Dinuclear Platinum Compounds Research Articles

Thermally Activated Delayed Fluorescence of a Dinuclear Platinum(II) Compound: Mechanism and Roles of an Upper Triplet State.

A dinuclear Pt(II) compound was reported to exhibit thermally activated delayed fluorescence (TADF); however, the luminescence mechanism remains elusive. To reveal relevant excited-state properties and luminescence mechanism of this Pt(II) compound, both density function theory (DFT) and time-dependent DFT (TD-DFT) calculations were carried out in this work. In terms of the results, the S1 and T2 states show mixed intraligand charge transfer (ILCT)/metal-to-ligand CT (MLCT) characters while the T1 state exhibits mixed ILCT/ligand-to-metal CT (LMCT) characters. Mechanistically, a four-state (S0 , S1 , T1 , and T2 ) model is proposed to rationalize the TADF behavior. The reverse intersystem crossing (rISC) process from the initial T1 to final S1 states involves two up-conversion channels (direct T1 →S1 and T2 -mediated T1 →T2 →S1 pathways) and both play crucial roles in TADF. At 300 K, these two channels are much faster than the T1 phosphorescence emission enabling TADF. However, at 80 K, these rISC rates are reduced by several orders of magnitude and become very small, which blocks the TADF emission; instead, only the phosphorescence is observed. These findings rationalize the experimental observation and could provide useful guidance to rational design of organometallic materials with superior TADF performances.

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.

Associative intraligand substitution of anticancer azolato-bridged compounds without a square-pyramidal intermediate: Formation of a unique tetranuclear, µ3-1,2,3-triazolato-N1,N2,N3-bridged Pt(II) compound

The reaction of the anticancer azolato-bridged dinuclear platinum(II) compound [{cis-Pt(NH3)2}2(µ-OH)(µ-1,2,3-triazolato-N1,N2)](NO3)2 (AMTA) in 0.2 M DCl-D2O solution was monitored at 298 K using 1H NMR spectroscopy. Acid hydrolysis of AMTA first provided a dinuclear Pt(II) cationic species [{cis-Pt(NH3)2Cl}2(µ-1,2,3-triazolato-N1,N2)]+ (intermediate A) which then turned into [{cis-Pt(NH3)2Cl}2(µ-1,2,3-triazolato-N1,N3)]+ (intermediate B) by migration of a Pt(II) ion, initially bound to N2, to N3. Hence, intramolecular ligand substitution of N3 for N2 occurred after substitution of two chloride ligands for the hydroxido bridge. Under the reaction conditions, the intermediate A and B were unambiguously detected, and both or either of the intermediate species then dimerized by a substitution of the chlorido ligand by N3 or N2 of a partner molecule to yield an unprecedented tetranuclear Pt(II) compound [{cis-Pt(NH3)2Cl}µ-{cis-Pt(NH3)2}2(µ-1,2,3-triazolato-N2,N3)2-N1,N1′]Cl2(NO3)2 (compound 1), whose 3D structure has been determined by X-ray crystal analysis. The fact that all triazolate nitrogen atoms coordinated to 3 different Pt(II) ions indicates that 1,2,3-triazolate derivatives could be important as a unique tridentate building block for metal-organic framework.

Ligand modulation of a dinuclear platinum compound leads to mechanistic differences in cell cycle progression and arrest

Despite similar structures and DNA binding profiles, two recently synthesized dinuclear platinum compounds are shown to elicit highly divergent effects on cell cycle progression. In colorectal HCT116 cells, BBR3610 shows a classical G2/M arrest with initial accumulation in S phase, but the derivative compound BBR3610-DACH, formed by introduction of the 1,2-diaminocyclohexane (DACH) as carrier ligand, results in severe G1/S as well as G2/M phase arrest, with nearly complete S phase depletion. The origin of this unique effect was studied. Cellular interstrand crosslinking as assayed by comet analysis was similar for both compounds, confirming previous in vitro results obtained on plasmid DNA. Immunoblotting revealed a stabilization of p53 and concomitant transient increases in p21 and p27 proteins after treatment with BBR3610-DACH. Cell viability assays and cytometric analysis of p53 and p21 null cells indicated that BBR3610-DACH-induced cell cycle arrest was p21-dependent and partially p53-dependent. However, an increase in the levels of cyclin E was observed with steady state levels of CDK2 and Cdc25A, suggesting that the G1 block occurs downstream of CDK/cyclin complex formation. The G2/M block was corroborated with decreased levels of cyclin A and cyclin B1. Surprisingly, BBR3610-DACH-induced G1 block was independent of ATM and ATR. Finally, both compounds induced apoptosis, with BBR3610-DACH showing a robust PARP-1 cleavage that was not associated with caspase-3/7 cleavage. In summary, BBR3610-DACH is a DNA binding platinum agent with unique inhibitory effects on cell cycle progression that could be further developed as a chemotherapeutic agent complementary to cisplatin and oxaliplatin.

