Polynuclear Platinum Complexes Research Articles

An overview of the anticancer activity of some mononuclear and polynuclear platinum(II) complexes

A famous cisplatin anticancer agent is one of the most widely used chemotherapeutics for treating several human solid tumors. Toxicity of the normal cell is a life-threatening issue that restricts the therapeutic potential of cisplatin complex as an anticancer drug. Even though every year thousands of cisplatin-based analogs have been prepared, screened, and reported, only very few compounds entered the medical trials. Hence, new research work is still sensible. In the last few years, many mononuclear and polynuclear platinum complexes have been considerably investigated, in vitro and in vivo studies evaluated, with some compounds demonstrating significant anticancer potential. In this review, various mono-metallic and poly-metallic platinum‐based complexes with various derivatives used as ligands that have anticancer potential are defined and numerous typical examples are discussed briefly. Present investigation, numerous mononuclear cisplatin derivatives exhibited greater anticancer potency than the parent cisplatin drug. However, polynuclear cisplatin derivatives showed much better anticancer activity than mononuclear cisplatin analogs against various cancer cell lines.

A Comparison of Di- and Trinuclear Platinum Complexes Interacting with Glycosaminoglycans for Targeted Chemotherapy.

Heparan sulfate proteoglycans (HSPGs) and their associated proteins aid in tumor progression through modulation of biological events such as cell invasion, angiogenesis, metastasis, and immunological responses. Metalloshielding of the anionic heparan sulfate (HS) chains by cationic polynuclear platinum complexes (PPCs) prevents the HS from interacting with HS-associated proteins and thus diminishes the critical functions of HSPG. Studies herein exploring the PPC-HS interactions demonstrated that a series of PPCs varying in charge, nuclearity, distance between Pt centers, and hydrogen-bonding ability influence HS affinity. We report that the polyamine-linked complexes have high HS affinity and display excellent in vivo activity against breast cancer metastases and those arising in the bone and liver compared to carboplatin. Overall, the PPC-HS niche offers an attractive approach for targeting HSPG-expressing tumor cells.

Substitution-inert polynuclear platinum complexes and Glycosaminoglycans: A molecular dynamics study of its non-covalent interactions

An impressive class of formally substitution-inert polynuclear platinum complexes known as Substitution-inert Polynuclear Platinum (II) Complexes (SI-PPCs) present an attractive approach for medicinal inorganic chemistry through high-affinity non-covalent interactions with biomolecules, such as DNA and Glycosaminoglycans (GAGs). This interaction occurs through the formation of non-covalent cyclic structures called clamps and forks with the phosphate and sulfate groups present in these biomolecules. This work shows several analyses of the non-covalent interactions formed between heparin (PDB code: 1HPN) and SI-PPCs obtained through molecular dynamics (MD) simulations. Root Mean Square Deviation (RMSD) results showed that the “non-covalent” di-nuclear platinum compound, DiplatinNC ([{trans-Pt(NH3)2(NH2(CH2)6NH3+)}2-μ-NH2(CH2)6NH2]6+) and AH44 ([{Pt(NH3)3}2{(μ-(H2N(CH2)6NH2)2-(trans-Pt(NH3)2}]6+, 0,0,0/t,t,t,) complexes, which are both 6+ charged complexes, were the most rigid. On the other hand, the Root Mean Square Fluctuation (RMSF) showed that there is a reduction in the atomic fluctuation of atoms in the central region of the heparin molecule; the solvent accessible surface area (SASA) analysis also indicates a reduction in the accessible area by the heparin when interacting with SI-PPCs. The evaluation of H-Bond data confirms the formation of the non-covalent interactions, which may suggest a decrease in the action of 1HPN by preventing the action of enzymes on this substrate. In addition, thermodynamic results indicate that this interaction is spontaneous, considering the negative variations in the Gibbs free energy presented by the studied systems.

Platinum complexes act as shielding agents against virus infection.

We determine that the substitution-inert polynuclear platinum complex (PPC) TriplatinNC is an antiviral agent and protects cells from enterovirus 71 and human metapneumovirus infection. This protection occurs through the formation of adducts with cell-surface glycosaminoglycans. Our detailed mechanistic investigation demonstrates that TriplatinNC blocks viral entry by shielding cells from virus attack, opening new directions for metalloshielding antiviral drug development.

