Introduction of Fluorine into Antitumor-Active Dinuclear Platinum(II) Complexes Leads to Modulation of In Vivo Antitumor Activity in Mice.

Tetrazolato-bridged dinuclear platinum(II) complexes ([{cis-Pt(NH3)2}2(µ-OH)(µ-5-R-tetrazolato-N2,N3)]2+; tetrazolato-bridged complexes) show remarkable cytotoxic effects in vitro and antitumor activity in vivo. Here, we examined the structure-activity relationship of a series of fluorine-containing derivatives (R = CFH2, CF2H, or CF3), focusing on their lipophilicity, cellular accumulation, cytotoxicity, interactions with a nucleobase and double-stranded deoxyribonucleic acid, and in vivo antitumor efficacy. Fluorination had a little effect on the properties of the derivatives in vitro; however, marked differences in in vitro cytotoxicity and in vivo tumor growth inhibition activity were observed. In BALB/c mice bearing colon-26 tumors, the antitumor efficacies of the derivatives were markedly altered, even by changing the number of fluorine atoms by one. In addition, one derivative, [{cis-Pt(NH3)2}2(µ-OH)(µ-5-difluoromethyltetrazolato-N2,N3)](NO3)2, showed a significantly higher antitumor efficacy compared with oxaliplatin, a current first-line drug and the only platinum-based drug approved for the treatment of colon cancer. Together, the present results indicate that introducing fluorine into tetrazolato-bridged complexes may be useful for modulating in vivo activities.

Data on synthesis and structure-activity relationships of tetrazolato-bridged dinuclear platinum(II) complexes.

In this data file, the synthetic procedures for the preparation of a series of anticancer tetrazolato-bridged dinuclear platinum(II) complexes ([{cis-Pt(NH3)2}2(µ-OH)(µ-5-R-tetrazolato-N2,N3)]n+ (n = 1 or 2, tetrazolato-bridged complexes)) and of the bridging ligands of 5-substituted 1H-tetrazoles (5-R-1H-tetrazoles) are described. These compounds were characterized by 1H-, 13C-, 19F- and 195Pt-NMR spectroscopy and mass spectrometry.

Different Effects of Cisplatin and Transplatin on the Higher-Order Structure of DNA and Gene Expression.

Despite the effectiveness of cisplatin as an anticancer agent, its trans-isomer, transplatin, is clinically ineffective. Although both isomers target nuclear DNA, there is a large difference in the magnitude of their biological effects. Here, we compared their effects on gene expression in an in vitro luciferase assay and quantified their effects on the higher-order structure of DNA using fluorescence microscopy (FM) and atomic force microscopy (AFM). The inhibitory effect of cisplatin on gene expression was about 7 times that of transplatin. Analysis of the fluctuation autocorrelation function of the intrachain Brownian motion of individual DNA molecules showed that cisplatin increases the spring and damping constants of DNA by one order of magnitude and these visco-elastic characteristics tend to increase gradually over several hours. Transplatin had a weaker effect, which tended to decrease with time. These results agree with a stronger inhibitory effect of cisplatin on gene expression. We discussed the characteristic effects of the two compounds on the higher-order DNA structure and gene expression in terms of the differences in their binding to DNA.

Synthesis and structure-activity relationships of tetrazolato-bridged dinuclear platinum(II) complexes: A small modification at tetrazole C5 markedly influences the in vivo antitumor efficacy.

We synthesized and characterized 15 new derivatives of the highly anticancer-active platinum(II) complex [{cis-Pt(NH3)2}2(µ-OH)(µ-tetrazolato-N2,N3)]2+ (5-H-Y) by making substitutions at tetrazole C5. We then evaluated the comprehensive structure-cytotoxicity relationships of a total of 23 derivatives in two murine lymphocytic leukaemia cell lines, sensitive and resistant to cisplatin. We also report the in vivo antitumor efficacy of three ester derivatives, two of which exhibited much higher efficacy than oxaliplatin against mouse homografted Colon-26 colorectal tumor.

Kinetic analysis of and platinum(II) migration in the reactions of tetrazolato-bridged dinuclear platinum(II) complexes with nucleotides.

