Roy, Sudeshna
Citation
Roy, S. (2008, November 25). Synergy of intercalation and coordination binding to design novel DNA-targeting antineoplastic metallodrugs. Retrieved from
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| 8
Dinuclear compounds with a flexible linker and comparison of their DNA interaction modes †
Chapter
Coupling of two terpyridines via an ethylene glycol linker yields a flexible ligand. This ligand can bind to a single metal or to two metal centers in a tridentate binding motif. Upon coordination to three different transition metals, (i.e., ruthenium, platinum and copper) three dinuclear homometallic compounds have been synthesised and characterised. Further, the DNA interaction modes have been studied by CD spectroscopy using CT DNA as a substrate. The free ligand and all the metal compounds distort the right handed helicity of the B-DNA form to a significant extent. A significant change in the positive band has been induced by the platinum dinuclear compound, [ClPt(dtdeg)PtCl]Cl2 (denaturation and intercalation). An induced signal originating from the interaction of DNA with the known ruthenium compound, [Cl3Ru(dtdeg)RuCl3], had been observed; whereas the copper compound, [Cl2Cu(dtdeg)CuCl2]does not show any induced CD signal. The platinum compound, [ClPt(dtdeg)PtCl]Cl2 has been tested for its cytotoxicity and it exhibits a high activity against seven human tumour cell lines, even better compared to cisplatin.
8.1. Introduction
A recent approach to formulate better chemotherapeutic drugs than cisplatin and to overcome the unavoidable side effects, resistance (intrinsic or acquired) and difficulty of administration is to synthesise dinuclear compounds. These compounds are assumed to interact with biomolecules in a different way than cisplatin and the resistance issue may be reduced or solved. The activity of this class of compounds originates from interstrand crosslinks with DNA base pairs and multiple factors such as (a) spacer length, (b) charge on the spacer, (c) overall charge of compounds, (d) lipophilicity and (e) nature of the ancillary ligands.
The first series of polynuclear compounds has been introduced by Farrell et al.1-6 These trinuclear compounds (BBR3464 and analogues) exert toxic side effects and instability in physiological environment. Afterwards, several dinuclear platinum compounds have been synthesised with all possible variations in coordination spheres of two platinum centers and spacers in between.7-22 Some very interesting cytotoxic compounds have been studied for DNA binding and cellular processing.23-25 None of these compounds made it to clinical trials yet, though some compounds show a promising cytotoxic profile.
The ruthenium dinuclear compounds have been introduced in coordination chemistry by Lincoln and Nordén.26, 27 Conjugation of two intercalators [RuII(phen)2(dppz)] made a unique DNA-threading agent and additionally potent anti- cancer drug (Fig. 8.1).28-31
N N N N
N N N
N
N N
N N
N N N
N Ru Ru
4+
[(phen)2Ru(bidppz)Ru(phen)2]4+
Figure 8.1. Schematic structure of a threading dinuclear metallointercalator after Nordén.26
Some representative compounds of this class are referred to in the following text.
The well-known antimetastatic agent, NAMI also inspired the synthesis of dinuclear NAMI-based compounds linked via several heterocyclic spacer.32, 33 Another probable cancer-cell targeting dinuclear ruthenium compound (cleaves DNA under hypoxic condition) could be [(phen)2Ru(tatpp)Ru(phen)2]4+ (where, tatpp = 9,11,20,22- tetraazatetrapyrido[3,2-a:2',3'-c:3",2"-1:2"',3"'-n]pentacene).34, 35 The known dinuclear compound with a longer spacer group, [(phen)2Ru(hat)Ru(phen)2]4+ (where, hat = 1,4,5,8,9,12-hexaazatriphenylene) has shown strong binding to DNA and photosensitised DNA cleavage.36-39 The dinuclear ruthenium compounds with a helicate cylinder has shown interesting DNA-binding properties and could be a potential drug.34, 40, 41
Apart from the homometallic dinuclear compounds, a handful of active heterometallic compounds have been incorporated in literature. This series of compounds generally contains ruthenium and platinum s. The design of these compounds involves the coupling of a groove binder (generally a coordinatively saturated ruthenium compound) with a coordinative binder (cisplatin or analogues) connected by a spacer. Therefore, two types of interaction would be possible via groove binding or intercalation, and in addition coordinative binding by a single molecule.42-49 This series of compounds generally contains ruthenium and platinum centers. Recently, a new approach has been introduced by coupling a DNA-cleaving agent with a coordinative binder, typically Cu-clipphen and cisplatin.50, 51 Further variation can be mentioned as the addition of intercalator, or groove binder (ruthenium moiety) to a DNA cutter (a copper moiety).51 The dual mechanism of coordinative and non-coordinative binding of this class of compounds may lead to different DNA adducts, which possibly assist to overcome resistance and may provide a wider spectrum of activity.
