Trinuclear Platinum Complex Research Articles

Syntheses of Di- and Trinuclear Platinum Complexes with Multibridged Germanium Centers Derived from Unsymmetrical Digermanes

A trigonal-bipyramidal Pt3Ge2 cluster was synthesized by the reaction of the zerovalent platinum complex [Pt(dppe)(η2-C2H4)] (dppe = 1,2-bis(diphenylphosphino)ethane) with the unsymmetrical digermane H3GeGeEt3 at a 3/2 molar ratio. The platinum centers formed a triangular plane bridged by two germylyne ligands, one of which maintained the Ge–Ge bond. To investigate the Pt3Ge2 cluster formation process, the phenyl-substituted digermanes HPh2GeGeMe3 and H2PhGeGeR3 (R = Me, Et), in which two hydrogen atoms and one hydrogen atoms of the reactive GeH3 moiety were replaced by the bulkier phenyl group(s) together with the substitution of the GeEt3 group by a GeMe3 group, respectively, were used to simplify the reaction system. They provided the digermylplatinum hydride [Pt(dppe)(H)(GePh2GeMe3)] (2) and the bis(μ-germylene)diplatinum complexes [Pt2(dppe)2(μ-GeHPh)(μ-Ge(Ph)GeR3)] (3, R = Me; 4, R = Et) in moderate yields, respectively. For 3 and 4, the first-formed digermylplatinum hydride I-1 underwent dissociati...

Efficacy of newly developed platinum complexes against osteosarcoma, bone-targeting platinum, and proteasome inhibitory platinum.

10075 Background: Cisplatin is one of the most effective anti-cancer drugs available for the treatment of human solid tumors including osteosarcoma. As we had already reported, we have utilized caffeine in our chemotherapy protocol. And we achieved excellent clinical results. But effectiveness of cisplatin has been limited by side effects, and resistance. Here we developed two novel platinum compounds. 3Pt is trinuclear platinum complex bearing geminal bisphosphonate moieties, 1Pt is mononuclear platinum complex which has proteasome inhibitory activity. We performed comparative studies of our novel platinum compounds with osteosarcoma. Methods: Two novel platinum complexes were synthesized by Prof. Odani at school of pharmaceutical sciences of our university and cisplatin and caffeine were obtained from constructor. Three cell lines (MG63, 143B, and LM8) were used. Cell survival after a 72 hrs exposure to these compounds was assessed by WST-8 assay, and IC50 value was calculated for each compound. Apoptosis was assessed by DNA fragmentation and Annexin V-FITC/propidium iodine assay. Results: Each compound strongly caused concentration-dependent cytocidal effect. IC50 value of trinuclear compound is superior to cisplatin, and both complexes showed caffeine potentiation. Apoptosis induction and acetylation of histon H2AX were observed. In vivo, 1Pt showed almost same, 3Pt showed strong antitumor effect compared to cisplatin. Conclusions: Two novel platinum compounds that we developed showed strong ant-tumor effect in osteosarcoma in vitro and in vivo. As bisphosphonate has high affinity to calcium ions, 3Pt targets bone tissue and expected to reduce side effects at extraskeletal sites and to overcome the drug resistance. Proteasome inhibitory platinum compound has never been reported before, we will investigate its anti-tumor mechanism precisely.

Increased toxicity of a trinuclear Pt-compound in a human squamous carcinoma cell line by polyamine depletion

