Trinuclear Platinum Research Articles

Enhanced Electrical Conductivity of Polyoxometalates by Bridging with Mixed‐Valent Multinuclear Platinum Complexes

AbstractPolyoxometalates (POMs) are nanosized molecular metal oxide anion clusters with tuneable structures and functionalities, and they exhibit a redox chemistry and catalytic activity in multielectron redox processes. These are typically poor electrical conductors (<10−10 Scm−1), which is attributed to negligible electronic interactions among anions in the solid state. Since the reduced electrons on the d0 metals in POMs are delocalized, electrical conductivity was improved when judicious pathways for the electrons were created by bridging the POMs. Utilized with the electronic interactions between bridging oxygen atoms with the highest occupied molecular orbital in the POMs and the metal dz2 orbitals in the multinuclear platinum complexes, and three mixed‐valent assemblies were synthesized and characterized. Simply mixing Keggin‐type or Dawson‐type POMs with tetranuclear or trinuclear platinum complexes in solution afforded three single crystals, and all three compounds were paramagnetic with mixed oxidation states and better conductivities at room temperature than the parent compounds.

Enhanced Electrical Conductivity of Polyoxometalates by Bridging with Mixed-Valent Multinuclear Platinum Complexes.

Polyoxometalates (POMs) are nanosized molecular metal oxide anion clusters with tuneable structures and functionalities, and they exhibit a redox chemistry and catalytic activity in multielectron redox processes. These are typically poor electrical conductors (<10-10 Scm-1), which is attributed to negligible electronic interactions among anions in the solid state. Since the reduced electrons on the d0 metals in POMs are delocalized, electrical conductivity was improved when judicious pathways for the electrons were created by bridging the POMs. Utilized with the electronic interactions between bridging oxygen atoms with the highest occupied molecular orbital in the POMs and the metal dz2 orbitals in the multinuclear platinum complexes, and three mixed-valent assemblies were synthesized and characterized. Simply mixing Keggin-type or Dawson-type POMs with tetranuclear or trinuclear platinum complexes in solution afforded three single crystals, and all three compounds were paramagnetic with mixed oxidation states and better conductivities at room temperature than the parent compounds.

Platinum(IV)-Gold(I) Agents with Promising Anticancer Activity: Selected Studies in 2D and 3D Triple-Negative Breast Cancer Models.

New heterometallic binuclear and trinuclear platinum(IV)-gold(I) compounds of the type [Pt(L)n Cl2 (OH){(OOC-4-C6 H4 -PPh2 )AuCl}x ] (L=NH3 , n=2; x=1, 2; L=diaminocyclohexane, DACH, n=1; x=2) are described. These compounds are cytotoxic and selective against a small panel of renal, bladder, ovarian, and breast cancer cell lines. We selected a trinuclear PtAu2 compound containing the PtIV core based on oxaliplatin, to further investigate its cell-death pathway, cell and organelle uptake and anticancer effects against the triple-negative breast cancer (TNBC) MDA-MB-231 cell line. This compound induces apoptosis and accumulates mainly in the nucleus and mitochondria. It also exerts remarkable antimigratory and antiangiogenic properties, and has a potent cytotoxic effect against TNBC 3D spheroids. Trinuclear compounds do not seem to display relevant interactions with calf thymus (CT) DNA and plasmid (pBR322) even in the presence of reducing agents, but inhibit pro-angiogenic enzyme thioredoxin reductase (TrxR) in TNBC cells.

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.

Probing Disaccharide Binding to Triplatin as Models for Tumor Cell Heparan Sulfate (GAG) Interactions.