Conformational Modulation of Iduronic Acid-Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound and Implications for Development of Antimetastatic Platinum Drugs.

1 H NMR spectroscopic studies on the 1:1 adduct of the pentasaccharide Fondaparinux (FPX) and the substitution-inert polynuclear platinum complex TriplatinNC show significant modulation of geometry around the glycosidic linkages of the FPX constituent monosaccharides. FPX is a valid model for the highly sulfated cell signalling molecule heparan sulfate (HS). The conformational ratio of the 1 C4 :2 S0 forms of the FPX residue IdoA(2S) is altered from ca. 35:65 (free FPX) to ca. 75:25 in the adduct; the first demonstration of a small molecule affecting conformational changes on a HS oligosaccharide. Functional consequences of such binding are suggested to be inhibition of HS cleavage in MDA-MB-231 triple-negative breast cancer (TNBC) cells. We further describe inhibition of metastasis by TriplatinNC in the TNBC 4T1 syngeneic tumour model. Our work provides insight into a novel approach for design of platinum drugs (and coordination compounds in general) with intrinsic anti-metastatic potential.

Conformational Modulation of Iduronic Acid‐Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound and Implications for Development of Antimetastatic Platinum Drugs

Abstract1H NMR spectroscopic studies on the 1:1 adduct of the pentasaccharide Fondaparinux (FPX) and the substitution‐inert polynuclear platinum complex TriplatinNC show significant modulation of geometry around the glycosidic linkages of the FPX constituent monosaccharides. FPX is a valid model for the highly sulfated cell signalling molecule heparan sulfate (HS). The conformational ratio of the 1C4:2S0 forms of the FPX residue IdoA(2S) is altered from ca. 35:65 (free FPX) to ca. 75:25 in the adduct; the first demonstration of a small molecule affecting conformational changes on a HS oligosaccharide. Functional consequences of such binding are suggested to be inhibition of HS cleavage in MDA‐MB‐231 triple‐negative breast cancer (TNBC) cells. We further describe inhibition of metastasis by TriplatinNC in the TNBC 4T1 syngeneic tumour model. Our work provides insight into a novel approach for design of platinum drugs (and coordination compounds in general) with intrinsic anti‐metastatic potential.

Substitution-inert polynuclear platinum compounds inhibit human cytomegalovirus attachment and entry

Human cytomegalovirus (HCMV) infects up to 90–100% of the world population. Although HCMV infection is not a concern for immunocompetent patients, it can be life threatening for immunocompromised individuals. Additionally, congenital HCMV infections can cause serious neurological deficits in neonates. Since viral resistance mutations arise for all current treatments, new treatments targeting novel processes are needed. A well-defined target for HCMV is heparan sulfate, a highly sulfated glycosaminoglycan (GAG) necessary for virion/host cell attachment. In this study, we investigated as possible antiviral agents substitution-inert cationic polynuclear platinum complexes (PPCs) that demonstrate charge-dependent high affinity for GAGs (Katner et al., 2018; Peterson et al., 2017). Certain PPCs had anti-HCMV activities in low micromolar concentrations and antiviral activity correlated with their GAG-binding affinity. Time of addition, removal, and mechanistic studies were consistent with PPCs binding to cells and blocking HCMV virion attachment; however, evidence also suggested that PPC/virion interactions could inhibit fibroblast but not epithelial cell infection. We hypothesize that the PPC-heparan sulfate interaction described here is a general approach to inhibition of virion/host cell attachment and viral entry mediated by other anionic GAGs and sialic acids on the cell surface. Through metalloshielding of the critical sulfate receptors, PPCs offer an attractive alternative to current antiviral compounds, with the potential to target a broad spectrum of viruses that utilize GAGs for attachment and entry.

