Antitumor Platinum Compounds Research Articles

Assessment of antibacterial activity of vinyltriphenylphosphonium hexabromoplatinate

Introduction. One of the biological effects of platinum compounds is antibacterial action against Gram-positive and Gram-negative bacteria. Thus, some platinum compounds may inhibit the synthesis of DNA, RNA and proteins in Escherichia coli cells.Aim — to study the antibacterial effect of vinyltriphenylphosphonium hexabromoplatinate (VH) against E. coli and Staphylococcus aureus bacteria.Materials and methods. The antibacterial effect of VH was studied by the quantitation of the grown colonies of E. coli strain ATCC 25922 and S. aureus strain ATCC 6538 on a nutrient medium in test (suspension of microorganisms, solution of the test substance) and control (suspension of microorganisms). The significance of differences between the outcomes in test and control groups was estimated by two-sided Fisher's exact test.Results. The minimum inhibitory concentration of VH solution for E. coli strain ATCC 25922 was 14,0625 µg/ml, for S. aureus strain ATCC 6538 — 225 µg/ml.Conclusion. VH exhibits a more pronounced antibacterial effect against E. coli compared to S. aureus — the minimum inhibitory concentration of VH observed for E. coli (14,0625 µg/ml, 11,17 µM) is comparable to the effective concentrations of platinum antitumor compounds — therefore, further studies with this bacterium, including in vivo studies, are promising.

Antitumor Platinum(II) Compounds of a Chiral Diamine with Functionalized Cyclobutane-1,1-Dicarboxylates as Leaving Ligands

Antitumor Platinum(II) Compounds of a Chiral Diamine with Functionalized Cyclobutane-1,1-Dicarboxylates as Leaving Ligands

Design and Antitumor Activity of Platinum Complexes

This review presents the main advances in the design of antitumor platinum complexes over the last five years. Particular attention is paid to unconventional antitumor platinum compounds (complexes in the trans configuration, Pt(IV) complexes with S and P donor ligands, multinuclear complexes).

Current Status for Oral Platinum (IV) Anticancer Drug Development

Platinum-based chemotherapeutic drugs such as cisplatin, carboplatin and oxaliplatin are widely applied for the treatment of various types of tumors. However, poor solubility, serious side effects, and more importantly, the intrinsic and acquired resistance limit their clinical applications. These factors motivate scientists to design and synthesize novel and more potent analogues lacking disadvantages of clinical platinum drugs. Platinum (IV) complexes are one of representatives. In this review, we summarized the investigations undertaken into Platinum (IV) antitumor compounds since Rosenberg first noted their antitumor activity. The synthesis method and mechanism of action of Platinum (IV) complexes are outlined, as well as their chemical and pharmacological properties. Recent advances in Platinum (IV) anticancer agents that have been in clinical trials and photoactivatable Platinum (IV) complexes are also summarized, and the purpose here is to provide insight into the requirements for the antitumor activity of Platinum (IV) complexes and a basis for progressing in a new platinum compound.

Translesion DNA synthesis across double-base lesions derived from cross-links of an antitumor trinuclear platinum compound: primer extension, conformational and thermodynamic studies.

Polynuclear platinum complexes represent a unique structural class of DNA-binding agents of biological significance. They contain at least two platinum coordinating units bridged by a linker, which means that the formation of double-base lesions (cross-links) in DNA is possible. Here, we show that the lead compound, bifunctional [{trans-PtCl(NH3)2}2μ-trans-Pt(NH3)2{H2N(CH2)6NH2}2]4+ (Triplatin or BBR3464), forms in DNA specific double-base lesions which affect the biophysical and biochemical properties of DNA in a way fundamentally different compared to the analogous double-base lesions formed by two adducts of monofunctional chlorodiethylenetriamineplatinum(ii) chloride (dienPt). We find concomitantly that translesion DNA synthesis by the model A-family polymerase, the exonuclease deficient Klenow fragment, across the double-base lesions derived from the intrastrand CLs of Triplatin was markedly less extensive than that across the two analogous monofunctional adducts of dienPt. Collectively, these data provide convincing support for the hypothesis that the central noncovalent tetraamine platinum linker of Triplatin, capable of hydrogen-bonding and electrostatic interactions with DNA and bridging the two platinum adducts, represents an important factor responsible for the markedly lowered tolerance of DNA double-base adducts of Triplatin by DNA polymerases.