Zinc finger peptide cleavage by a dinuclear platinum compound

Electrospray ionisation mass spectrometry (ESI-MS) and {(1)H, (15)N HSQC} NMR spectroscopy has elucidated the binding of a dinuclear platinum compound to a zinc finger peptide with induced backbone cleavage. Cleavage is selective on the N-terminal side of the cysteine residue following incubation at neutral pH, and is further dependent on structure of dinuclear compound.

Cytotoxicity and induction of apoptosis of human breast cancer cells by novel platinum(II) complexes

The current work investigates the influence of novel dinuclear platinum(II) compounds of structure: Pt2(3-ethylpyridine)4(berenil)2 (Pt10) and Pt2(3-butylpyridine)4(berenil)2 (Pt11) on growth and viability of MDA-MB-231 and MCF-7 breast cancer cells as well as their putative mechanism of cytotoxicity. Evaluation of the cytotoxicity of Pt10 and Pt11 employing a MTT assay and inhibition of [3H]thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 breast cancer cells demonstrated that these compounds were more potent antiproliferative agents than cisplatin. In our study the induction of apoptosis by Pt10 and Pt11 in human breast cancer cells was confirmed by several biochemical markers, such as: phosphatidylserine externalization, loss of mitochondrial membrane potential ΔΨm, caspase-3, -8, -9 activity, and DNA degradation. Pt10 and Pt11 induce apoptosis of breast cancer cells via mechanisms dependent on caspases activation and associated with mitochondrial membrane potential disruption.

Mechanistic insights into toxic effects of a benzotriazolate-bridged dinuclear platinum(II) compound in tumor cells

We examined toxicity in tumor cells as well as some early phases of the mechanism underlying biological properties of benzotriazolate (Btaz)-bridged dinuclear PtII complex ([{cis-Pt(NH3)2Cl}2(μ-Btaz-H)]Cl (1)). This dinuclear bifunctional PtII complex utilizes rigid aromatic ring of azole as a linker between two Pt atoms, featuring at the same time non-bridging chloride ions as leaving groups. The results of the present work demonstrate that the toxicity of 1 in several human tumor cell lines was lower than that of conventional cisplatin. The results obtained are consistent with the idea, and support the postulate that deactivation of 1 by sulfur-containing compounds is a significant factor contributing to reduced DNA binding of 1 in cells and subsequently to its reduced cytotoxicity. In addition, the observations that DNA adducts of 1 and cisplatin distort DNA conformation differently and that monofunctional DNA adducts of 1 are converted to more toxic bifunctional cross-links considerably more slowly in comparison with cisplatin may contribute to the reduced cytoxicity of 1. The results of the present work afford further details on the mechanism underlying biological effects of bifunctional polynuclear PtII compounds and should provide a more rational basis for the design of new antitumor metallodrugs and chemotherapeutic strategies.

Combined action of the dinuclear platinum compound BBR3610 with the PI3‐K inhibitor PX‐866 in glioblastoma

Polynuclear platinum compounds are more effective at killing glioblastoma cells than cisplatin, work by a different mechanism, and typically do not induce high levels of apoptosis at early time points after exposure. Here, we tested the hypothesis that combining BBR3610, the most potent polynuclear platinum, with a phosphoinositide-3-kinase (PI3K) inhibitor would promote apoptosis and enhance the impact on glioblastoma cells. The PI3K pathway is commonly activated in glioblastoma and promotes tumor cell survival, suggesting that its inhibition would make cells more sensitive to cytotoxic agents. We chose PX-866 as a PI3K inhibitor as it is a clinically promising agent being evaluated for brain tumor therapy. Combining BBR3610 and PX-866 resulted in synergistic killing of cultured glioma cells and an extension of survival in an orthotopic xenograft animal model. Both agents alone induced autophagy, and this appeared to be saturated, because when they were combined no additional autophagy was observed. However, the combination of PX-866 and BBR3610 did induce statistically significant increases in the level of apoptosis, associated with a reduction in pAkt and pBad, as well as inhibition of transwell migration. We conclude that combining polynuclear platinums with PI3K inhibitors has translational potential and alters the cellular response to include early apoptosis.