The series of tetrazolato-bridged complexes with the formula [{cis­Pt(NH3)2}2(µ-OH)(µ-5-H-tetrazolato-N1,N2)]2+ (5-H-X) or [{cis­Pt(NH3)2}2(µ-OH)(µ-5-R-tetrazolato-N2,N3)]n+ (R=H (5-H-Y), CH3 (1), CH2COOCH2CH3 (2), CH2COO- (3), n=2 (5-H-Y, 1, 2) or 1 (3)) are promising candidate complexes for formulation as next-generation platinum-based anticancer drugs that form multimodal bindings with DNA molecules. These multimodal bindings involve both non-covalent and covalent interactions, the latter of which are acknowledged to be essential for platinum-based drugs to exert their anticancer activity. In the present study, the tetrazolato-bridged complexes reacted with two molar equivalents of guanosine-5'-monophosphate (GMP) to yield the 1:2 reaction products [{cis­Pt(NH3)2(GMP-N7)}2(µ-5-R-tetrazolato-N1,N3)]2- or 1-. This reaction was accompanied by an intramolecular Pt(II) migration that contributed to the formation of diverse DNA crosslinking, such as interhelical crosslinks. The second-order reaction rate constants for the reactions performed in phosphate-buffered D2O solution showed that the reactivity of the complexes decreased in the order 5-H-X≳5-H-Y>2≳1>3 and that reactivity was correlated with the cytotoxicity of the complexes. A similar result was obtained for the reaction of the complexes with calf thymus DNA in which the formation of covalent DNA adducts was quantified by means of inductively coupled plasma mass spectrometry. These results suggest that overall charge affects the kinetics of the reactions of platinum complexes with GMP and calf thymus DNA. Thus, the positive charge of the complexes affects not only the non-covalent but also the covalent interactions between the complexes and nucleotides and DNA, which are negatively charged molecules.

Specific Conformational Change in Giant DNA Caused by Anticancer Tetrazolato-Bridged Dinuclear Platinum(II) Complexes: Middle-Length Alkyl Substituents Exhibit Minimum Effect.

Derivatives of the highly antitumor-active compound [{cis-Pt(NH3)2}2(µ-OH)(µ-tetrazolato-N2,N3)]2+ (5-H-Y), which is a tetrazolato-bridged dinuclear platinum(II) complex, were prepared by substituting a linear alkyl chain moiety at C5 of the tetrazolate ring. The general formula for the derivatives is [{cis-Pt(NH3)2}2(µ-OH)(µ-5-R-tetrazolato-N2,N3)]2+, where R is (CH2)nCH3 and n = 0 to 8 (complexes 1-9). The cytotoxicity of complexes 1-4 in NCI-H460 human non-small-cell lung cancer cells decreased with increasing alkyl chain length, and those of complexes 5-9 increased with increasing alkyl chain length. That is, the in vitro cytotoxicity of complexes 1-9 was found to have a U-shaped association with alkyl chain length. This U-shaped association is attributable to the degree of intracellular accumulation. Although circular dichroism spectroscopic measurement indicated that complexes 1-9 induced comparable conformational changes in the secondary structure of DNA, the tetrazolato-bridged complexes induced different degrees of DNA compaction as revealed by a single DNA measurement with fluorescence microsopy, which also had a U-shaped association with alkyl chain length that matched the association observed for cytotoxicity. Complexes 7-9, which had alkyl chains long enough to confer surfactant-like properties to the complex, induced DNA compaction 20 or 1000 times more efficiently than 5-H-Y or spermidine. A single DNA measurement with transmission electron microscopy revealed that complex 8 formed large spherical self-assembled structures that induced DNA compaction with extremely high efficiency. This result suggests that these structures may play a role in the DNA compaction that was induced by the complexes with the longer alkyl chains. The derivatization with a linear alkyl chain produced a series of complexes with unique cellular accumulation and DNA conformational change profiles and a potentially useful means of developing next-generation platinum-based anticancer drugs. In addition, the markedly high ability of these complexes to induce DNA compaction and their high intracellular accumulation emphasized the difference in mechanism of action from platinum-based anticancer drugs.

Chromatin folding and DNA replication inhibition mediated by a highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex.