The selection of the spacer for dinuclear compounds plays an important role in their activity profile. Polypyridines are in extensive use for their excellent photochemical behaviour and DNA interaction. Terpyridine (commonly called terpy) is a heterocyclic aromatic ligand which belongs to the polypyridines family. Terpy and its 4'-chloro derivative exhibit an excellent cytotoxic profile (vide Chapter 7, section 7.3). In literature, it has been demonstrated that coordination compounds with terpy intercalate into the DNA.52-56 However, these metallointercalators often do not exhibit cytostatic properties.57 The possible modification to improve the activity could be done by using two active terpy moieties. The use of diethylene glycol assists the flexibility of the ligand in such a way that it could wrap around the DNA. The ligand, L12 (dtdeg, Fig. 8.2) therefore has two binding
sites and coordinates to a transition metal by its N,N,N-donor motif. Several compounds have been synthesised using this ligand and DNA model-base studies have been performed using 9-ethylguanine.48, 58 So far no report regarding the DNA-interaction studies has been reported.
N N N
O
O O
N N N
L12
N N N
O O O
N N
Ru N Ru
Cl Cl
Cl Cl Cl
Cl
C15
N N N
O
O O
N N
Pt N Pt Cl
Cl Cl2
C16
N N N
O
O O
N N
Cu N Cu
Cl Cl Cl Cl
C17
Figure 8.2. Schematic structures of ligand L12 and its dinuclear compounds (C15-C17).
Three dinuclear compounds are studied in this chapter. The ruthenium compound C15 is a paramagnetic, neutral Ru(III) compound bearing six chlorides. This compound has been synthesised previously and has been used as precursor for other dinuclear compounds.
However, no biological study had been reported with this compound. The platinum compound C16 contains one chloride on each Pt-centre and two Pt(II) ions make this compound cationic. Therefore, initially an electrostatic interaction might occur with DNA.
The copper compound C17 carries two chlorides on each Cu-centre and is expected to be able to cleave DNA. Therefore, the three compounds differ in the number of chlorides they carry, in the oxidation state and in overall charge. DNA interaction has been studied with all these compounds to rationalise the effect of metal centres on biological activity. The cytotoxicity has been measured for C15 and C16 against seven human tumour cell lines.
The structures of all three compounds along with the free ligand have been drawn in Fig.
8.2.
8.2. Experimental 8.2.1. Materials
K2PtCl4 and RuCl3·3H2O were generously provided by Johnson-Matthey (Reading, U.K.) as a loan. CuCl2·2H2O was purchased from Fisher Emergo B.V.(The Netherlands).
The so-called “ruthenium(III) solution” was prepared following the method described in the literature by the following recipe.48, 58 Commercial RuCl3·3H2O (1.2 g, 5 mmol) was dissolved in 50 mL of solvent mixture [ethanol (25 mL) and 1 M HCl (25 mL)] and refluxed for 3 h. The deep brown mixture was passed through a glass frit and the filtrate was reduced to 10 mL under reduced pressure. 40 mL of aqueous 1 M HCl solution was added to get 50 mL acidic ∼ 0.1 M Ru(III) solution. This solution was protected from light and preserved for further use.
The ligand, L12 was synthesised according to the reported synthetic procedure.59 Pt(cod)Cl2 has been synthesised according to the reported route.60 The solvents used for synthesis were purchased from Biosolve (AR grade) and used without further purification.
Deuterated solvents (for NMR experiments) and Na2PtCl6 (external standard for 195Pt NMR) was purchased from Sigma-Aldrich (Germany). The source of other materials was previously mentioned in Chapter 2 (vide section 2.2).
