cisplatin resistant.92 Molecular pharmacology studies on the underlying mechanisms of its antitumour effects revealed that the complex has a unique DNA binding mode thereby forming trifunctional intrastrand DNA adducts.93 All three Pt(II) centres of the complex were found to coordinate to DNA base pairs leading to broad conformational modifications.92
N H
N
NH N Pt
H3N NH3 Cl
Pt NH3 H3N Cl
N H
N
NH N N
H N
NH N Pt
Cl Cl
Pt Cl
Cl
Pt N Cl NH3
H3N X N Pt
Cl NH3
NH3
N N Pt Pt
NH3 NH3 O
H3N H3N
H R
N N
Pt Pt
Cl H3N H3N
NH3
NH3 Cl
N N
Pt NH3
NH3 Cl Pt
H3N
H3N Cl
N N Pt
Cl NH3
NH3 Pt
Cl NH3 H3N
2+ 2+ 2+
2+
2+
2+
(12) (13) X = Se (14b)
X = S (14a)
R = H (15a) R = Phenyl (15b) (16) (17)
(18)
(19) HN N
NH N
Pt NH3 H3N Cl N
H N
NH N Pt
H3N NH3 Cl
Pt NH3 H3N
N Pt N N
Cl
Pt N N
N Cl
N Pt N
N
(20) Cl
Figure 1.5 Multinuclear platinum (II) complexes with rigid linkers which have shown anticancer activity.25a,84a,85,93-94
Often, azine bridged dinuclear complexes (Figure 1.6), (21), (22), (23), (24), (25) and (26) compared to cisplatin, were found to show lower cytotoxicity in several human cell-lines. However, their activity (as chloride complexes) against mouse leukemia cells, which is cisplatin resistant, was found to be comparably higher.25a Furthermore, the complexes undergo substitution reactions with thiourea and biologically active nucleophiles. Another group of polynuclear complexes bridged by phenyldiamine and
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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