Antitumor bifunctional dinuclear PtII complex BBR3535 forms interduplex DNA cross-links under molecular crowding conditions

When antitumor platinum drugs react with DNA they form various types of intrastrand and interstrand cross-links (CLs). One class of new antitumor platinum compounds comprises bifunctional Pt(II) compounds based on the dinuclear or trinuclear geometry of leaving ligands. It has been shown that the DNA-binding modes of dinuclear or trinuclear bifunctional Pt(II) agents are distinct from those of mononuclear cisplatin, forming markedly more intramolecular interstrand CLs. However, at least two types of DNA interstrand cross-linking by bifunctional Pt(II) complexes can be envisaged, depending on whether the platinum complex coordinates to the bases in one DNA molecule (intramolecular interstrand CLs) or in two different DNA duplexes (interduplex CLs). We hypothesized that at least some antitumor bifunctional poly(di/tri)nuclear complexes could fulfill the requirements placed on interduplex DNA cross-linkers. To test this hypothesis we studied the interduplex cross-linking capability of a representative of antitumor polynuclear agents, namely, dinuclear Pt(II) complex [{trans-PtCl(NH(3))(2)}(2)-μ-{trans-(H(2)N(CH(2))(6)NH(2)(CH(2))(2)NH(2)(CH(2))(6)NH(2))}](4+) (BBR3535). The investigations were conducted under molecular crowding conditions mimicking environmental conditions in the cellular nucleus, namely, in medium containing ethanol, which is a commonly used crowding agent. We found with the aid of native agarose gel electrophoresis that the DNA interduplex cross-linking efficiency of BBR3535 under molecular crowding conditions was remarkable: the frequency of these CLs was 54%. In contrast, the interduplex cross-linking efficiency of mononuclear cisplatin or transplatin was markedly lower (approximately 40-fold or 18-fold, respectively). We suggest that the production of interduplex CLs in addition to other DNA intramolecular adducts may provide polynuclear Pt(II) compounds with a wider spectrum of cytotoxicity.

Reduction of Aminoglycoside and Anti-tumor Platinum Compound Ototoxicity by Fosfomycin

Reduction of Aminoglycoside and Anti-tumor Platinum Compound Ototoxicity by Fosfomycin

ChemInform Abstract: The Relevance of Hydrogen Bonding in the Mechanism of Action of Platinum Antitumor Compounds

Abstract A brief review is presented dealing with the mechanism of action of platinum antitumor drugs with the general formula cis-PtX2(NHR2)2 in which R can be almost any organic fragment, and X can be any leaving group, such as chloride, sulfate, or (chelating bis)carboxylate. Special emphasis is given on the role of hydrogen bonding in the several reactions taking place. It turns out that the NH group in the amine is important in determining the overall activity of the Pt compound. It is also likely to be responsible for the preferred ionic/dipolar interaction with nucleic acids, over proteins. Studies with single-stranded and double-stranded oligonucleotides have shown that the NH group also plays a role in discriminating between adenine and guanine. Finally the stabilization of the distorted DNA, after Pt binding, has been shown to originate from NH···Ophosphate interactions.

3: Proteomics and SPRi biochips: application to the screening of proteins interacting with DNA lesions induced by platinum antitumor compounds

Xeroderma pigmentosum is a photosensitive syndrome caused by a defect in nucleotide excision repair or postreplication repair. Individuals of xeroderma pigmentosum group E (xeroderma pigmentosum E) have a mild clinical form of the disease and their cells exhibit a high level of nucleotide excision repair as measured by unscheduled DNA synthesis, as well as biochemical heterogeneity. Cell strains from one group of xeroderma pigmentosum E patients have normal damage-specific DNA binding activity (Ddb+), whereas others do not (Ddb−). Using a refinement of a previously reported cell fusion complementation assay, the previously assigned Ddb+ xeroderma pigmentosum E strains, XP89TO, XP43TO, and XP24KO, with various phenotypes in DNA repair markers, were reassigned to xeroderma pigmentosum group F, xeroderma pigmentosum variant, and ultraviolet-sensitive syndrome, respectively. The Ddb− xeroderma pigmentosum E strains, XP82TO, and GM02415B, which showed almost normal cellular phenotypes in DNA repair markers, however, remained assigned to xeroderma pigmentosum group E. With the exception of the Ddb+ strain XP89TO, which demonstrated defective nucleotide excision repair, both Ddb− and Ddb+ xeroderma pigmentosum E cells exhibited the same levels of variation in unscheduled DNA synthesis that were seen in normal control cells. By genome DNA sequencing, the two Ddb− xeroderma pigmentosum E strains were shown to have mutations in the DDB2 gene, confirming previous reports for XP82TO and GM02415B, and validating the classification of both cells. As only the Ddb− strains investigated remain classified in the xeroderma pigmentosum E complementation group, it is feasible that only Ddb− cells are xeroderma pigmentosum E and that mutations in the DDB2 gene are solely responsible for the xeroderma pigmentosum E group.