Graphical Abstract: Eur. J. Inorg. Chem. 10/2009

AbstractThe cover picture shows an impression of the binding of dinuclear platinum compounds to double‐stranded DNA. Details are presented in the Microreview by J. Reedijk on p. 1303 ff.

Platinum Anticancer Coordination Compounds: Study of DNA Binding Inspires New Drug Design (Eur. J. Inorg. Chem. 10/2009)

AbstractThe cover picture shows an impression of the binding of dinuclear platinum compounds to double‐stranded DNA. Details are presented in the Microreview by J. Reedijk on p. 1303 ff.

Mono- and dinuclear platinum(II) compounds with 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine. Structure, cytotoxic activity and reaction with 5′-GMP

Mono- and dinuclear platinum(II) coordination compounds of formula cis-[PtCl(2)(NH(3))(dmtp)], 1, cis-[PtCl(2)(dmtp)(2)], 2 and {H(+)[C(28)H(32)Cl(2)N(16)Pt(2)](2+)(NO(3))(3)(H(2)O)(6)}, 3, in which dmtp is 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine have been synthesized and characterized by infrared and by (1)H, (13)C, (195)Pt NMR spectroscopy. The coordination units of the cationic species of formula [Pt(2)(mu-dmtp)(2)Cl(2)(dmtp)(2)](2+) are built up by two platinum atoms in a square-planar environment. Two sites are occupied by two 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) bridging ligands which are linked to both metal atoms through their nitrogen atoms in positions 3 and 4. The other two positions are occupied by one monodentate 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) molecule and a coordinated chloride. This compound is the first in which the same triazolopyrimidine ligand (dmtp) coordinates to a metal ion in two different ways, i.e. bridging bidentate and non-bridging monodentate. In addition, the interaction of compounds 1 and 2 with 5'-GMP was investigated in solution by (1)H NMR spectroscopy. The cytotoxicity of all the new platinum(II) compounds were studied by using two different cell lines: T47D (breast cancer) and HCV29T (bladder cancer).

{μ-N,N′-Bis[(E)-4-pyridylmethylidene]naphthalene-1,5-diamine}bis[dichlorido(dimethyl sulfide)platinum(II)

The title dinuclear platinum compound, [Pt2Cl4(C22H16N4)(C2H6S)2], with a long bridging bipyridyl-type ligand, is centrosymmetric and the PtII cation shows a slightly distorted square-planar coordination geometry. The Cl ligands are trans to each other, with a Cl—Pt—Cl angle of 178.83 (8)°. The pyridine ring forms a dihedral angle of 48.8 (2)° with the planar PtCl2SN unit. Within the mol­ecule, the distance between Pt atoms is 20.262 (5) Å and the N⋯N separation between the terminal pyridyl rings is 16.23 (1)Å.

New mononuclear and homodinuclear Pt(ii) complexes with heterocyclic nitrogen chelates: Synthesis, characterization, intercalating ability and in vitro cytotoxic activity evaluation

A series of new mononuclear and dinuclear platinum(ii) compounds based on two bipyridyl systems, linked by an alkyl chain {1,2-bis[4-(4'-methyl-2,2'-bipyridinyl)]ethane, L2, (a), and 1,6-bis[4-(4'-methyl-2,2'-bipyridinyl)]hexane, L6, (b)} have been synthesized and characterized by IR and multinuclear and multidimensional NMR spectroscopy. The coordination sphere of the complexes, designed to give intercalating and/or covalent interactions with DNA, is completed only by exchangeable (Cl(-), I(-) or H(2)O) and/or not leaving (chelate ethylenediamine, en) saturating ligands. Quenching of the DNA-ethidium fluorescence was performed in order to verify the intercalating capability of the water soluble compounds. Furthermore, the in vitro cytotoxicity of all water soluble complexes has been assessed with respect to cisplatin on platinum-sensitive human endometrium (HeLa) and platinum-resistant human breast (MCF-7) cancer cell lines.