BackgroundMononuclear platinum anticancer agents hold a pivotal place in the treatment of many forms of cancers, however, there is a potential to improve response to evade resistance development and toxic side effects. BBR3464 is a promising trinuclear platinum anticancer agent, which is a polyamine mimic. The aim was to investigate the influence of polyamine pool reduction on the cytotoxic effects of the trinuclear platinum complex BBR3464 and cisplatin. Polyamine pool reduction was achieved by treating cells with either the polyamine biosynthesis inhibitor α-difluoromethylornithine (DFMO) or the polyamine analogue N1,N11-diethylnorspermine (DENSPM).MethodsA human squamous cell carcinoma cell line, LU-HNSCC-4, established from a primary head and neck tumour was used to evaluate cellular effects of each drug alone or combinations thereof. High-performance liquid-chromatography was used to quantify intracellular polyamine contents. Inductively coupled mass spectroscopy was used to quantify intracellular platinum uptake. Cells were exposed to DFMO or DENSPM during 48 h at concentrations ranging from 0 to 5 mM or 0 to 10 μM, respectively. Thereafter, non-treated and treated cells were exposed to cisplatin or BBR3464 during 1 h at concentrations ranging from 0 to 100 μM. A 96-well assay was used to determine cytotoxicity after five days after treatment.ResultsThe cytotoxic effect of BBR3464 on LU-HNSCC-4 cells was increased after cells were pre-treated with DENSPM or DFMO, and the interaction was found to be synergistic. In contrast, the interaction between cisplatin and DFMO or DENSPM was near-additive to antagonistic. The intracellular levels of the polyamines putrescine and spermidine were decreased after treatment with DFMO, and treatment with DENSPM resulted in an increase in putrescine level and concomitant decrease in spermidine and spermine levels. The uptake of BBR3464 was significantly increased after pre-treatment of the cells with DFMO, and varied dependent on the concentration of DENSPM. The uptake of cisplatin was unchanged.ConclusionsTaken together, these results demonstrate that combinations of polyamine synthesis inhibitors with BBR3464 appear to be a promising approach to enhance the anticancer activity against HSCC.

Sulfur containing platinum(ii) complexes with N-heterocyclic carbene ligands obtained by reactions of a hydrosulfido complex

A hydrosulfido platinum(ii) complex with a chelated N-heterocyclic carbene (NHC) ligand was oxidised with O(2) in the presence of excess hydrogen sulfide, to give a linear tetrasulfido complex, and without hydrogen sulfide, to give a thiosulfato-bridged dinuclear complex. The hydrosulfido complex also reacted with an acetato complex containing the chelating NHC platinum unit to afford a trinuclear platinum complex with two triply bridging sulfido ligands showing an equilibrium in solution between two isomers based on the arrangement of the chelating NHC ligands.

Unique DNA Binding Mode of Antitumor Trinuclear Tridentate Platinum(II) Compound

The new trinuclear tridentate Pt(II) complex [Pt(3)Cl(3)(hptab)](3+) (1; hptab = N,N,N',N',N'',N''-hexakis(2-pyridylmethyl)-1,3,5-tris(aminomethyl)benzene) exhibits promising cytotoxic effects in human and mouse tumor cells including those resistant to conventional cisplatin (Dalton Trans. 2006, 2617; Chem. Eur. J. 2009, 15, 5245). The present study is focused on the molecular pharmacology of 1, in particular on its interactions with DNA (which is the major pharmacological target of platinum antitumor drugs), to elucidate more deeply the mechanism underlying its antitumor effects. Results obtained with the aid of methods of molecular biophysics and pharmacology reveal new details of DNA modifications by 1. Complex 1 binds to DNA forming in the absence of proteins and molecular crowding agents mainly trifunctional intrastrand cross-links. In these DNA adducts all three Pt(II) centers of 1 are coordinated to DNA base residues, which leads to extensive conformational alterations in DNA. An intriguing aspect of the DNA-binding mode of this trinuclear Pt(II) complex 1 is that it can cross-link proteins to DNA. Even more interestingly, 1 can cross-link in the presence of molecular crowding agent, which mimics environmental conditions in cell nucleus, two DNA duplexes in a high yield--a feature observed for the first time for antitumor trinuclear platinum complexes. Thus, the concept for the design of agents capable of forming intramolecular tridentate DNA adducts, DNA-protein and interduplex DNA-DNA cross-links based on trinuclear tridentate Pt(II) complexes with semirigid aromatic linkers may result in new compounds which exhibit a variety of biological effects and can be also useful in nucleic acids research.