8.2.2. Chemical synthesis of dinuclear compounds (a) C15, [Cl3RuIII(dtdeg)RuIIICl3]
This neutral compound has been reproduced following the reported synthetic route.58 The ligand, L12 (500 mg, 0.24 mmol), was dissolved in dmf under heating at 75 °C with stirring for 30 min. The ‘ruthenium solution’58 (100 mL, ∼0.24 mmol) was added
drop-wise to the white suspension of ligand. The resulting reddish brown solution was stirred at 80 °C for 18 h and filtered under hot conditions afterwards. The brown precipitate was washed with dmf (3×1 mL) and diethyl ether (5×3 mL). This precipitate was then air dried and collected.
(b) C16, [ClPtII(dtdeg)PtIICl]Cl2
This cationic compound was synthesised from [Pt(cod)Cl2] and L12 employing a ligand exchange synthetic route. The starting materials, [Pt(cod)Cl2] (100 mg, 0.2686 mmol) was dissolved in 15 mL of absolute methanol at room temperature and recrystallised dtdeg, L12 (76.30 mg, 0.1342 mmol) was dissolved in 70 mL absolute methanol under heating at 65 °C for 45 min., respectively. The white suspension of the ligand was added dropwise to the clear solution of Pt(cod)Cl2 and the reaction solution was stirred for 24 h in the dark at 45 °C. The reaction solution was filtered under warm conditions to yield a bright yellow filtrate. This filtrate was evaporated to 5 mL under reduced pressure and a yellow shiny microcrystalline powder started precipitating. This compound was collected by filtration and after thorough washing with cold methanol (4×1 mL), diethyl ether (5×4 mL) was air dried.
(c) C17,[Cl2CuII(dtdeg)CuIICl2]
This compound was synthesised from CuCl2·2H2O and L12 employing a simple synthetic route. The starting materials, CuCl2·2H2O(60 mg, 0.3517 mmol) was dissolved in 10 mL of methanol at room temperature and recrystallised L12 (100 mg, 0.1758 mmol) was dissolved in methanol under heating at 75 °C. The white suspension of the ligand was added dropwise to the blue solution of CuCl2 and the reaction solution was stirred for 24 h at 50 °C. The reaction solution was filtered and a green solid precipitate was obtained. This solid residue was washed with cold methanol (3×1 mL) and finally thoroughly with diethyl ether (5×1 mL). The product was then air dried and dried green powder was collected.
8.2.3. Analysis
The one-dimensional (1H and 195Pt) spectra were recorded in a 300 MHz Bruker spectrometer with a 5 mm multi-nucleus probe at ambient temperature (25 °C) in dmso-d6
solution. For 195Pt NMR, Na2PtCl6 was used as external reference with δ = 0 ppm. The ESI-MS spectra were recorded on a Finnigan AQA instrument equipped with Electro Spray Interface (ESI). Elemental analysis of the samples was performed in a Perkin Elmer Series
II CHNS/O Analyser 2400. Typically 2 mg to 2.2 mg of sample was used for C, H, N and S percentage analysis.
The ligand L12, after recrystallisation, has been characterised by 1H NMR, ESI-MS and elemental analysis. The proton numbering scheme has been shown in Fig. 8.3 and the peak position (in ppm) has been mentioned in Table 8.1. The mass spectroscopy measurements in dmso solution showed two major peaks at m/z = 592.4 and 568.8, which correspond to the species Na++L12 and L12, respectively. Elemental analysis (%) for C34H28N6O3: expt.(calcd.) C 69.2 (71.80), N 14.5 (14.79), H 4.56 (4.97) and yield of the recrystallised product was 72%.
N N
O O N
N N N
O
L12 1 2
5
6 3
4 5' 5"
3' 3"
4"
6"
Figure 8.3. Proton numbering scheme for the ligand L12 and dinuclear compounds.
Table 8.1. Proton resonating positions (in ppm) for the ligand L12 and the dinuclear compounds C15 and C16.
Samples H1 H2 H5,5" H3',5' H4,4" H3,3" H6,6"
L12 3.95 4.41 7.45 7.94 7.98 8.54 8.66
C15 3.95 16.53 -10.22 4.41 -0.74 -11.82 -34.5
C16 3.97 4.42 7.26 8.02 7.91 8.65 8.59
The dinuclear ruthenium compound, C15, was characterised by paramagnetic proton NMR spectroscopy. The compound in dmso-d6 showed peaks in the -50 to +50 ppm range, which is typical for paramagnetic Ru(III) compounds.58 Elemental analysis (%) for Ru2C34H28N6Cl6O3: expt.(calcd.) C 40.12 (41.52), N 8.17 (8.55), H 2.47 (2.87).