The First Example of a Dinuclear Platinum(III) Complex with Three Bridging Ligands

AbstractThe first triply bridged dinuclear platinum(III) compound with acetamidate ligands, X[Pt2Cl4{N(H)C(CH3)O}3] (X = K+ or AsPh4+), has been isolated in the solid state and characterized by one‐ and two‐dimensional NMR spectroscopy and X‐ray crystallography. Owing to the asymmetry of the bridging acetamidate ligands, three isomers can be formed (HHH, HHT, and HTH), although only two are found in the crude reaction product: HHT and HTH. The HTH species is thermodynamically less stable and slowly (half life of around two days at room temperature) isomerizes into the HHT form. The more stable and less symmetric HHT isomer crystallizes from chloroform/pentane (AsPh4+ counter ion). The two [Pt2Cl4{N(H)C(CH3)O}3]– anions of the unit cell are linked by two strong N–H···O H‐bonds while contiguous anions of adjacent cells are linked together by two, slightly weaker N–H···Cl H‐bonds. The result is a chain of anions running along the a direction. The crystal packing allows for the formation of one‐dimensional pore channels, also running along the a direction, which are filled with disordered pentane molecules. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Effects of geometric isomerism in dinuclear antitumor platinum complexes on their interactions with N-acetyl-L-methionine

In this study, the reactions of N-acetyl-L-methionine (AcMet) with [{trans-PtCl(NH(3))(2)}(2)-mu-H(2)N(CH(2))(6)NH(2)](NO(3))(2) (BBR3005: 1,1/t,t 1) and its cis analog [{cis-PtCl(NH(3))(2)}(2)-mu-{H(2)N(CH(2))(6)NH(2)}]Cl(2) (1,1/c,c 2) were analyzed to determine the rate and reaction profile of chloride substitution by methionine sulfur. The reactions were studied in PBS buffer at 37 degrees C by a combination of multinuclear ((195)Pt, {(1)H-(15)N} HSQC) magnetic resonance (NMR) spectroscopy and electrospray ionization time of flight mass spectrometry (ESITOFMS). The diamine linker of the 1,1/t,t trans complex was released as a result of the trans influence of the coordinated sulfur atom, producing trans-[PtCl(AcMet)(NH(3))(2)](+) (III) and trans-[Pt(AcMet)(2)(NH(3))(2)](2+) (IV). In contrast the cis geometry of the dinuclear compound maintained the diamine bridge intact and a number of novel dinuclear platinum compounds obtained by stepwise substitution of sulfur on both platinum centers were identified. These include (charges omitted for clarity): [{cis-PtCl(NH(3))(2)}-mu-NH(2)(CH(2))(6)NH(2)-{cis-Pt(AcMet)(NH(3))(2)}] (V); [{cis-Pt(AcMet)(NH(3))(2)}(2)-mu-NH(2)(CH(2))(6)NH(2)] (VI); [{cis-PtCl(NH(3))(2)}-mu-NH(2)(CH(2))(6)NH(2)-{PtCl(AcMet)NH(3)] (VII); [{PtCl(AcMet)(NH(3))}(2)-mu-NH(2)(CH(2))(6)NH(2)] (VIII); [{trans-Pt(AcMet)(2)(NH(3))}-mu-NH(2)(CH(2))(6)NH(2)-{PtCl(AcMet)(NH(3))] (IX) and the fully substituted [{trans-Pt(AcMet)(2)(NH(3))}(2)-mu-{NH(2)(CH(2))(6)NH(2)] (X). For both compounds the reactions with methionine were slower than those with glutathione (Inorg Chem 2003, 42:5498-5506). Further, the 1,1/c,c geometry resulted in slower reaction than the trans isomer, because of steric hindrance of the bridge, as observed previously in reactions with DNA and model nucleotides.

Vapochromic Behavior Accompanied by Phase Transition between Charge-Polarization and Charge-Density-Wave States in a Quasi-One-Dimensional Iodine-Bridged Dinuclear Platinum Compound

Farbsinn: Der reversible Phasenübergang, der in einer Halogen-verbrückten zweikernigen 1D-Platinverbindung [NH3(C4H8)NH3]2[Pt2(pop)4I]⋅4 H2O (pop=P2O5H22−) beim Kontakt mit Wasserdampf auftritt, wird von einer Farb- und Strukturänderung begleitet (siehe die in Reflexion aufgenommenen Mikroskopbilder). Der Wechsel erfolgt zwischen einem paramagnetischen Ladungspolarisierungszustand (296 K) und einem diamagnetischen Ladungsdichtewellenzustand (340 K).