Methimazole complexes of platinum(II): Synthesis, characterization and redox behavior

A variety of platinum(II) complexes of methimazole (2-mercapto-1-methylimidazole; HImS=neutral form and ImS=thiolate form), coordinated in both thione and thiolate forms, have been isolated by reacting methimazole with [PtCl(terpy)]Cl (terpy=2,2′:6′,2″ terpyridine), [PtCl2(bipy)] (bipy=bipyridine), [PtCl2(o-phen)] (o-phen=o-phenanthroline), [PtCl2(CH3CN)2] and [PtCl2(COD)] (COD=1,5-cyclooctadiene). These complexes were characterized by electronic absorption, IR and NMR (1H, 13C, 195Pt) spectroscopies. Molecular structure of [Pt(bipy)(HImS)2]Cl2·3H2O (3a·3H2O) has been established by single crystal X-ray crystallography. Platinum thiolate complex, [Pt(ImS)2(HImS)2] (5), could be obtained by treatment of [Pt(HImS)4]Cl2 with sodium methoxide in methanol. The solution of 5 in organic solvents yielded bi- and tri-nuclear platinum complexes. The effect of diimine ligands on oxidation of methimazole moiety in the complexes has been studied by electrochemical oxidation and pulse radiolytic oxidation employing specific one-electron oxidant, N3 radical.

ChemInform Abstract: Excited State Properties of the Low-Valent Bi- and Trinuclear Complexes of Palladium and Platinum

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Syntheses of mono- and dinuclear silylplatinum complexes bearing a diphosphino ligand via stepwise bond activation of unsymmetric disilanes

Zero-valence platinum complex [Pt(dppe)(eta(2)-C(2)H(4))] (1, dppe = 1,2-bis(diphenylphosphino)ethane) treated with disilanes HR(1)R(2)SiSiMe(3) (a, R(1) = R(2) = Me; b, R(1) = R(2) = Ph; c, R(1) = H, R(2) = Ph) afforded the corresponding disilanylplatinum hydrides [Pt(dppe)(H)(SiR(1)R(2)SiMe(3))] (2a-c) by oxidative addition of the Si-H bond to the platinum center. The 1,2-silyl migration in 2a,b led to the formation of bis(silyl)platinum complexes [Pt(dppe)(SiHR(1)R(2))(SiMe(3))] (3a,b) with a first-order rate constant of 7.2(2) x 10(-4) s(-1) at 25 degrees C for 2a and 3.86(4) x 10(-4) s(-1) at 40 degrees C for 2b, whereas 2c with R(1) = H followed by the transient generation of 3c dimerized rapidly to give the bis(mu-silylene)diplatinum complex [Pt(dppe)(mu-SiHPh)](2) (4c) in a mixture of cis/trans isomers. Heating of the toluene solution of 3b at 100 degrees C resulted in a similar dimerization to 4b. In addition, a trinuclear platinum complex [Pt(3)(dppe)(3)(mu(3)-SiPh)(2)] (5) with a trigonal bipyramidal Pt(3)Si(2) core arose from the reaction of 4c with 1 at 60 degrees C in toluene. Unsymmetric disilanes therefore accomplished the syntheses of various monomeric and dimeric platinum complexes via 1,2-hydrogen and silyl migration to the platinum center.

Synthesis and Structure of a Trinuclear Platinum Complex with μ3-Silylyne Ligands Derived from a Disilane

The platinum complex [Pt(dppe)(η2-C2H4)] (1) reacted with the disilane H2SiMeSiMe3, affording the bis(μ-silylyne)triplatinum complex [Pt3(dppe)3(μ3-SiMe)2] (4) by a stepwise Si−H and Si−Si bond activation.