Chromatin DNA must be read out for various cellular functions, and copied for the next cell division. These processes are targets of many anticancer agents. Platinum-based drugs, such as cisplatin, have been used extensively in cancer chemotherapy. The drug-DNA interaction causes DNA crosslinks and subsequent cytotoxicity. Recently, it was reported that an azolato-bridged dinuclear platinum(II) complex, 5-H-Y, exhibits a different anticancer spectrum from cisplatin. Here, using an interdisciplinary approach, we reveal that the cytotoxic mechanism of 5-H-Y is distinct from that of cisplatin. 5-H-Y inhibits DNA replication and also RNA transcription, arresting cells in the S/G2 phase, and are effective against cisplatin-resistant cancer cells. Moreover, it causes much less DNA crosslinking than cisplatin, and induces chromatin folding. 5-H-Y will expand the clinical applications for the treatment of chemotherapy-insensitive cancers.

Highly efficient uptake into cisplatin-resistant cells and the isomerization upon coordinative DNA binding of anticancer tetrazolato-bridged dinuclear platinum(II) complexes.

We examined the cytotoxicity and cellular uptake in L1210 murine leukemia cells, as well as the coordinative reaction with the guanine derivative 9-ethylguanine (9EtG), of a series of µ-hydroxo-µ-tetrazolato dinuclear platinum(II) complexes (tetrazolato-bridged complexes), [{cis-Pt(NH3)2}2(µ-OH)(µ-tetrazolato-N1,N2)](2+) (5-H-X) and [{cis-Pt(NH3)2}2(µ-OH)(µ-5-R-tetrazolato-N2,N3)](n+), where R = H (5-H-Y), CH3 (1), C6H5 (2), CH2COOCH2CH3 (3), or CH2COO(-) (4), and n = 2 (5-H-Y, 1-3) or 1 (4). Most tetrazolato-bridged complexes overcame cross-resistance to cisplatin and were more efficiently taken up into cisplatin-resistant cells (L1210R) than into parental cisplatin-sensitive cells (L1210), whereas cisplatin uptake into L1210R was decreased compared with that into L1210. The cellular uptake was most likely controlled by the total charge of the complexes. There was no correlation between the cytotoxicity and the kinetics of the coordinative reactions of 1-4 with 9EtG, but the isomerization involved in the reactions could contribute to determining the higher order structures of the compacted DNA. The cytotoxicity of tetrazolato-bridged complexes appears to correlate with the efficiency of cellular uptake and DNA compaction.

Second- and higher-order structural changes of DNA induced by antitumor-active tetrazolato-bridged dinuclear platinum(II) complexes with different types of 5-substituent.

Here, we used circular dichroism (CD) and fluorescence microscopy (FM) to examine the interactions of a series of antitumor-active tetrazolato-bridged dinuclear platinum(II) complexes, [{cis-Pt(NH3)2}2(µ-OH)(µ-5-R-tetrazolato-N2,N3)](n+) (R=CH3 (1), C6H5 (2), CH2COOCH2CH3 (3), CH2COO(-) (4), n=2 (1-3) or 1 (4)), which are derivatives of [{cis-Pt(NH3)2}2(µ-OH)(µ-tetrazolato-N2,N3)](2+) (5-H-Y), with DNA to elucidate the influence of these interactions on the secondary or higher-order structure of DNA and reveal the mechanism of action. The CD study showed that three derivatives, 1-3, with a double-positive charge altered the secondary structures of calf thymus DNA but that 4, the only complex with a single positive charge, induced almost no change, implying that the B- to C-form conformational change is influenced by ionic attraction. Unexpectedly, single-molecule observations with FM revealed that 4 changed the higher-order structure of T4 DNA into the compact-globule state most efficiently, at the lowest concentration, which was nearly equal to that of 5-H-Y. These contradictory results suggest that secondary structural changes are not necessarily linked to higher-order ones, and that the non-coordinative interaction could be divided into two distinct interactions: (1) ionic attraction and (2) hydrogen bonding and/or van der Waals contact. The relationship between diffusion-controlled non-coordinative DNA interactions and cytotoxicities is also discussed.

Synthesis of antitumor azolato-bridged dinuclear platinum(ii) complexes with in vivo antitumor efficacy and unique in vitro cytotoxicity profiles.