Antimicrobial activity of mono- and polynuclear platinum and palladium complexes

Introduction. Infectious diseases remain a serious threat to humanity worldwide as bacterial pathogens grow more diverse. Bacteria, fungi, and parasites develop resistance to clinically approved antimicrobials, which reduces the efficacy of available drugs and treatment measures. As a result, there is an ever growing demand for new highly effective pharmaceuticals. This review describes mono- and polynuclear platinum and palladium complexes with antimicrobial properties. We compared several groups of antibacterial agents: antibiotics, antioxidant biologically active substances, antimicrobial nanoparticles, nanocomposite materials, biopolymers, micellar systems, and plant extracts.
 Study objects and methods. The review covered relevant articles published in Web of Science, Scopus, and Russian Science Citation Index for the last decade. The list of descriptors included such terms as mononuclear and binuclear complexes of platinum, palladium, and antimicrobial activity.
 Results and discussion. Chelates of platinum, palladium, silver, iridium, rhodium, ruthenium, cobalt, and nickel are popular therapeutic agents. Their antimicrobial activity against pathogenic microorganisms can be enhanced by increasing their bioavailability. Metalbased drugs facilitate the transport of organic ligands towards the bacterial cell. The nature of the ligand and its coordination change the thermodynamic stability, kinetic lability, and lipophilic properties of the complex, as well as the reactivity of the central atom. Polynuclear platinum and palladium complexes contain two or more bound metal (coordinate) centers. Covalent bonding with bacterial DNA enables them to form a type of DNA adducts, which is completely different from that of mononuclear complexes.
 Conclusion. Metal-based drugs with functional monodentate ligands exhibit a greater antimicrobial effect compared to free ligands. Poly- and heteronuclear complexes can increase the number of active centers that block the action of bacterial cells. When combined with other antibacterial agents, they provide a synergistic effect, which makes them a promising subject of further research.

Substitution-Inert Polynuclear Platinum Complexes Inhibit Reverse Transcription Preferentially in RNA Triplex-Forming Templates.

RNA triplexes are significant tertiary structure motifs that are found in many functional RNAs. Hence, small molecules capable of recognition, binding, and stabilization of the triple-helical RNA structures are emerging as attractive potential molecular biology tools and therapeutic agents. Here, we utilize methods of molecular biology and biophysics to study the interactions of a series of antitumor substitution-inert polynuclear platinum complexes (SI-PPCs) with triple-helical RNA structures. We show that SI-PPCs recognize and stabilize RNA triplexes and inhibit reverse transcription preferentially in the RNA template prone to the triplex formation. These so far unexplored properties of SI-PPCs suggest that the targeting of triple-stranded regions in RNA might contribute to the biological effects of SI-PPCs.

Molecular dynamics simulation of non-covalent interactions between polynuclear platinum(II) complexes and DNA.

Several studies with substitution-inert polynuclear platinum(II) complexes (SI-PPC) have been carried out in recent years due to the form of DNA binding presented by these compounds. This form of bonding is achieved by molecular recognition through the formation of non-covalent structures, commonly called phosphate clamps and forks, which generate small extensions of the major and minor grooves. In this work, we use molecular dynamics simulations (MD) to study the formation of these cyclical structures between six different SI-PPCs and a double DNA dodecamer, here called 24_bp_DNA. The results showed the influence of the complex expressed on the number of phosphate clamps and forks formed. Based on the conformational characterization of the DNA fragment, we show that the studied SI-PPCs interact preferentially in the minor groove, causing groove spanning, except for two of them, Monoplatin and AH44. The phosphates of C-G pairs are the main sites for such non-covalent interactions. The Gibbs interaction energy of solvated species points out to AH78P, AH78H, and TriplatinNC as the most probable ones when coupled with DNA. As far as we know, this work is the very first one related to SI-PPCs which brings MD simulations and a complete analysis of the non-covalent interactions with a double DNA dodecamer.

Abstract C068: Toward precision medicine for platinums

Abstract Over half of all cancer patients will receive a platinum drug during their treatment. Recent interest in our labs involve exploiting the high affinity of a discrete class of platinum-based anticancer agents, polynuclear platinum complexes (PPCs), for sulfated glycosaminoglycans (sGAGs). sGAGs are increasingly seen as potential biomarkers and molecular targets in many forms of cancer. sGAG expression levels were quantified in patient derived xenograft (PDX) and cellular models of triple negative breast cancer (TNBC) and ovarian cancer. PPCs, but not carboplatin, show increased levels of tumor uptake and efficacy in models expressing high levels of sGAGs. sGAGs may provide a viable target for PPCs, producing a significant advantage over clinical platinum agents in this setting. Citation Format: Jennifer E Koblinski, Erica J Peterson, James D. Hampton, J Chuck Harrell, Nicholas P Farrell. Toward precision medicine for platinums [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C068. doi:10.1158/1535-7163.TARG-19-C068

Substitution-Inert Polynuclear Platinum Complexes with Dangling Amines: Condensation/Aggregation of Nucleic Acids and Inhibition of DNA-Related Enzymatic Activities.