DNA Cross‐Linking Patterns Induced by an Antitumor‐Active Trinuclear Platinum Complex and Comparison with Its Dinuclear Analogue

The DNA binding and cross-linking modes of a trinuclear platinum complex [Pt(3)Cl(3)(hptab)][ClO(4)](3) (1; hptab = N,N,N',N',N'',N''-hexakis(2-pyridylmethyl)-1,3,5-tris(aminomethyl)benzene) and its dinuclear analogue [Pt(2)Cl(2)(m-tpxa)]Cl(2) (2; m-tpxa = N,N,N',N'-tetra(2-pyridylmethyl)-m-xylylene diamine) are reported and compared. The adducts of 1 and 2 with 18-mer duplex N1, 5'-d(GAAGAAGTCACAAAATGT)-3'5'-d(ACATTTTGTGACTTCTTC)-3', have been characterized by means of denaturing polyacrylamide gels, Maxam-Gilbert sequencing, and MALDI-TOF mass spectrometry combined with enzymatic degradation to obtain insights into structural features responsible for the differences in their antitumor activities. The cytotoxic-active complex 1 readily forms various DNA adducts, such as through 1,3- and 1,4-intrastrand cross-links, and in particular, the unique and unprecedented interstrand cross-linked triadducts. In contrast, the cytotoxic-inactive complex 2 preferentially forms 1,4-intrastrand rather than 1,3-intra- and -interstrand cross-links. Digestion of the DNA adducts of 1 shows that the cleavage is completely blocked at one nucleotide before the cross-linked guanine residues on the opposite strand, a feature that appears to be unprecedented in antitumor platinum complexes. In the case of 2, the cleavage bypasses the first platinated guanine site and stops at one nucleotide prior to the second platinated site, confirming that very few 1,3-intrastrand cross-links are formed by 2. These results are supported by molecular-modeling studies of intra- and interstrand cross-links of duplex N1 with 1 and 2. The remarkable differences between 1 and 2 in DNA binding and cross-linking provide mechanistic insights into their different cytotoxicity against the tumor cell lines; these insights are useful for designing future antitumor agents.

Structural consequences of a 3'-->3' DNA interstrand cross-link by a trinuclear platinum complex: unique formation of two such cross-links in a 10-mer duplex.

Combined multidimensional nuclear magnetic resonance spectroscopy and electrospray mass spectrometry was used to analyze the platinated DNA adduct of the phase II anticancer drug [[trans-PtCl(NH(3))(2)](2)-mu-[trans-Pt(NH(3))(2)(NH(2)(CH(2))(6)NH(2))(2)]](NO(3))(4) (BBR3464) with [5'-d(ACG*TATACG*T)-3'](2). Two 1,2-interstrand cross-links were formed by concomitant binding of two trinuclear moieties to the oligonucleotide. The four DNA-bound platinum atoms coordinated in the major groove at N7 positions of guanines in the 3' --> 3' direction and the central platinum unit is expected to lie in the DNA minor groove. This is the first report of such a DNA lesion. The melting temperature of the adduct is 76 degrees C and is 42 degrees C higher than that of the unplatinated DNA. The sugar residues of the platinated bases are in the N-type conformation and the G9 nucleoside is in the syn orientation, while the G3 nucleoside appears to retain the anti configuration. The secondary structure of DNA was significantly changed upon cross-linking of the two BBR3464 molecules. Base destacking occurs between A1/C2 and C2/G3 and weakened stacking is seen for the C8/G9 and G9/T10 bases. The lack of Watson-Crick base pairing is also seen for A1-T10 and C2-G9 base pairs, whereas Watson-Crick base pairs in the central sequence of the DNA (T4 --> A7) are well maintained. While DNA repair proteins may "see" different platinated adducts as bulky "lesions", the subtle differences involved in base pairing and stacking, as summarized here, may extend to their role as a substrate for repair enzymes. Thus, differences in protein recognition and repair efficiency among the various interstrand cross-links are likely and a subject worthy of detailed exploration.