In this study, we have used [1H, 15N] NMR spectroscopy to investigate the interactions of the trinuclear platinum anticancer drug triplatin (1) (1,0,1/t,t,t or BBR3464) with site-specific sulfated and carboxylated disaccharides. Specifically, the disaccharides GlcNS(6S)-GlcA (I) and GlcNS(6S)-IdoA(2S) (II) are useful models of longer-chain glycosaminoglycans (GAGs) such as heparan sulfate (HS). For both the reactions of 15N-1 with I and II, equilibrium conditions were achieved more slowly (65 h) compared to the reaction with the monosaccharide GlcNS(6S) (9 h). The data suggest both carboxylate and sulfate binding of disaccharide I to the Pt with the sulfato species accounting for <1% of the total species at equilibrium. The rate constant for sulfate displacement of the aqua ligand (kL2) is 4 times higher than the analogous rate constant for carboxylate displacement (kL1). There are marked differences in the equilibrium concentrations of the chlorido, aqua, and carboxy-bound species for reactions with the two disaccharides, notably a significantly higher concentration of carboxylate-bound species for II, where sulfate-bound species were barely detectable. The trend mirrors that reported for the corresponding dinuclear platinum complex 1,1/t,t, where the rate constant for sulfate displacement of the aqua ligand was 3 times higher than that for acetate. Also similar to what we observed for the reactions of 1,1/t,t with the simple anions, aquation of the sulfato group is rapid, and the rate constant k-L2 is 3 orders of magnitude higher than that for displacement of the carboxylate (k-L1). Molecular dynamics calculations suggest that extra hydrogen-bonding interactions with the more sulfated disaccharide II may prevent or diminish sulfate binding of the triplatin moiety. The overall results suggest that Pt-O donor interactions should be considered in any full description of platinum complex cellular chemistry.

A novel star-shaped trinuclear platinum(II) complex based on a 1,3,5-triazine core displaying potent antiproliferative activity against TNBC by the mitochondrial injury and DNA damage mechanism.

Polynuclear platinum(II) complexes represent a class of great prospective Pt-based antitumor drugs that may expand the antitumor spectrum and overcome the clinical problems of drug resistance and side effects of platinum-based drugs. Herein, a novel star-shaped trinuclear platinum(II) complex [Pt3(L-3H)Cl3] (1, L = 2,4,6-tris[(2-hydroxybenzyl)(2-pyridylmethyl)amine]-1,3,5-triazine) and its monomer [Pt(L'-H)Cl] (2, L' = (2-hydroxybenzyl)(2-pyridylmethyl)amine) were synthesized and characterized. The in vitro antiproliferative activities of complexes 1 and 2 against a panel of human cancer cell lines including MDA-MB-231 (triple-negative breast cancer, TNBC), MCF-7 (breast), HepG-2 (liver), and A549 (lung) were investigated. The results revealed that 1 exhibited much higher antiproliferative properties than its monomer 2 against the tested cell lines. Importantly, 1 possessed 3.3-fold higher antiproliferative activity as compared with cisplatin against the TNBC cell line MDA-MB-231. Another TNBC cell line MDA-MB-468 is also sensitive to 1. The results indicated that 1 might have the potential to act as a candidate for the treatment of TNBC. Cellular uptake and distribution studies showed that 1 could pass through the membrane of cells and enter into cells and mainly accumulate in the nuclei and mitochondria. 1 could bind to DNA in a cooperative groove-electrostatic-platinating binding mode and induce stronger DNA double-strand breaks (DSBs) and damaging effects on MDA-MB-231 than cisplatin (upregulation of γ-H2AX). Moreover, the DNA damage could not be easily repaired (upregulation of p53), which would exert a much positive influence on the overcoming of drug resistance. Additionally, flow cytometry studies showed that 1 arrested the cell cycle in the G0/G1 phase, induced mitochondrial membrane depolarization, increased ROS generation, and induced cell apoptosis. The results demonstrated that 1 could target simultaneously mitochondria and nuclei that gave rise to mitochondrial injury and DNA damage and ultimately efficiently promote the apoptotic death of tumor cells. Further mechanistic studies showed that 1 induced MDA-MB-231 cell apoptosis via the p53-mediated mitochondrial pathway by upregulating Bax and cytochrome c and downregulating Bcl-2 proteins, leading to the activation of caspase-3 and upregulation of the cleaved-PARP level. Taken together, 1 with such a synergic mechanism has great potential to be an effective anticancer agent that can overcome treatment resistance in TNBC.

Coordination Methods of Thioligands in Trinuclear Complexes of Platinum (II)

The trinuclear complexes with simple and mixed ligands of platinum (II) with mercaptoethanol and mercaptoethylamine have been generated and their contents and structures investigated by numerous physicochemical methods. Mercaptoethanol (SHCH2CH2OH) is coordinated monodentally with just sulfur atom and forms pentacyclic metalchelate ring, where as mercaptoethylamine (HSCH2CH2NH2) is coordinated monodentally as well as bidentally and forms an identical ring (pentacyclic metalchelate). The sulfur atom of ligands plays a bridge role between the metals in the trinuclear platinum complexes. The hydroxyl group of mercaptoethanol does not participate in the coordination

DNA Structural Distortions Induced by a Monofunctional Trinuclear Platinum Complex with Various Cross-Links Using Molecular Dynamics Simulation.