Metallothioneins and Platinum(II) Anti-Tumor Compounds

The classical square planar transition metal complex cis-diamminodichlorido platinum(II) (cisplatin) ranks among the most successful and widely applied antitumor drugs for the treatment of a number of cancers. However, the risk of unforeseen resistance formation and the appearance of severe side effects in cancer patients constitutes a considerable need for the development of novel platinum based antitumor compounds. Since the introduction of cisplatin into the clinic, a few similar compounds, like cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (carboplatin), were developed, which can partly overcome the problems. The ubiquitously occurring small zinc and copper binding proteins metallothioneins (MTs) constitute the most potent cytosolic sink for platinum drugs. It appeared that, besides the formation of the very strong platinum(II)-sulfur bond involving the twenty cysteine residues of MT, the incorporation of platinum(II) into the MT structure contributes effectively to the scavenging of the drug. However, recently it became evident that the extent, to which MT sequesters platinum drugs, depends not only on the type of cancer, but also on the interaction of MT with the ligand sphere of the platinum center. For example, in contrast to cis-platinum(II) compounds, trans-platinum(II) compounds retain their N-donor ligands upon reaction with MT. From these studies, guidelines may be derived for the development of N-donor carrier ligands leading to novel platinum(II) drugs. This review describes the role of metallothioneins for the platinum(II) drug sequestration in vivo. Furthermore, it summarizes the recent developments toward the understanding of the reaction between platinum(II) and MT thiols and the structural aspects of the platinum(II) incorporation into the MT domains, and comments about future perspectives are given.

Inhibition of transcription by platinum antitumor compounds.

Cisplatin, carboplatin, and oxaliplatin are three FDA-approved members of the platinum anticancer drug family. These compounds induce apoptosis in tumor cells by binding to nuclear DNA, forming a variety of structural adducts and triggering cellular responses, one of which is the inhibition of transcription. In this report we present (i) a detailed review of the structural investigations of various Pt-DNA adducts and the effects of these lesions on global DNA geometry; (ii) research detailing inhibition of cellular transcription by Pt-DNA adducts; and (iii) a mechanistic analysis of how DNA structural distortions induced by platinum damage may inhibit RNA synthesis in vivo. A thorough understanding of the molecular mechanism of action of platinum antitumor agents will aid in the development of new compounds in the family.

Bisphosphonate complexation and calcium doping in silica xerogels as a combined strategy for local and controlled release of active platinum antitumor compounds

The production of bone substitute biomimetic materials which could also act as antitumoral drug release agents is of enormous interest. We report in this paper the synthesis and characterization of a novel platinum dinuclear complex containing a geminal bisphosphonate and its embodiment into xerogels prepared by the sol-gel method. Our goal was to obtain a hybrid inorganic matrix that could release a platinum species active against bone tumors or metastases, upon local implant. Two silica xerogels were considered: one was composed of pure silica, while the other contained also some calcium as potential release-modulating agent thanks to its high affinity for bisphophonates. The platinum-complex loading capacity of the inorganic matrices, the release kinetics in buffer simulating physiological conditions, and the stability upon storage were investigated as a function of Pt-complex concentration and calcium addition. We found that the presence of calcium in the composites deeply influences not only the stability of the formulations but also the nature of the platinum complex liberated in solution.