The dinuclear platinum compound, C16, was characterised by standard 1H and 195Pt NMR spectroscopy. The proton NMR of this compound shows small shifts when compared with free ligands and shifts are also listed in Table 8.1. The compound in dmso-d6 showed a peak at δ = -2344 ppm, which corresponds to a PtN3Cl coordination environment.
Elemental analysis (%) for Pt2C34H28N6Cl4O3: expt.(calcd.) C 38.24 (37.10), N 7.92 (7.64), H 2.69 (2.56).
The dinuclear copper compound, C17, was characterised by elemental analysis and mass spectroscopy. The compound showed a major ESI-MS measurement in the dmso solution (elution with methanol) gave rise to a major peak at m/z = 799, corresponding to the species, [Cl2Cu(dtdeg)CuCl]+ along with the fragments assignable to the lower masses after dissociation of chlorides. Elemental analysis (%) for Cu2C34H28N6Cl4O3·6H2O (water molecules have been added to fit the elemental analysis): expt.(calcd.) C 43.04 (43.19), N 8.96 (8.89), H 4.35 (4.26).
8.2.4. Biological studies
The experimental details of CD spectroscopy has previously mentioned in Chapter 2 (vide section 2.2) and will not be mentioned in this chapter. The cell viability tests have been performed using the same experimental details as previously mentioned in Chapter 2 by SRB assay (vide section 2.2) and will not be mentioned in this chapter.
8.3. Results 8.3.1. Syntheses
The synthesis of the ligand L12 has been already optimised and reproduced in good yield for every cycle of synthesis. The care to keep the reaction medium devoid of water helped to improve the yield. The recrystallisation procedure from refluxing ethanol was essential to obtain dry flaky powder, as the solvent used in the reaction was dmso.
The ruthenium compound C15, [Cl3Ru(dtdeg)RuCl3] was synthesised by coordinating L12 to a ruthenium precursor, the so-called ‘ruthenium solution’. This precursor was an acidic solution of ruthenium trichloride of 0.1 M concentration48, 58 and highly soluble in common organic solvent to facilitate the reaction. The reaction condition used (dmf as solvent and 80 °C with 18 h reaction time) selectively yielded the symmetric dinuclear compound. The reaction between L12 and ‘ruthenium solution’ in ethanol and shorter reaction time (5 h) also yields C15, but the possibility of impurity of [Cl3Ru(dtdeg)]
would be higher. The characterisations were all in good agreement with reported data.48, 58
The platinum compound, C16 [ClPt(dtdeg)PtCl]Cl2 was easily synthesised. The very reactive precursor, [Pt(cod)Cl2](where, cod = 1,5-cyclooctadiene) reacts easily with the ligand and the dinuclear compound has been isolated and characterised by common spectroscopic techniques.
The synthesis of the copper compound, C17 [Cl2CudtdegCuCl2] involved the reaction between common copper source (the dichloride) and the ligand, yielding a green powder. The solubility of this compound is limited in protic solvents and the crystallisation attempts have not been successful yet.
8.3.2. DNA-interaction studies
One of the main goals of this study is to compare the mode of action of all three dinuclear compounds with the common cellular target, DNA. The CD experiments were performed with CT DNA and some selected spectra are shown in the following figures. All the samples have been measured after 24 h incubation at physiological temperature (37 °C) (Fig. 8.4). The samples were also measured after immediate mixing (0 h incubation time) and some spectra are shown in Fig. 8.5.
The samples exhibit significant changes in the B-DNA right-handed helix. Three different R values (R = 0.1, 1 and 10) have been used, which represent excess compound, intermediate ratio and higher DNA concentration, respectively. The free ligand, L12 [Fig.
8.4(d)] shows denaturation at R = 1 (decrease in intensity of the positive band at 270 nm) along with destabilisation of the helix to a smaller extent (red shifted to 2 nm). In addition, there is a new negative band appearing at 235 nm. These changes would be expected to be present in the compounds as well.
The ruthenium compound exhibits a prominent induced signal (ICD) at 315 nm.
The DNA base pairing has been retained, but significant unwinding of the helix (R = 1) is observed. The appearance of two new peaks is clear, one negative band at 215 nm and a positive band at 205 nm. At this concentration, the overall B-DNA conformation has started to get disturbed. No confirmative form change (to the A- or the Z-form) can be assigned, but the most probable transition could be indicated to the A-form, as the right handedness has remained intact.