The monofunctional trinuclear platinum complex (MTPC), as a promising antitumor agent, can form MTPC-DNA adducts via bifunctional and trifunctional cross-links. Molecular dynamics simulations were used to investigate DNA structural distortions of the MTPC-DNA adducts. MTPC coordinating to DNA results in the decrease of base-pair thermal stability and DNA structural distortions. It is found that there are more significant DNA structural distortions in the trifunctional cross-link than in the bifunctional cross-link, in the 1,4-GG than in the 1,3-GG cross-link, and in the intrastrand than in the interstrand cross-link with the same spans. The results provide a better understanding of DNA structural distortions induced by MTPC with various cross-links at the nucleotide level and are helpful for exploring novel Pt-based anticancer drugs.

A Triangular Platinum(II) Multinuclear Complex with Cytotoxicity Towards Breast Cancer Stem Cells.

The preparation of multinuclear metal complexes offers a route to novel anticancer agents and delivery systems. The potency of a novel triangular multinuclear complex containing three platinum atoms, Pt-3, towards breast cancer stem cells (CSCs) is reported. The trinuclear platinum(II) complex, Pt-3 exhibits selective toxicity towards breast CSCs over bulk breast cancer cells and non-tumorigenic breast cells. Remarkably, Pt-3 inhibits the formation, size, and viability of mammospheres to a better extent than salinomycin, an established CSC-potent agent, and cisplatin and carboplatin, clinically used platinum drugs. Mechanism of action studies show that Pt-3 effectively enters breast CSCs, penetrates the nucleus, induces genomic DNA damage, and prompts caspase-dependent apoptosis. To the best of our knowledge, Pt-3 is the first multinuclear platinum complex to selectively kill breast CSCs over other breast cell types.

A Triangular Platinum(II) Multinuclear Complex with Cytotoxicity Towards Breast Cancer Stem Cells

AbstractThe preparation of multinuclear metal complexes offers a route to novel anticancer agents and delivery systems. The potency of a novel triangular multinuclear complex containing three platinum atoms, Pt‐3, towards breast cancer stem cells (CSCs) is reported. The trinuclear platinum(II) complex, Pt‐3 exhibits selective toxicity towards breast CSCs over bulk breast cancer cells and non‐tumorigenic breast cells. Remarkably, Pt‐3 inhibits the formation, size, and viability of mammospheres to a better extent than salinomycin, an established CSC‐potent agent, and cisplatin and carboplatin, clinically used platinum drugs. Mechanism of action studies show that Pt‐3 effectively enters breast CSCs, penetrates the nucleus, induces genomic DNA damage, and prompts caspase‐dependent apoptosis. To the best of our knowledge, Pt‐3 is the first multinuclear platinum complex to selectively kill breast CSCs over other breast cell types.

Glycans as Ligands in Bioinorganic Chemistry. Probing the Interaction of a Trinuclear Platinum Anticancer Complex with Defined Monosaccharide Fragments of Heparan Sulfate