Vapochromic Behavior Accompanied by Phase Transition between Charge‐Polarization and Charge‐Density‐Wave States in a Quasi‐One‐Dimensional Iodine‐Bridged Dinuclear Platinum Compound

Color sense: A reversible phase transition occurs with a change in color and structural properties on exposure to water vapor of the 1D halogen-bridged dinuclear platinum compound [NH3(C4H8)NH3]2[Pt2(pop)4I]⋅4 H2O (pop=P2O5H22−; see microscope images in reflection mode). This transition takes place between a paramagnetic charge-polarization state (296 K) and a diamagnetic charge-density-wave state (340 K).

Trifunctional dinuclear platinum complexes as DNA-protein cross-linking agents.

The trifunctional dinuclear platinum compounds 1,2/c,c [[cis-PtCl(NH(3))(2)]mu-H(2)N(CH(2))(6)NH(2)[cis-PtCl(2)(NH(3))]](+) and 1,2/t,c [[trans-PtCl(NH(3))(2)]mu-H(2)N(CH(2))(6)NH(2)[cis-PtCl(2)(NH(3))]](+) contain a monofunctional platinum coordination sphere linked to a cis-[PtCl(2)(amine)(2)] moiety. The compounds have been examined for their DNA binding and ability to induce covalent ternary DNA-protein cross-links. Comparison was made with representative bifunctional dinuclear platinum compounds [[PtCl(NH(3))(2)](2)mu-H(2)N(CH(2))(n)NH(2)](2+). DNA modified by the trifunctional compounds is able to bind and cross-link BamHI, a sequence-specific DNA-binding protein that recognizes the palindromic sequence GGATCC and also very efficiently binds and cross-links SP1, a sequence-specific Zn finger protein that induces a bend in the DNA upon binding. Two representative nonsequence-specific DNA-binding proteins, the Klenow fragment from DNA polymerase I and Klenow exonuclease minus (which has been mutated to remove the 3'-5' proofreading domain), both bind modified DNA and effectively cross-link to the DNA. Data from circular dichroism, inhibition of ethidium bromide fluorescence, interstrand cross-linking and unwinding assays are all consistent with (Pt,Pt) interstrand cross-links as the dominant lesion of trifunctional compounds and the most likely structure to form the ternary DNA-protein cross-links. In vitro transcription of RNA is inhibited by the platinum compounds and indicate G residues as primary binding sites. Binding to calf thymus DNA as assessed by differential pulse polarography is rapid and essentially quantitative. An increase in melting temperature of CT DNA adducted by the platinum compounds is observed at low salt concentrations but at high salt, modification results in a decrease of t(m). In summary, the trifunctional agents may find use as protein-targeting drugs and as probes for conformational effects on DNA-protein interactions.

Stable η1-Alkynyl−μ,η1:η2-Alkenyl Complexes from the Reaction of Terminal Alkynes with Encumbered Dinuclear Platinum Compounds and Their Formyl, Methoxycarbonyl, and Hydride Derivatives

The stepwise reaction of terminal alkynes with [(OC)Pt(μ-PBut2)2Pt(H)(PBut2H)]OTf yields intermediate η1-alkynyl−hydride-bridged complexes, and then stable η1-alkynyl/alkenyl-bridged derivatives co...

Circular dichroism study of the irreversibility of conformational changes induced by polyamine-linked dinuclear platinum compounds

In this work, the reversibility of both the B→Z and B→A conformational change in polymer DNA induced by polynuclear platinum compounds was studied. The compounds examined were: [{trans-PtCl(NH3)2}2{NH2 (CH2)6NH2}]2+ (BBR3005); [{trans-PtCl(NH3)2}2{μ-spermine-N1,N12}]4+ (BBR3535); [{trans-PtCl(NH3)2}2{μ-spermidine-N1,N8}]3+ (BBR3571); [{trans-PtCl(NH3)2}2{μ-BOC-spermidine}]2+ (BBR3537); and [{trans-PtCl(NH3)2}2{μ-trans-Pt(NH3)2(H2N(CH2)6NH2)2}]4+ (BBR3464). The conformational changes were assessed by circular dichroism and the reversibility of the transitions was tested by subsequent titration with the DNA intercalator ethidium bromide (EtBr). Fluorescent quenching was also used to assess the ability of ethidium bromide to intercalate into A and/or Z-DNA induced by the compounds. The results were compared with those produced by the simple hexamminecobalt cation [Co(NH3)6]3+. The data suggest that while conformational changes induced by electrostatic interactions are confirmed to be reversible, covalent binding induces irreversible changes in both the A and Z conformation. The relevance of these changes to the novel biological action of polynuclear platinum compounds is discussed.