We synthesised four tetrazolato-bridged dinuclear Pt(ii) complexes, [{cis-Pt(NH3)2}2(µ-OH)(µ-5-R-tetrazolato-N2,N3)](n+), where R is CH3 (1), C6H5 (2), CH2COOC2H5 (3), or CH2COO(-) (4) and n = 2 (1-3) or 1 (4). Their structures were characterised by (1)H, (13)C, and (195)Pt NMR spectroscopy, mass spectrometry, and elemental analysis, and the crystal structure of 1 was determined by X-ray crystallography. The cytotoxicities of the complexes to human non-small-cell lung cancer (NSCLC) cell lines sensitive and resistant to cisplatin were assayed. Complex 1 was more cytotoxic than cisplatin in both PC-9 and PC-14 NSCLC cell lines, and cross-resistance to 1 in the cisplatin-resistant cells was largely circumvented. Complex 3 was moderately cytotoxic, whereas 2 and 4 were only marginally cytotoxic. We also determined the growth inhibitory activities of 1 and 3, as well as prototype azolato-bridged complexes [{cis-Pt(NH3)2}2(µ-OH)(µ-pyrazolato)](2+) (AMPZ), [{cis-Pt(NH3)2}2(µ-OH)(µ-1,2,3-triazolato-N1,N2)](2+) (AMTA), [{cis-Pt(NH3)2}2(µ-OH)(µ-tetrazolato-N1,N2)](2+) (5-H-X), and [{cis-Pt(NH3)2}2(µ-OH)(µ-tetrazolato-N2,N3)](2+) (5-H-Y), against a panel of 39 human cancer cell lines (JFCR39). The average 50% growth inhibition concentrations of the complexes against the JFCR39 cell lines ranged from 0.933 to 23.4 µM. The cytotoxicity fingerprints of the complexes based on the JFCR39 cytotoxicity data were similar to one another but completely different from the fingerprints of clinical platinum-based anticancer drugs. Complex 3 exhibited marked antitumor efficiency when tested in vivo on xenografts of PANC-1 pancreatic cancer in nude mice. The high potency of 3 confirmed that the tetrazolato-bridged structure exhibits high in vivo antitumor efficacy.

DNA conformation and repair of polymeric natural DNA damaged by antitumor azolato-bridged dinuclear Pt(II) complex.

Design of new antitumor Pt drugs is currently also focused on those new Pt complexes which form on DNA major adducts that can hardly be removed by DNA repair systems. An attempt of this kind has already been done by designing and synthesizing new antitumor azolato-bridged dinuclear Pt(II) complexes, such as [{cis-Pt(NH(3))(2)}(2)(µ-OH)(µ-pyrazolate)](2+) (AMPZ). This new Pt(II) complex exhibits markedly higher toxic effects in some tumor cell lines than conventional mononuclear cisplatin. The primary objective in the present study was to further delineate differences in the interactions of AMPZ and cisplatin with natural, high-molecular-mass DNA using a combination of biochemical and molecular biophysics techniques. The results demonstrate for the first time that little conformational distortions induced by AMPZ in highly polymeric DNA with a random nucleotide sequence represent a structural motif recognizable by DNA repair systems less efficiently than distortions induced by cisplatin. Thus, DNA adducts of azolato-bridged dinuclear Pt(II) complexes can escape repair mechanisms more easily than those of cisplatin, which may potentiate antitumor effects of these new metallodrugs in cancer cells.

Energetics, conformation, and recognition of DNA duplexes containing a major adduct of an anticancer azolato-bridged dinuclear Pt(II) complex.

BACKGROUND: The design of anticancer metallodrugs is currently focused on platinum complexes which form on DNA major adducts that cannot readily be removed by DNA repair systems. Hence, antitumor azolato-bridged dinuclear Pt(II) complexes, such as [{cis-Pt(NH(3))(2)}(2)(µ-OH)(µ-pyrazolate)](2+) (AMPZ), have been designed and synthesized. These complexes exhibit markedly higher toxic effects in tumor cell lines than mononuclear conventional cisplatin. METHODS: Biophysical and biochemical aspects of the alterations induced in short DNA duplexes uniquely and site-specifically modified by the major DNA adduct of AMPZ, namely 1,2-GG intrastrand cross-links, were examined. Attention was also paid to conformational distortions induced in DNA by the adducts of AMPZ and cisplatin, associated alterations in the thermodynamic stability of the duplexes, and recognition of these adducts by high-mobility-group (HMG) domain proteins. RESULTS: Chemical probing of DNA conformation, DNA bending studies and translesion synthesis by DNA polymerase across the platinum adduct revealed that the distortion induced in DNA by the major adduct of AMPZ was significantly less pronounced than that induced by similar cross-links from cisplatin. Concomitantly, the cross-link from AMPZ reduced the thermodynamic stability of the modified duplex considerably less. In addition, HMGB1 protein recognizes major DNA adducts of AMPZ markedly less than those of cisplatin. GENERAL SIGNIFICANCE: The experimental evidence demonstrates why the major DNA adducts of the new anticancer azolato-bridged dinuclear Pt(II) complexes are poor substrates for DNA repair observed in a previously published report. The relative resistance to DNA repair explains why these platinum complexes show major pharmacological advantages over cisplatin in tumor cells.