Synthesis and Activity of a Trinuclear Platinum Complex: [{trans‐PtCl(NH3)2}2μ‐{trans‐Pt(3‐hydroxypyridine)2(H2N(CH2)6NH2)2}]Cl4 in Ovarian Cancer Cell Lines

This paper describes the synthesis, characterisation, and cytotoxicity of a novel trinuclear platinum complex code named TH1. In addition to its activity against human ovarian cancer cell lines: A2780, A2780(cisR), and A2780(ZD0473R), cell uptake, DNA-binding, and the nature of the compound interaction with pBR322 plasmid DNA have been determined. TH1 is found to be significantly more cytotoxic than cisplatin - two times more active than cisplatin against the parent cell line A2780, thirteen times more active against the cisplatin-resistant cell line A2780(cisR) and 11.5 times more active against the cell line A2780(ZD0473R). Whereas the resistance factors for cisplatin as applied to the cell lines A2780 and A2780(cisR), and A2780 and A2780(ZD0473R) are 12.9 and 3.0 respectively, the corresponding values for TH1 are 1.98 and 0.5. The results suggest that TH1 has been able to significantly overcome resistance in A2780(cisR) and A2780(ZD0473R) cell lines. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH1 should bind with DNA forming mainly interstrand GG adducts that would cause more of a global change in DNA conformation. Provided it has favourable toxicity profile, TH1 has the potential to be developed into a highly active anticancer drug with a wider spectrum of activity than cisplatin.

カテコール型デヒドロベンゾ[12]アヌレンを配位子とする三核白金錯体の合成と性質

カテコール型デヒドロベンゾ[12]アヌレンを配位子とする三核白金錯体の合成と性質

Trinuclear Platinum(II) 4,6-Diphenyl-2,2‘-bipyridyl Complex with Bis(diphenylphosphinomethyl)phenylphosphine Auxiliary Ligand: Synthesis, Structural Characterization, and Photophysics

A trinuclear cyclometalated Pt(II) 4,6-diphenyl-2,2'-bipyridyl complex with bis(diphenylphosphinomethyl)phenylphosphine bridging ligand ([4-Ph(C--N--N)Pt](3)dpmp) has been synthesized and characterized. It exhibits a broad electronic absorption band from 400 to 600 nm because of its intramolecular Pt...Pt interactions that have been revealed by X-ray crystal structure analysis. This complex shows strong red emission in acetonitrile at room temperature and 77 K. The electronic and emission spectra exhibit concentration and temperature dependence. With increased concentrations, the UV band of the absorption spectrum gradually decreases and broadens, accompanied by an increase of the (1)[dsigma*,pi*] band between 400 and 600 nm. For emission spectra, the 550 nm band that originates from the mononuclear platinum(II) component gradually decreases with increased concentrations, while the band at approximately 700 nm that corresponds to the (3)[dsigma*,pi*] state increases. In addition, the UV-vis and emission spectra exhibit temperature and viscosity-dependence. The concentration-, temperature-, and viscosity-dependent characteristics indicate a conformational change of the complex arising from the rotation along the oligophosphine axis. This complex exhibits broad, positive, and strong transient difference absorption bands from the near-UV to near-IR spectral region. However, because of the increased ground-state absorption in the visible region, the nonlinear transmission of this trinuclear platinum complex decreases.