The platinum compound on the other hand, showed different changes in the CD signal. The stable B-DNA conformation has been started denaturing, with a broad induced signal stretched from 320-360 nm (R = 1) and the negative band has been increased in
intensity. The positive sharp band also started decreasing at 225 nm, which is different from C15 and C17.
Figure 8.4. CD spectral changes in CT DNA upon addition of dinuclear compounds or ligand (a) C15, (b) C16, (c) C17 and (d) L12 after 24 h incubation.
The copper compound did not show any induced CD signal (ICD) and the base stacking band (280 nm) has remained undisturbed. The helicity of the DNA strand has been distorted to a higher extent. A sharp prominent negative band appears at 215 nm.
The compounds were also measured for instant interaction, Fig. 8.5, at R = 0.1, i.e., with a large excess of metal or ligand. All four samples including the free ligand exhibit different behaviour. Any of them hardly maintained the B-DNA conformation. In the presence of such high concentration of compounds, there could be a possibility of self- stacking, parallel or antiparallel to DNA double strand. L12 gave rise to a small positive band at 260 nm along with another strong band at 240 nm. The negative sharp band appears at 210 nm. C15 showed two positive bands at 320 nm and 248 nm, respectively, and the first band appeared as very strong in intensity. C16 showed almost similar spectral
bands as L12. However, the intensity of the bands has been reduced compared to free ligand. An intense positive band appeared at 230 nm with a shoulder at 220 nm. C17 showed a positive band at 270 nm and a negative band at 230 nm, respectively. A broad band appeared at 200-220 nm in the positive region of the spectrum.
Figure 8.5. CD spectral changes in CT DNA upon addition of dinuclear compounds or ligand (a) C15, (b) C16, (c) C17 and (d) L12 with R = 0.1.
8.3.3. Cytotoxicity assay
The cytotoxicity of C16 has been tested generously by Teva Pharmachemie B.V., (The Netherlands) against seven human cancer cell lines using SRB assay. The result from the experiment has been tabulated below (Table 8.2). The ruthenium compound is not active at all against the cell line tested and the platinum compound is very cytotoxic in the selected cell panel.
The IC50 values clearly demonstrate the promising cytostatic property of C16. It shows that the compound is even more active than some of the clinically used drugs, such as 5-fluorouracil and cisplatin. In fact, cisplatin exhibits a lower activity in all cell lines
when compared to C16. In the H226 and WIDR cell lines, the activity of C16 is even comparable to that of doxorubicin. The cytotoxicity of the platinum compounds is often correlated to their DNA-binding properties. As seen in this study, the DNA binding property of C16 is different than that of cisplatin. Therefore, it is reasonable to propose a different way of cellular processing and consequently this may be a promising drug to overcome cisplatin resistance.
Table 8.2. IC50 values (μM) for some clinically used drugs and C15, C16 using the SRB assay.
Cell lines
Samples A498 EVSA-T H226 IGROV M19 WIDR MCF7
cisplatin 7.51 1.41 10.8 0.56 1.85 2.32 3.22 Doxorubicin 0.16 0.02 0.36 0.11 0.03 0.02 0.02 5-flurouracil 1.09 3.65 2.61 2.28 3.39 5.76 1.72
Methotrexate 0.08 0.01 5.03 0.02 0.05 0.04 0.01
Etoposide 2.23 0.54 6.68 0.98 0.86 4.41 0.25
C15 59.2 63.5 51.9 63.5 63.5 56.8 63.5
C16 1.86 1.08 0.59 1.51 1.02 0.96 1.33
8.4. Discussion
The design and synthesis of new antitumour drugs may possibly originate from terpyridine derivatives. The ligand, terpy has been used in coordination chemistry from the 1970’s to synthesise planar platinum compounds, which are excellent metallointercalators.
The Ru(II)-terpy compounds are also well known for their photophysical properties. Cu- terpy and Au-terpy compounds have also been well investigated for their DNA interaction and antitumour properties, respectively. Therefore, to enhance the activity profile, the bisterpyridine ligand has been synthesised. This ligand has been used extensively to synthesise a series of heterometallic or homometallic compounds with single or multiple metal centres. These compounds have been investigated mostly for model-base studies
(using 9-EtG) and mono- or bidentate adducts have been identified and isolated. So far very limited cytotoxicity assay and DNA-interaction studies have been performed.