We report herein a detailed NMR study of the aquation and subsequent covalent binding of the trinuclear clinical agent [{ trans-PtCl(15NH3)2}2{μ- trans-Pt(15NH3)2(15NH2(CH2)615NH2)2}]4+ (1, 1,0,1/ t, t, t or Triplatin) with three d-glucosamine residues containing varied O-sulfate and N-sulfate or N-acetyl substitutions, which represent monosaccharide fragments present within the repeating disaccharide sequences of cell surface heparan sulfate (HS). The monosaccharides GlcNS(6S), GlcNS, and GlcNAc(6S) were synthesized in good yield from a common 4,6-diol α-methyl glucopyranoside intermediate. The reactions of 15N-1 with sodium sulfate, GlcNS(6S), GlcNS, and GlcNAc(6S) were followed by 2D [1H,15N] heteronuclear single quantum coherence (HSQC) NMR spectroscopy using conditions (298 K, pH ≈5.4) similar to those previously used for other anionic systems, allowing for a direct comparison. The equilibrium constants (p K1) for the aquation of 1 in the presence of GlcNS(6S) and GlcNS were slightly higher compared to that of the aquation in a sulfate solution, while a comparable p K1 value was observed in the presence of GlcNAc(6S). A comparison of the rate constants for sulfate displacement of the aqua ligand showed preferential binding to 2- N-sulfate compared to 6- O-sulfate but a more rapid liberation. For disulfated GlcNS(6S), equilibrium conditions were achieved rapidly (9 h) and strongly favored the dichloro form, with <2% sulfato species observed. The value of kL1 was up to 15-fold lower than that for binding to sulfate, whereas the rate constant for the reverse ligation ( k-L1) was comparable. Equilibrium conditions were achieved much more slowly (∼ 100 h) for the reactions of 1 with GlcNS and GlcNAc(6S), attributed to covalent binding also to the N-donor of the sulfamate (GlcNS) group and the O-donor of the N-acetyl [GlcNAc(6S)] group. The rate constants ( kL2) were 20-40-fold lower than that for binding to the 2- N- or 6- O-sulfate, but the binding was less reversible, so that their equilibrium concentrations (5-8%) were comparable to the 2- N- or 6- O-sulfate-bound species. The results emphasize the relevance of glycans in bioinorganic chemistry and underpin a fundamental molecular description of the HS-Pt interactions that alter the profile of platinum agents from cytotoxic to metastatic in a systematic manner.

The trinuclear platinum(ii) complex in Vèzes' red salt as a building block of coordination polymers.

One-dimensional (1D) and three-dimensional (3D) coordination polymers comprising triangular [Pt3(NO2)6(μ3-O)]2- ([Pt3]2-) units were prepared from K2[Pt3]·3H2O (1), also known as Vèzes' red salt. The reaction between 1 and excess 18-crown-6 ether afforded the 1D coordination polymer [K(18-crown-6)]2[Pt3] (2), whereas the reaction between 1, excess 18-crown-6 ether, and AgPF6 afforded the 1D coordination polymer [Ag(18-crown-6)]2[Pt3]·(CH3)2CO (3). However, the reaction between 1 and equimolar amounts of 18-crown-6 and AgPF6 afforded the 3D coordination polymer [Ag2(18-crown-6)][Pt3]·(CH3)2CO (4). Furthermore, the 3D coordination polymer [Ag2Pt3(μ3-O)(NO2)6((CH3)2CO)2]·(CH3)2CO (5) containing three Pt2+ → Ag+ dative bonds was obtained by the reaction of 1, Bu4NPF6, and AgPF6. The N2, O2, and CO2 gas absorption isotherms of 1-5 were obtained, revealing that the dry crystals of 4 exhibit a selective CO2 absorption ability.

Synthesis, characterization and DNA interactions of [Pt3(TPymT)Cl3], the trinuclear platinum(II) complex of the TPymT ligand

The triplatinum complex of the 2,4,6-Tris(2-pyrimidyl)-1,3,5-triazine ligand, Pt3TPymT hereafter, has been prepared and characterized for the first time. NMR studies point out that the three platinum(II) centers possess an identical coordination environment. The interactions of Pt3TPymT with DNA were explored in comparison to the free ligand. Specifically, fluorescence, mass spectrometry, viscometry and melting measurements were carried out. In contrast to expectations, the obtained data reveal that no intercalative binding takes place; we propose that binding of Pt3TPymT to DNA mainly occurs through external/groove binding.

Hydrosilylation of Aromatic Aldehydes and Ketones Catalyzed by Mono- and Tri-Nuclear Platinum(0) Complexes

Abstract Hydrosilylation of aromatic aldehydes and acetophenone with H2SiPh2 was studied by using Pt complexes as the catalyst. Reaction of aromatic aldehydes, such as PhCHO, 4-FC6H4CHO, 4-MeC6H4CHO and 4-CF3C6H4CHO with H2SiPh2 in the presence of [Pt(PPh3)3] catalyst proceeds smoothly at room temperature with similar reaction rates. The hydrosilylation of PhCHO with H2Si(C6H4-4-Me)2 proceeds faster than that with H2SiPh2. Comparison of the reactions of PhCHO with H2SiPh2 and with D2SiPh2 demonstrated a large kinetic isotope effect (3.1). The hydrosilylation of the aldehydes catalyzed by [Pt(PMe3)(μ-SiPh2)]3, reported in our previous paper, shows large dependence of the reaction rate on the aryl group of the substrate, in the order, 4-MeC6H4CHO ≫ PhCHO = 4-FC6H4CHO &amp;gt; 4-CF3C6H4CHO. Hydrosilylation of (3-vinyl)benzaldehyde and 10-undecenal in the presence of [Pt(PPh3)3] catalyst occurs at the carbonyl group selectively to form the corresponding alkoxysilanes. The hydrosilylation of acetophenone with H2SiPh2 catalyzed by [Pt(PPh3)3] forms 1-phenylethyl(diphenylsilyl)ether, while the reaction using the Pt3 catalyst is accompanied by dehydrosilylation to yield a mixture of the saturated and unsaturated silyl ethers.