An in vivo highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex largely circumvents in vitro cisplatin resistance: two linkage isomers yield the same product upon reaction with 9-ethylguanine but exhibit different cytotoxic profiles.

Cytotoxicity assays of azolato-bridged dinuclear Pt(II) complexes, [{cis-Pt(NH(3))(2)}(2)(µ-OH)(µ-azolato)](2+), where the azolato was pyrazolato (1), 1,2,3-triazolato-N1,N2 (2), tetrazolato-N1,N2 (3), or tetrazolato-N2,N3 (4), were performed in cisplatin-sensitive and -resistant human non-small-cell lung cancer cell lines (PC-9 and PC-14). These complexes largely circumvented the cisplatin resistance in both cell lines, with resistance factors for 1-4 in the range of 0.5-0.8 and 0.9-2.0 for PC-9 and PC-14 cells, respectively. Complex 4 exhibited approximately 10 times the cytotoxicity of 3. When 3 and 4 were reacted with 2 molar equiv. of 9-ethylguanine (9EtG), they yielded an identical product, [{cis-Pt(NH(3))(2)(9EtG-N7)}(2)(µ-tetrazolato-N1,N3)](3+), that had N1,N3 platinum coordination through a Pt(II) migration process on the tetrazolate ring. The second-order rate kinetics of these isomers were almost the same as each other and faster than those of 1 and 2. The cytotoxicity of azolato-bridged complexes, except for 3, increases as their kinetic rates in the 9EtG reaction increase.

A circular dichroism study uncovers a two-step interaction of antitumor azolato-bridged dinuclear platinum(II) complexes with calf thymus DNA.

The interactions of four antitumor azolato-bridged dinuclear platinum(II) complexes, [{cis-Pt(NH(3))(2)}(2)(µ-OH)(µ-azolato)](2+), with calf thymus DNA were monitored dose- and time-dependently, by using circular dichroism. Complexes 1-4 reacted with DNA via a two-step interaction that comprised a prompt diffusion-controlled reaction, which induced a B- to C-form transition, and a relatively slow temperature-dependent reaction.

[Drug discovery research in in-vivo antitumor-active azolato-bridged dinuclear Pt(II) complexes].

Cis-diamminedichloridoplatinum(II) (cisplatin), which was first introduced as a clinical anticancer agent in the 1970s, is still among the most-utilized agents in current cancer chemotherapy. The discovery of cisplatin antitumor activity has catalyzed drug discovery research on antitumor platinum coordination compounds with improved efficacy. Some of new compounds show fewer side effects or expanded clinical applications. Apart from some clinical inconveniences, such as side effects, the high therapeutic efficacy of platinum-based agents implies that further modifications may lead to more effective anticancer platinum drugs which are effective against cancers that are typically resistant to chemotherapy, such as pancreatic cancer, and platinum-refractory cancer. Most of the cisplatin analogs cause cross-resistance to cisplatin, probably because of the similar biological consequences. It is suggested that platinum complexes which interact with DNA; the most probable target molecule, through a mechanism different from that of cisplatin can provide unique anticancer spectra required for next-generation anticancer drugs. Therefore, we synthesized a series of azolato-bridged dinuclear Pt(II) complexes with a general formula, [{cis-Pt(NH(3))(2)}(2)(µ-OH)(µ-azolato)](2+), which can form 1,2-intrastrand crosslinks with a minimal DNA distortion, whereas clinical platinum-based drugs provide 1,2-intrastrand crosslink with severe DNA distortion. Indeed, they exhibit much higher in vitro cytotoxicity than cisplatin, and we have recently found one of the dinuclear Pt(II) complexes exhibits markedly high in vivo antitumor efficacy against pancreatic cancer. Here, I update our drug-discovery research on the series of azolato-bridged dinuclear Pt(II) complexes that may be more effective and safer than current anticancer chemotherapeutic agents.

Next-generation anticancer metallodrugs.