The syntheses of the homometallic dinuclear compounds have been successful. The interaction with CT DNA has been followed by CD spectroscopy. All of the three compounds are linked by the same ligand, L12. The differences in the structural motif have been (a) metal centres and (b) number of chloride ligands on the coordination sphere and (c) the charge of the compound (neutral or dicationic). The compounds induce major changes in the stability of the helix. The most probable mode of binding of the dinuclear compounds has been reported to be interstrand crosslinks.61 Unlike the local kink of DNA resulting from the intrastrand crosslinks by cisplatin, the interstrand crosslinks exert global changes in the DNA conformation. In this study, the observations agree with this fact. The induced CD signal indicates additional intimate interaction on top of the simple coordinative binding.62-64 The changes shown by C16 may originate from the combined effect of denaturation while intercalating, which is not shown by the other two metal compounds. All the three compounds have a number of chlorides available for hydrolysis followed by binding to guanine sites, eventually. For these compounds evidently not a single mode of action is operative, but rather a complicated or conjugative mode may be effective via intercalation, aggregation and/or denaturation. However, most of the results were obtained at very high Ru/DNA ratio.
The cytotoxicity assay for the dinuclear platinum compound makes it an interesting antiproliferative agent. The mononuclear [Pt(terpy)Cl]Cl (450 μM against L1210 cell line) has not been found cytotoxic, but the substitution of chloride by thiolate (5 μM) enhanced its cytotocicity to 90-fold.57 It has been also reported that dinuclear Pt-terpy compounds are less active with a flexible linker attached at the 4'-position than rigid, or short linkers.65, 66 The compound reported in this chapter appears to be an exception. C16 is active against all cell lines tested with better or similar activity compared to cisplatin. In the H226 cell lines, the activity is comparable to doxorubicin and twenty times higher than cisplatin. In the WIDR cell line, the activity is even higher than cisplatin, 5-Flurouracil and Etoposide.
Therefore, platinum compounds with L12 as a linker are very interesting to study further. It has been shown that platinum dinuclear compounds with an azole or azine bridge enter slowly in the cancer cells.23 There are several mechanisms operating intracellularly to process the accumulated platinum drugs.67 It has been also established that lipophilicity can influence the activity. The origin of activity of dinuclear compounds may also be a long- range interstrand adduct to DNA.8, 68-70
8.5. Conclusions
In conclusion, it has been demonstrated that L12 strongly interacts with DNA and all three dinuclear metal compounds synthesised using the ligand as the linker retain this property. The mode of interaction assumably is a combination of several binding modes.
The decrease in positive band intensity indicates the denaturation or cleavage of DNA, whereas the deformation of the right-handed helicity points to either unwinding, or canonical form changes. The generally considered labile chloride ligands are attached to all the dinuclear compounds and under physiological conditions one or more chloride possibly gets solvolysed or may form adducts with other biological targets.
Only one compound has been tested against cancer cells as yet. This compound, C16, shows a high activity in all cell lines and in some cells it is far better than cisplatin.
This preliminary data hints to the possibility of several modifications to produce better drugs. When compared to the original mononuclear [Pt(terpy)Cl]Cl, the activity of the dinuclear compound is shown to be higher. On the contrary, neither C15 nor the mononuclear [Ru(trerpy)Cl3]inhibit cell proliferation in the chosen cell lines. From these results, it would not be rational to comment on the probable activity of either C17 or the mononuclear [Cu(terpy)Cl]Cl.
The homo- or heterometallic ruthenium compounds with dtdeg as linker are devoid of activity in most cases. The IC50 values range between 50-60 μM and it has also been shown that ruthenium compounds are taken up by the cancer cells. The reasons for inactivity at this point are not clear and further cellular trafficking studies are needed to explain the observations of cell viability assays.
The dinuclear compounds belong to the polypyridyl metal compounds. Variation of metal centres has significant effect on cytotoxicity profile. These compounds could be interesting samples to study DNA cleavage studies as heterometallic compounds with this linker show DNA-cutting properties. Changing chlorides to other monodentate ligands (pyridine, ammine, sulfoxide) in case of platinum compound can lead to potential anticancer agents. Detailed study with the homometallic and heterometallic dinuclear compounds with dtdeg as linker can provide an insight to design better compounds.
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