The substitution-inert polynuclear platinum complexes (SI-PPCs) are now recognized as a distinct subclass of platinum anticancer drugs with high DNA binding affinity. Here, we investigate the effects of SI-PPCs containing dangling amine groups in place of NH3 as ligands to increase the length of the molecule and therefore overall charge and its distribution. The results obtained with the aid of biophysical techniques, such as total intensity light scattering, gel electrophoresis, and atomic force microscopy, show that addition of dangling amine groups considerably augments the ability of SI-PPCs to condense/aggregate nucleic acids. Moreover, this enhanced capability of SI-PPCs correlates with their heightened efficiency to inhibit DNA-related enzymatic activities, such as those connected with DNA transcription, catalysis of DNA relaxation by DNA topoisomerase I, and DNA synthesis catalyzed by Taq DNA polymerase. Thus, the addition of the dangling amine groups resulting in structures of SI-PPCs, which differ so markedly from the derivatives of cisplatin used in the clinic, appears to contribute to the overall biological activity of these molecules.

Substitution-Inert Polynuclear Platinum Complexes Act as Potent Inducers of Condensation/Aggregation of Short Single- and Double-Stranded DNA and RNA Oligonucleotides.

Compounds condensing DNA and RNA molecules can essentially affect important biological processes including DNA replication and transcription. Here, this work shows with the aid of total intensity light scattering, gel electrophoresis, and atomic force microscopy (AFM) that the substitution-inert polynuclear platinum complexes (SI-PPCs), particularly [{trans-Pt(NH3 )2 (NH2 (CH2 )6 - NH3 + )}2 -μ-{trans-Pt(NH3 )2 (NH2 (CH2 )6 NH2 )2 }]8+ (Triplatin NC), exhibit an unprecedented high potency to condense/aggregate fragments of DNA and RNA as short as 20 base pairs. SI-PPCs condensates are distinctive from those generated by the naturally occurring polyamines (commonly used DNA compacting/condensing agents). Collectively, the results further confirm that SI-PPCs are very efficient inducers of condensation of DNA and RNA, including their short fragments that might have potential in gene therapy, biotechnology, and bionanotechnology. Moreover, the data confirm the structural advantages of the phosphate clamp, with a well-defined rigid DNA recognition motif in initiating condensation and aggregation phenomena on oligonucleotides.

Abstract 3941: Heparan sulfate, a new target for platinum in metastatic TNBC

Abstract Heparan sulfate (HS) are linear polysaccharides conjugated to proteins, heparan sulfate proteoglycans (HSPGs), located on the cell surface and extracellular matrix. The HS chains display varying degrees of sulfation. These sulfate clusters mediate the interaction of polynuclear platinum complexes (PPCs) with HSPG through a “sulfate clamp.” Such PPC-HS interactions can be conceptualized as “polyarginine” mimics. Strong HS-PPC binding protects the oligosaccharide against sulfate loss through metalloshielding. The biological consequences of PPCs metalloshielding HS will in principle affect HS interactions with relevant enzymes and proteins such as heparanase and growth factors, similar in concept to inhibition of DNA-protein binding through modification of DNA structure and conformation. HSPGs, associated growth factors, and heparanase promote tumor progression by facilitating invasion, angiogenesis, and metastasis. High heparanase expression correlates with increased metastatic potential and poor clinical prognosis. PPC-HS interactions inhibit cleavage of a model pentasaccharide by heparanase and further modulated bFGF binding to HS, and bFGF-induced migration and signaling in colon cancer cells. The end-point of functional modulation of HS interactions is inhibition of angiogenesis and metastasis. We report proof-of-principle of strong in vivo anti-metastatic activity of PPCs in triple negative breast cancer (TNBC) models. Further, we examine the anti-metastatic and anti-angiogenic effects of PPC-HS metalloshielding in these in vivo models through multiple growth factor signaling pathways (bFGF, HB-EGF, VEGF), and heparanase activity in breast cancer and endothelial cells. PPCs represent a novel class of intrinsically dual-function agents combining platinum cytotoxicity through DNA targeting with anti-angiogenic effects through glycan targeting. Chicago 14-17 April 2018 Citation Format: Samantha J. Katner, James D. Hampton, Erica J. Peterson, Eriko Katsuta, Megan R. Sayyad, Kazuaki Takabe, Jennifer Koblinski, Nicholas P. Farrell. Heparan sulfate, a new target for platinum in metastatic TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3941.