Alkylthio Bridged 44 cve Triangular Platinum Clusters: Synthesis, Oxidation, Degradation, Ligand Substitution, and Quantum Chemical Calculations

Acetylplatinum(II) complexes trans-[Pt(COMe)Cl(L)2] (L = PPh3, 2a; P(4-FC6H4)3, 2b) were found to react with dialkyldisulfides R2S2 (R = Me, Et, Pr, Bu; Pr = n-propyl, Bu = n-butyl), yielding trinuclear 44 cve (cluster valence electrons) platinum clusters [(PtL)3(mu-SR)3]Cl (4). The analogous reaction of 2a-b with Ph2S2 gave SPh bridged dinuclear complexes trans-[{PtCl(L)}2(mu-SPh)2] (5), whereas the addition of Bn2S2 (Bn = benzyl) to 2a ended up in the formation of [{Pt(PPh3)}3(mu3-S)(mu-SBn)3]Cl (6). Theoretical studies based on the AIM theory revealed that type 4 complexes must be regarded as triangular platinum clusters with Pt-Pt bonds whereas complex 6 must be treated as a sulfur capped 48 ve (valence electrons) trinuclear platinum(II) complex without Pt-Pt bonding interactions. Phosphine ligands with a lower donor capability in clusters 4 proved to be subject to substitution by stronger donating monodentate phosphine ligands (L' = PMePh2, PMe2Ph, PBu3) yielding clusters [(PtL')3(mu-SR)3]Cl (9). In case of the reaction of clusters 4 and 9 with PPh2CH2PPh2 (dppm), a fragmentation reaction occurred, and the complexes [(PtL)2(mu-SMe)(mu-dppm)]Cl (12) and [Pt(mu-SMe)2(dppm)] (13) were isolated. Furthermore, oxidation reactions of cluster [{Pt(PPh3)}3(mu-SMe)3]Cl (4a) using halogens (Br2, I2) gave dimeric platinum(II) complexes cis-[{PtX(PPh3)}2(mu-SMe)2] (14, X = Br, I) whereas oxidation reactions using sulfur and selenium afforded chalcogen capped trinuclear 48 ve complexes [{Pt(PPh3)}3(mu3-E)(mu-SMe)3] (15, E = S, Se). All compounds were fully characterized by means of NMR and IR spectroscopy, microanalyses, and ESI mass spectrometry. Furthermore, X-ray diffraction analyses were performed for the triangular cluster 4a, the trinuclear complex 6, as well as for the dinuclear complexes trans-[{Pt(AsPh3)}2(mu-SPh)2] (5c), [{Pt(PPh3)}2(mu-SMe)(mu-dppm)]Cl (12a), and [{{PtBr(PPh3)}2(mu-SMe)2] (14a).

Crystal structure and infrared analysis of a new trinuclear platinum(II) complex with L-cysteine

A new trinuclear platinum(II) complex with cysteine of composition [Pt(C3H6NO2S)Cl]3·(C2H6SO)3 was obtained and structurally characterized by X-ray diffraction and infrared analysis. The compound crystallizes in the trigonal system, space group R3, and is described in a hexagonal cell with a=17.739(1), c=9.531(1) and Z=3. Cysteine is coordinated to Pt(II) through the nitrogen and sulphur atoms. Each cysteine sulphur bridges between two metal atoms. A square planar coordination sphere of platinum is completed by a chlorine atom. The complex is soluble in dimethyl sulfoxide.

Mechanism of the Membrane Interaction of Polynuclear Platinum Anticancer Agents. Implications for Cellular Uptake