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.

Linear Triplatinum Tetrahydride Complex Supported by Triphosphine Ligands, [Pt3(µ‐H)2(H)2(µ‐dpmp)2](BF4)2 {dpmp = bis(diphenylphosphinomethyl)phenylphosphine}

By treating [Pt6(µ‐H)(H)2(µ‐dpmp)4]BH4 [4, dpmp = bis(diphenylphosphinomethyl)phenylphosphine] with an excess amount of HBF4 in N,N‐dimethylformamide (DMF), a triplatinum tetrahydride complex, [Pt3(µ‐H)2(H)2(µ‐dpmp)2](BF4)2 (5), was obtained in 51 % yield and was characterized by IR, UV/Vis, 1H NMR, and 31P{1H} NMR spectroscopy in addition to ESI mass spectrometry, X‐ray crystallography, and DFT calculations. Complex 5 is composed of linear trinuclear platinum centers supported by two dpmp ligands, {Pt3(µ‐dpmp)2}6+, which accommodate two terminal and two bridging hydrides in a HPtHPtHPtH zigzag structure. The hydride positions were determined by DFT optimization with B3LYP/GD3BJ functionals. Variable‐temperature 1H{31P} NMR spectroscopy in [D7]DMF revealed that the bridging hydrides exhibit fluxional behavior and migrate along the Pt3 chain by switching the bridging site, whereas the terminal hydrides are not exchanged with the bridging ones. The present results suggest that the divalent linear triplatinum unit of {Pt3(µ‐dpmp)2}2+ (Pt3II), which is a building block to construct [Pt6(µ‐H)(H)2(µ‐dpmp)4]+ (4, Pt3IIPt3II), formally acts as a four‐electron source to result in [Pt3(µ‐H)2(H)2(µ‐dpmp)2]2+ (5, Pt3VI) through protonation.

Inhibition of nuclear factor kappaB proteins-platinated DNA interactions correlates with cytotoxic effectiveness of the platinum complexes.

Nuclear DNA is the target responsible for anticancer activity of platinum anticancer drugs. Their activity is mediated by altered signals related to programmed cell death and the activation of various signaling pathways. An example is activation of nuclear factor kappaB (NF-κB). Binding of NF-κB proteins to their consensus sequences in DNA (κB sites) is the key biochemical activity responsible for the biological functions of NF-κB. Using gel-mobility-shift assays and surface plasmon resonance spectroscopy we examined the interactions of NF-κB proteins with oligodeoxyribonucleotide duplexes containing κB site damaged by DNA adducts of three platinum complexes. These complexes markedly differed in their toxic effects in tumor cells and comprised highly cytotoxic trinuclear platinum(II) complex BBR3464, less cytotoxic conventional cisplatin and ineffective transplatin. The results indicate that structurally different DNA adducts of these platinum complexes exhibit a different efficiency to affect the affinity of the platinated DNA (κB sites) to NF-κB proteins. Our results support the hypothesis that structural perturbations induced in DNA by platinum(II) complexes correlate with their higher efficiency to inhibit binding of NF-κB proteins to their κB sites and cytotoxicity as well. However, the full generalization of this hypothesis will require to evaluate a larger series of platinum(II) complexes.