More than 99% of currently approved clinical drugs are organic compounds. In contrast, the percentage of metal-containing drugs (metallodrugs) is very low. In cancer chemotherapy, however, platinum coordination compounds represented by cisplatin and derivatives thereof are essential anticancer agents with proven effects against a variety of tumors. Because of the proven clinical applications of these platinum-based drugs, the number of research initiatives to identify other metallodrugs that can be used for cancer therapy has increased considerably in the field of inorganic biochemistry. Anticancer platinum compounds continue to be designed and synthesized through several different approaches in order to improve the therapeutic effects and to overcome the disadvantages of current platinum-based drugs. The use of transition metal compounds other than platinum has also attracted attention. Gold coordination complexes, for instance, demonstrate outstanding cytotoxic properties, and certain ruthenium complexes possess a strong ability to inhibit metastases of solid invasive tumors. In this review, the potential of anticancer metallodrugs is described and representative examples from the most recent families of Pt-, Ru-, and Au-based compounds are discussed with respect to their possible modes of action and most probable biomolecular targets.

Highly efficient DNA compaction mediated by an in vivo antitumor-active tetrazolato-bridged dinuclear platinum(II) complex.

We investigated the effects of antitumor-active tetrazolato-bridged dinuclear platinum(II) complexes [{cis-Pt(NH(3))(2)}(2)(µ-OH)(µ-tetrazolato-N(1),N(2))](2+) (1) and [{cis-Pt(NH(3))(2)}(2)(µ-OH)(µ-tetrazolato-N(2),N(3))](2+) (2) on the higher-order structure of a large DNA molecule (T4 phage DNA, 166 kbp) in aqueous solution through single-molecule observation by fluorescence microscopy. Complexes 1 and 2 cause irreversible compaction of DNA through an intermediate state in which coil and compact parts coexist in a single DNA molecule. The potency of compaction is in the order 2 > 1 ≫ cisplatin. Transmission electron microscopic observation showed that both complexes collapsed DNA into an irregularly packed structure. Circular dichroism measurements revealed that the dinuclear platinum(II) complexes change the secondary structure of DNA from the B to C form. These characteristics of platinum(II) complexes are markedly different from those of the usual condensing agents such as spermidine(3+) and [Co(III)(NH(3))(6)](3+). The ability to cause DNA compaction by the platinum(II) complexes is discussed in relation to their potent antitumor activity.

Unique platinum-DNA interactions may lead to more effective platinum-based antitumor drugs.

Platinum coordination compounds are among the most utilized anticancer agents, even though platinum has not been determined to be an essential trace element in any living organism. The success of platinum-based drugs has catalyzed research on other metal-containing agents that can be used to achieve therapeutic goals that cannot be achieved with organic compounds. The antitumor activities of recently reported platinum(ii) complexes indicate that further modification of platinum coordination compounds will lead to the development of anticancer agents with higher efficacies against chemotherapy-insensitive tumors.

The phosphate clamp: a small and independent motif for nucleic acid backbone recognition.

The 1.7 Å X-ray crystal structure of the B-DNA dodecamer, [d(CGCGAATTCGCG)]2 (DDD)-bound non-covalently to a platinum(II) complex, [{Pt(NH3)3}2-µ-{trans-Pt(NH3)2(NH2(CH2)6NH2)2}](NO3)6 (1, TriplatinNC-A,) shows the trinuclear cation extended along the phosphate backbone and bridging the minor groove. The square planar tetra-am(m)ine Pt(II) units form bidentate N-O-N complexes with OP atoms, in a Phosphate Clamp motif. The geometry is conserved and the interaction prefers O2P over O1P atoms (frequency of interaction is O2P > O1P, base and sugar oxygens > N). The binding mode is very similar to that reported for the DDD and [{trans-Pt(NH3)2(NH2(CH2)6(NH3(+))}2-µ-{trans-Pt(NH3)2(NH2(CH2)6NH2)2}](NO3)8 (3, TriplatinNC), which exhibits in vivo anti-tumour activity. In the present case, only three sets of Phosphate Clamps were found because one of the three Pt(II) coordination spheres was not clearly observed and was characterized as a bare Pt²(+) ion. Based on the electron density, the relative occupancy of DDD and the sum of three Pt(II) atoms in the DDD-1 complex was 1:1.69, whereas the ratio for DDD-2 was 1:2.85, almost the mixing ratio in the crystallization drop. The high repetition and geometric regularity of the motif suggests that it can be developed as a modular nucleic acid binding device with general utility.