Recognition of DNA modified by trans‐[PtCl2NH3(4‐hydroxymethylpyridine)] by tumor suppressor protein p53 and character of DNA adducts of this cytotoxic complex

trans-[PtCl(2)NH(3)(4-Hydroxymethylpyridine)] (trans-PtHMP) is an analogue of clinically ineffective transplatin, which is cytotoxic in the human leukemia cancer cell line. As DNA is a major pharmacological target of antitumor platinum compounds, modifications of DNA by trans-PtHMP and recognition of these modifications by active tumor suppressor protein p53 were studied in cell-free media using the methods of molecular biology and biophysics. Our results demonstrate that the replacement of the NH(3) group in transplatin by the 4-hydroxymethylpyridine ligand affects the character of DNA adducts of parent transplatin. The binding of trans-PtHMP is slower, although equally sequence-specific. This platinum complex also forms on double-stranded DNA stable intrastrand and interstrand cross-links, which distort DNA conformation in a unique way. The most pronounced conformational alterations are associated with a local DNA unwinding, which was considerably higher than those produced by other bifunctional platinum compounds. DNA adducts of trans-PtHMP also reduce the affinity of the p53 protein to its consensus DNA sequence. Thus, downstream effects modulated by recognition and binding of p53 protein to DNA distorted by trans-PtHMP and transplatin are not likely to be the same. It has been suggested that these different effects may contribute to different antitumor effects of these two transplatinum compounds.

A Surprisingly Stable Macrochelate Formed from the Reaction of Cis Dinuclear Platinum Antitumor Compounds with Reduced Glutathione

The structurally unique macrochelate [{Pt(en)}2-mu-{H2N(CH2)6 NH2}-mu-(SG)] (I) is the principal product of the reaction of the dinuclear compound [{PtCl(en)}2-mu-{H2N(CH2)6 NH2}]Cl2 (1) with reduced glutathione (GSH) in a stoichiometric 1:1 ratio in phosphate buffered saline (PBS) (pH 7.35). The macrochelate is formed through simultaneous bridging of the hexanediamine linker and glutathione thiolate. This represents a novel structure for glutathione adducts of platinum. At higher (1:4) ratios of Pt complex to GSH, an interesting interchange between bridged Pt-(SG)-Pt and terminal Pt-SG species is observed with the diamine linker still remaining intact in all cases. The integrity of I is further evident when reaction ratios are increased to 1:4 (Pt complex/GSH), and additional minor products are identified as [{Pt(en)SG}2-mu-{NH2(CH2)6 NH2}] (II), which transforms to [{Pt{NH2(CH2)2 NH2}(SG)}2-mu-{H2N(CH2)6 NH2}-mu-(SG)] (III), where the chelate ring is broken to produce a dangling monodentate ethylenediamine. The chemical shifts of the Pt-NH2 linker in all compounds are explained by consideration of the enhanced rigidity of the macrochelate (I) leading to shielding in comparison to the "open" monodentate structures (II, III). The remarkable stability of I is discussed in terms of possible biological implications.

DNA-protein cross-linking by trans-[PtCl(2)(E-iminoether)(2)]. A concept for activation of the trans geometry in platinum antitumor complexes.

The structure-pharmacological activity relationships generally accepted for antitumor platinum compounds stressed the necessity for the cis-[PtX(2)(amine)(2)] structure while the trans-[PtX(2)(amine)(2)] structure was considered inactive. However, more recently, several trans-platinum complexes have been identified which are potently toxic, antitumor-active and demonstrate activity distinct from that of conventional cisplatin (cis-[PtCl(2)(NH(3))(2)]). We have shown in the previous report that the replacement of ammine ligands by iminoether in transplatin (trans-[PtCl(2)(NH(3))(2)]) results in a marked enhancement of its cytotoxicity so that it is more cytotoxic than its cis congener and exhibits significant antitumor activity, including activity in cisplatin-resistant tumor cells. In addition, we have also shown previously that this new trans compound (trans-[PtCl(2)(E-iminoether)(2)]) forms mainly monofunctional adducts at guanine residues on DNA, which is generally accepted to be the cellular target of platinum drugs. In order to shed light on the mechanism underlying the antitumor activity of trans-[PtCl(2)(E-iminoether)(2)] we examined oligodeoxyribonucleotide duplexes containing a single, site-specific, monofunctional adduct of this transplatin analog by the methods of molecular biophysics. The results indicate that major monofunctional adducts of trans-[PtCl(2)(E-iminoether)(2)] locally distort DNA, bend the DNA axis by 21 degrees toward the minor groove, are not recognized by HMGB1 proteins and are readily removed from DNA by nucleotide excision repair (NER). In addition, the monofunctional adducts of trans-[PtCl(2)(E-iminoether)(2)] readily cross-link proteins, which markedly enhances the efficiency of this adduct to terminate DNA polymerization by DNA polymerases in vitro and to inhibit removal of this adduct from DNA by NER. It is suggested that DNA-protein ternary cross-links produced by trans-[PtCl(2)(E-iminoether)(2)] could persist considerably longer than the non-cross-linked monofunctional adducts, which would potentiate toxicity of this antitumor platinum compound toward tumor cells sensitive to this drug. Thus, trans-[PtCl(2)(E-iminoether)(2)] represents a quite new class of platinum antitumor drugs in which activation of trans geometry is associated with an increased efficiency to form DNA-protein ternary cross-links thereby acting by a different mechanism from 'classical' cisplatin and its analogs.