Potent in vitro antiproliferative properties for a triplatinum cluster toward triple negative breast cancer cells

The trinuclear platinum cluster [Pt3(μ-PBut2)3(CO)3]CF3SO3 (I) was designed featuring the presence of a nearly equilateral platinum triangle bridged by three di-tert-butylphosphide ligands; in addition, each platinum center bears a terminal carbonyl ligand. This triplatinum cluster was initially developed in view of applications in the field of cluster-containing innovative materials. Yet, due to the large success of platinum complexes in cancer treatment, we also decided to explore its cytotoxic and anticancer properties. Accordingly, the solubility profile of this compound in several solvents was preliminarily investigated, revealing a conspicuous solubility in DMSO and DMSO/buffer mixtures; this makes the biological testing of I amenable. UV–Vis measurements showed that the triplatinum cluster is stable for several hours under a variety of conditions, within aqueous environments. No measurable reactivity was observed for I toward two typical model proteins, i.e. lysozyme and cytochrome c. On the contrary, a significant reactivity was evidenced when reacting I with small sulfur-containing ligands. In particular, a pronounced reactivity with reduced glutathione and cysteine emerged from ESI-MS experiments, proving complete formation of I-GSH and I-Cys derivatives, with the loss of a single carbonyl ligand. Starting from these encouraging results, the cytotoxic potential of I was assayed in vitro against a panel of representative cancer cell lines, and potent cytotoxic properties were disclosed. Of particular interest is the finding that the triplatinum species manifests potent antiproliferative properties toward Triple Negative Breast Cancer Cells, often refractory to most anticancer drugs. Owing to the reported encouraging results, a more extensive biological and pharmacological evaluation of this Pt cluster is now warranted to better elucidate its mode of action.

The phosphate clamp as recognition motif in platinum–DNA interactions

This review summarizes studies on substitution-inert polynuclear platinum complexes (PPCs) which bind to DNA through the phosphate clamp – a discrete mode of DNA–ligand recognition distinct from the canonical intercalation and minor-groove binding. Especially, this review concentrates on comparing the binding and conformational changes induced by trinuclear platinum complexes with dinuclear spermine-linked complexes. The protonated central polyamine –+NH2–(CH2)4–N+H2– of spermine allows direct comparison with the central Pt(tetraamine) moiety of the trinuclear complexes. The weight of the evidence suggests that while overall charge on the small molecule determines binding affinity, the presence of minor groove spanning from the phosphate clamp is important in conformational changes and in sequence selectivity.

Competitive formation of DNA linkage isomers by a trinuclear platinum complex and the influence of pre-association.

2D [(1)H, (15)N] HSQC NMR spectroscopy has been used to monitor the reaction of fully (15)N-labelled [{trans-PtCl(NH3)2}2(μ-trans-Pt(NH3)2{NH2(CH2)6NH2}2)](4+) (BBR3464 ((15)N-1)) with the 14-mer duplex (5'-{d(ATACATG(7)G(8)TACATA)}-3'·5'-{d(TATG(18)TACCATG(25)TAT)}-3' or I) at pH 5.4 and 298 K, to examine the possible formation of 1,4 and 1,5-GG adducts in both 5'-5' and 3'-3' directions. In a previous study, the binding of the dinuclear 1,1/t,t to I showed specific formation of the 5'-5' 1,4 G(8)G(18) cross-link, whereas in this case a mixture of adducts were formed. Initial (1)H NMR spectra suggested the presence of two pre-associated states aligned in both directions along the DNA. The pre-association was studied in the absence of covalent binding, by use of the "non-covalent" analog [{trans-Pt(NH3)3}2(μ-trans-Pt(NH3)2{NH2(CH2)6NH2}2)](6+) (AH44, 0). Chemical shift changes of DNA protons combined with NOE connectivities between CH2 and NH3 protons of 0 and the adenine H2 protons on I show that two different molecules of 0 are bound in the minor groove. Molecular dynamic simulations were performed to study the interaction of 0 at the two pre-association sites using charges derived from density functional theory (DFT) calculations. Structures where the central platinum is located in the minor groove and the aliphatic linkers extend into the major groove, in opposite directions, often represent the lowest energy structures of the snapshots selected. In the reaction of (15)N-1 and I, following the pre-association step, aquation occurs to give the mono aqua monochloro species 2, with a rate constant of 3.43 ± 0.03 × 10(-5) s(-1). There was evidence for two monofunctional adducts (3, 4) bound to the 3' (G8) and 5' (G7) residues and the asymmetry of the (1)H,(15)N peak for 3 suggested two conformers of the 3' adduct, aligned in different directions along the DNA. The rate constant for combined monofunctional adduct formation (0.6 ± 0.1 M(-1)) is ca. 2-fold lower for 1 compared to 1,1/t,t, whereas the rate constant for conversion of the combined monofunctional species to combined bifunctional adducts (5) (8.0 ± 0.2 × 10(-5) s(-1)) is two-fold higher.