Substitution‐Inert Polynuclear Platinum Complexes That Inhibit the Activity of DNA Polymerase in Triplex‐Forming Templates

AbstractThe formation of triple‐helical DNA is implicated in the regulation of gene expression. The triplexes are, however, unstable under physiological conditions so that effective stabilizers for the triplex formation are needed. Herein, we describe a new strategy for the stabilization of such triplexes that is based on antitumor substitution‐inert polynuclear platinum complexes (SI‐PPCs). These compounds were previously shown to bind to DNA through the phosphate clamp—a discrete mode of DNA–ligand recognition distinct from the canonical intercalation and minor‐groove binding. We have found that SI‐PPCs efficiently inhibit DNA synthesis by DNA polymerase in sequences prone to the formation of pyrimidine‐ and purine‐motif triplex DNAs. Moreover, the results suggest that SI‐PPCs are able to induce the formation of triple‐helical DNA between duplexes and strands that are not completely complementary to each other. Collectively, these data provide evidence that SI‐PPCs are very efficient stabilizers of triple‐stranded DNA that might exert their action by stabilizing higher‐order structures such as triple‐helical DNA.

Substitution-Inert Polynuclear Platinum Complexes That Inhibit the Activity of DNA Polymerase in Triplex-Forming Templates.

The formation of triple-helical DNA is implicated in the regulation of gene expression. The triplexes are, however, unstable under physiological conditions so that effective stabilizers for the triplex formation are needed. Herein, we describe a new strategy for the stabilization of such triplexes that is based on antitumor substitution-inert polynuclear platinum complexes (SI-PPCs). These compounds were previously shown to bind to DNA through the phosphate clamp-a discrete mode of DNA-ligand recognition distinct from the canonical intercalation and minor-groove binding. We have found that SI-PPCs efficiently inhibit DNA synthesis by DNA polymerase in sequences prone to the formation of pyrimidine- and purine-motif triplex DNAs. Moreover, the results suggest that SI-PPCs are able to induce the formation of triple-helical DNA between duplexes and strands that are not completely complementary to each other. Collectively, these data provide evidence that SI-PPCs are very efficient stabilizers of triple-stranded DNA that might exert their action by stabilizing higher-order structures such as triple-helical DNA.

Substitution-Inert Polynuclear Platinum Complexes as Metalloshielding Agents for Heparan Sulfate.

Cleavage of heparan sulfate proteoglycans (HSPGs) by the enzyme heparanase modulates tumour-related events including angiogenesis, cell invasion, and metastasis. Metalloshielding of heparan sulfate (HS) by positively charged polynuclear platinum complexes (PPCs) effectively inhibits physiologically critical HS functions. Studies using bacterial P. heparinus heparinase II showed that a library of Pt complexes varying in charge and nuclearity and the presence or absence of a dangling amine inhibits the cleavage activity of the enzyme on the synthetic pentasaccharide, Fondaparinux (FPX). Charge-dependent affinity of PPC for FPX was seen in competition assays with methylene blue and ethidium bromide. The dissociation constant (Kd ) of TriplatinNC for FPX was directly measured by isothermal titration calorimetry (ITC). The trend in DFT calculated interaction energies with heparin fragments is consistent with the spectroscopic studies. Competitive inhibition of TAMRA-R9 internalization in human carcinoma (HCT116) cells along with studies in HCT116, wildtype CHO and mutant CHO-pgsA745 (lacking HS/CS) cells confirm that HSPG-mediated interactions play an important role in the cellular accumulation of PPCs.

Polynuclear Platinum Complexes. Structural Diversity and DNA Binding.