Enhanced antitumor activitiy of trans(±)-1,2-Diaminocyclo- hexaneglutamatoplatinum(II) formulated with stealth liposome

The antitumor platinum(II) compound, [Pt(dach)(Glu)] (dach= trans(±)-1,2-diaminocyclohexane, Glu=glutamate) was formulated with a stealth liposome to improve its biological activity. Liposomes were composed of PC/PEG2000-PE/CH (PC=1,2-diacyl-glycero-3-phosphocholine; PEG2000-PE=poly(ethylene glycol)2000-1,2-diacyl-glycero-3-phosphoethanolamine; CH=cholesterol) involving different acyl moieties of phospholipids such as DO (dioleoyl), DM (dimyristoyl) or DS (distearoyl) group. Among the different acyl groups in the stealth liposomes, the DM formulation was optimal for the preparation of the liposomal [Pt(dach)(Glu)] at the mole ratio of DMPC/PEG2000-DMPE/CH=50/5/45 and at the weight ratio of drug/lipid=1/20, which is represented as l-[Pt(dach)(Glu)]. In vitro cytotoxicity was examined in sensitive A2780 and ME180 and their cisplatin-resistant A2780/PDD and ME180/PDD cancer cells. l-[Pt(dach)(Glu)] was 2∼3 times more cytotoxic than the free complex [Pt(dach)(Glu)] and cisplatin in sensitive cells, and 4∼8 times more cytotoxic in resistant cells. Thus, the resistance index of l-[Pt(dach)(Glu)] was 1.3∼2 while those of the free complex and cisplatin were 5∼6, which indicates that l-[Pt(dach)(Glu)] overcome the cisplatin resistance in both resistant cells. In vivo antitumor activity was assayed against the L1210/S leukemia. The optimal activities (% T/C) of the free complex and l-[Pt(dach)(Glu)] were >459/20 and >442/200 mg/kg, respectively. Considering the amount of the platinum complex in l-[Pt(dach)(Glu)], the liposomal [Pt(dach)(Glu)] displayed 2-fold higher drug potency than the free complex. The biodistribution experiment using LE52 tumor-bearing mouse showed excellent lung targeting property of l-[Pt(dach)(Glu)].

Reaction of polynuclear platinum antitumor compounds with reduced glutathione studied by multinuclear (1H, 1H-15N gradient heteronuclear single-quantum coherence, and 195Pt) NMR spectroscopy.

A possible explanation for the low bioavailability of platinum antitumor compounds is their high reactivity with the sulfur-containing tripeptide glutathione (GSH; deprotonated GSH = SG). GSH is located in the intracellular matrix of the cell with a normal concentration of 5-10 mM. In vivo, only a small fraction of the administered drug will migrate into the cell, resulting in relatively high concentrations of GSH compared to that of the drug. The products of the reactions of [[trans-PtCl(NH(3))(2)](2)-mu-[trans-Pt(NH(3))(2)(NH(2)(CH(2))(6)NH(2))(2)]](NO(3))(4) (BBR3464; 1,0,1/t,t,t, n = 6), [[trans-PtCl(NH(3))(2)](2)-mu-(H(2)N(CH(2))(6)NH(2))](NO(3))(2) (BBR3005; 1,1/t,t, n = 6), [[trans-PtCl(NH(3))(2)](2)-mu-(H(2)N(CH(2))(3)NH(2)(CH(2))(4)NH(2))]Cl(3) (BBR3571; 1,1/t,t-spermidine, n = 3, 4), and trans-[PtCl(2)(NH(3))(2)] (t-DDP) with reduced GSH in phosphate-buffered saline (pH 7.35) have been characterized by (1)H, (195)Pt, and (1)H(-)(15)N gradient heteronuclear single-quantum coherence NMR spectroscopy and high-performance liquid chromatography (HPLC) coupled with electrospray ionization time-of-flight mass spectrometry to determine likely metabolites of the complexes with GSH. Chemical shifts (NMR) and retention times (HPLC) established via analysis of the t-DDP profile served as a fingerprint to compare results obtained for the products afforded by the degradation of the polynuclear compounds by GSH. Identical kinetic profiles and chemical shifts between the metabolites and the t-DDP/GSH products allowed identification of the final product for the 1:2 Pt:GSH reaction as a dinuclear species [[trans-Pt(SG)(NH(3))(2)](2)-mu-SG], in which glutathione bridges the two platinum centers via only the sulfur atom.