Polynuclear platinum complexes (PPCs) represent a discrete structural class of DNA-binding agents with excellent antitumor properties. The use of at least two platinum coordinating units automatically means that multifunctional DNA binding modes are possible. The structural variability inherent in a polynuclear platinum structure can be harnessed to produce discrete modes of DNA binding, with conformational changes distinct from and indeed inaccessible to, the mononuclear agents such as cisplatin. Since our original contributions in this field a wide variety of dinuclear complexes especially have been prepared, their DNA binding studied, and potential relevance to cytotoxicity examined. This chapter focuses on how DNA structure and reactivity is modulated through interactions with PPCs with emphasis on novel aspects of such structure and reactivity. How these major changes are further reflected in damaged DNA-protein binding and cellular effects are reviewed. We further review, for the first time, the great structural diversity achieved in PPC complex design and summarize their major DNA binding effects.

Metalloglycomics.

Glycosaminoglycans (GAGs) such as heparin and heparan sulfate (HS) are large complex carbohydrate molecules that bind to a wide variety of proteins and exercise important physiological and pathological processes. This chapter focuses on the concept of metalloglycomics and reviews the structure and conformation of GAGs and the role of various metal ions during the interaction of GAGs with their biological partners such as proteins and enzymes. The use of metal complexes in heparin analysis is discussed. Cleavage of heparan sulfate proteoglycans (HSPGs) by the enzyme heparanase modulates tumor-related events including angiogenesis, cell invasion, metastasis, and inflammation. HS is identified as a ligand receptor for polynuclear platinum complexes (PPCs) defining a new mechanism of cellular accumulation for platinum drugs with implications for tumor selectivity. The covalent and noncovalent interaction of PPCs with GAGs and the functional consequences of strong binding with HS are explained in detail. Sulfate cluster anchoring shields the sulfates from recognition by charged protein residues preventing the exercise of the HS-enzyme/protein function, such as growth factor recognition and the activity of heparanase on HS. The cellular consequences are inhibition of invasion and angiogenesis. Metalloglycomics is a potentially rich new area of endeavor for bioinorganic chemists to study the relevance of intrinsic metal ions in heparin/ HS-protein interactions and for development of new compounds for therapeutic, analytical, and imaging applications.

Synthesis, cytotoxic activity and DNA interaction studies of new dinuclear platinum(ii) complexes with an aromatic 1,5-naphthyridine bridging ligand: DNA binding mode of polynuclear platinum(ii) complexes in relation to the complex structure

The synthesis, spectroscopic characterization, cytotoxic activity and DNA binding evaluation of seven new dinuclear platinum(ii) complexes Pt1-Pt7, with the general formula [{Pt(L)Cl}2(μ-1,5-nphe)](ClO4)2 (1,5-nphe is 1,5-naphthyridine; while L is two ammines (Pt1) or one bidentate coordinated diamine: ethylenediamine (Pt2), (±)-1,2-propylenediamine (Pt3), trans-(±)-1,2-diaminocyclohexane (Pt4), 1,3-propylenediamine (Pt5), 2,2-dimethyl-1,3-propylenediamine (Pt6), and 1,3-pentanediamine (Pt7)), were reported. In vitro cytotoxic activity of these complexes was evaluated against three tumor cell lines, murine colon carcinoma (CT26), murine mammary carcinoma (4T1) and murine lung cancer (LLC1) and two normal cell lines, murine mesenchymal stem cells (MSC) and human fibroblast (MRC-5) cells. The results of the MTT assay indicate that all investigated complexes have almost no cytotoxic effects on 4T1 and very low cytotoxicity toward LLC1 cell lines. In contrast to the effects on LLC1 and 4T1 cells, complexes Pt1 and Pt2 had significant cytotoxic activity toward CT26 cells. Complex Pt1 had a much lower IC50 value for activity on CT26 cells compared with cisplatin. In comparison with cisplatin, all dinuclear Pt1-Pt7 complexes showed lower cytotoxicity toward normal MSC and MRC-5 cells. In order to measure the amount of platinum(ii) complexes taken up by the cells, we quantified the cellular platinum content using inductively coupled plasma mass spectrometry (ICP-QMS). Molecular docking studies performed to evaluate the potential binding mode of dinuclear platinum(ii) complexes Pt1-Pt7 and their aqua derivatives W1-W7, respectively, at the double stranded DNA showed that groove spanning and backbone tracking are the most stable binding modes.