Genotoxic Action of Cycloplatam, a New Platinum Antitumor Drug, on Mammalian Cells in vivo and in vitro

Cycloplatam (CP), a new antitumor platinum compound of the second generation, was first synthesized in Russia. This drug shows less toxicity in vivo than the widely used cisplatin and carboplatin and a higher antitumor activity than carboplatin. CP is not nephrotoxic with respect to the platinum-based antitumor agents. CP is actually studied in clinical phase II trials in Russia and Armenia. Promising results were obtained in patients with lung, ovary, and prostate cancers. The aim of this work was to study the micronuclei (MN) inducing effect of CP in vivo in murine bone marrow cells and in human lymphocytes in vitro. The mutagenic activity of CP in bone marrow of mice was significantly lower than that of cisplatin at equitoxic doses. In human lymphocytes CP induced a dose-dependent increase of MN, beginning at a very low dose (0.1 µM). Our results showed that CP is much less toxic and MN inducing in vivo in murine bone marrow than cisplatin. In vitro data evidenced that CP is more toxic and genotoxic to human cells than cisplatin. The evidence of a MN-induced activity of an antitumor drug suggests a potential risk for long-time survivors.

DNA Modifications by antitumor platinum and ruthenium compounds: Their recognition and repair

The development of metal-based antitumor drugs has been stimulated by the clinical success of cis-diamminedichloroplatinum(II) (cisplatin) and its analogs and by the clinical trials of other platinum and ruthenium complexes with activity against resistant tumors and reduced toxicity including orally available platinum drugs. Broadening the spectrum of antitumor drugs depends on understanding existing agents with a view toward developing new modes of attack. It is therefore of great interest to understand the details of molecular and biochemical mechanisms underlying the biological efficacy of platinum and other transition-metal compounds. There is a large body of experimental evidence that the success of platinum complexes in killing tumor cells results from their ability to form various types of covalent adducts on DNA; thus, the research of DNA interactions of metal-based antitumor drugs has predominated. The present review summarizes current knowledge on DNA modifications by platinum and ruthenium complexes, their recognition by specific proteins, and repair. It also provides strong support for the view that either platinum or ruthenium drugs, which bind to DNA in a fundamentally different manner from that of 'classical' cisplatin, have altered pharmacological properties. The present article also demonstrates that this concept has already led to the synthesis of several new unconventional platinum or ruthenium antitumor compounds that violate the original structure-activity relationships.

Comparison of DNA complexation with antitumor therapeutic cis-DDP and binuclear bivalent platinum compound containing pyrazine

Conformational properties of DNA molecule upon its complexation with binuclear compounds of bivalent platinum in the cis configuration containing pyrazine ligand were studied by circular dichroism, viscometry, and dynamic birefringence. Comparison with active antitumor therapeutic cis-diamminedichloroplatinum (cis-DDP) was made. Experimental data indicates that interaction of these compounds with DNA results in the formation of coordination bond of platinum with nitrogen bases. The structure of the complex depends on the ratio of platinum and DNA concentrations in initial solution. The study of DNA protonation in complex with the binuclear coordination compound showed that the binding of platinum with DNA bases occurs at the N7 atom of guanine. It was observed a competition between the studied compound and cis-DDP for binding site on DNA. The macromolecule binds stronger to the binuclear platinum compound as compared with cis-DDP.