The interaction between phospholipids and polynuclear platinum drugs was studied as a mechanism model for cellular uptake of anticancer drugs. The interaction was studied by differential scanning calorimetry (DSC), 31P nuclear magnetic resonance spectroscopy (NMR), inductively coupled plasma optical emission spectroscopy (ICP-OES), and electrospray ionization mass spectrometry (ESI-MS). The transition temperature, enthalpy, and entropy of negatively charged phospholipids DPPS, DPPA, and DPPG were changed upon reaction with the trinuclear platinum complex [{trans-PtCl(NH3)2}2mu-Pt(NH3)2{H2N(CH2)6NH2}2](NO3)4 (I, BBR3464) and the dinuclear analogue [{trans-PtCl(NH3)2}mu-{(NH2)(CH2)3NH2(CH2)4(NH2)}Cl3 (II, BBR3571). This suggests that these platinum complexes interacted not only with the phosphate headgroup but also with the region of the fatty acid tail of liposomes and finally changed the fluidity of the membrane. Both noncovalent (presumably electrostatic and hydrogen bonding) and covalent interactions were involved in the reactions of the negatively charged phospholipids DPPA, DPPS, and DPPG with the highly positively charged platinum complexes. In contrast, few differences were seen for the zwitterionic phospholipids DPPC and DPPE. The binding ratio of BBR3464 to DPPA liposomes was higher than the ratio of BBR3464 to DPPS liposomes, and similar differences were seen for BBR3571. The binding ratios of the platinum complexes to negatively charged phospholipids DPPA, DPPS, and DPPG were slightly lower in a 100 mM chloride solution than in a chloride-free solution. The binding of BBR3464 and BBR3571 with the liposomes was significantly stronger than that with cis-[PtCl2(NH3)2], cisplatin. ESI-MS confirmed that the products of the incubation of BBR3464 with DPPA and DPPS correspond to chloride displacement and formation of [Pt3(NH3)6{NH2(CH2)6NH2}2(DPPA)2]2+ (1) and [Pt3(NH3)6{NH2(CH2)6NH2}2(DPPS)2]2+ (2), respectively. Similar observations were made for BBR3571. 31P NMR spectra confirmed that the site of binding for DPPA was the phosphate oxygen, whereas for DPPS, a binding site of the nitrogen of the serine side chain is indicated. Noncovalent interactions were also confirmed by use of the analogue [{Pt(NH3)3}2mu-Pt(NH3)2{H2N(CH2)6NH2}2](NO3)6 (III, 0,0,0/t,t,t). The implications of these results for the mechanism of cellular uptake of polynuclear platinum complexes are discussed.

Synthesis, Characterization, and Cytotoxicity of a Novel Highly Charged Trinuclear Platinum Compound. Enhancement of Cellular Uptake with Charge

Charge delocalization (6+ to 8+) in "noncovalent" linear trinuclear platinum complexes produces compounds with cytotoxicity in some cases equivalent to cisplatin. The cellular uptake of a novel 8+ compound is greater than that of neutral cisplatin as well as other multinuclear Pt compounds.

Mechanistic studies on monodentate–ligand substitution of five-coordinate trigonal-bipyramidal platinum (II) complexes with tris[2-(diphenylphosphino)ethyl]phosphine

Reaction of the five-coordinate trigonal-bipyramidal platinum(II) complex, [Pt(pt)(pp 3)](BF 4) (pt = 1-propanethiolate, pp 3 = tris[2-(diphenylphosphino)ethyl]phosphine), with I − in chloroform gave the five-coordinate square-pyramidal complex with a dissociated terminal phosphino group and an apically coordinated iodide ion in equilibrium. The thermodynamic parameters for the equilibrium between the trigonal-bipyramidal and square-pyramidal geometries, [Pt(pt)(pp 3)] + + I − ⇄ [PtI(pt) (pp 3)], and the kinetic parameters for the chemical exchange were obtained as follows: K ex 298 = 7.5 × 10 - 1 mol - 1 kg , Δ H 0 = − 10 ± 2.4 kJ mol −1, Δ S 0 = − 36 ± 10 J K −1 mol −1, k ex 298 = 1.3 × 10 4 s - 1 , Δ H ‡ = 34 ± 4.7 kJ mol −1, Δ S ‡ = − 50 ± 21 J K −1 mol −1. The square-planar trinuclear platinum(II) complex was formed by bridging reaction of one of the terminal phosphino groups of trigonal-bipyramidal [PtCl(pp 3)]Cl with trans-[PtCl 2(NCC 6H 5) 2] in chloroform. From these facts, ligand substitution reactions of [PtX(pp 3)] + (X = monodentate anion) are expected to proceed via an intermediate with a dissociated phosphino group. The rate constants for the chloro-ligand substitution reactions of [PtCl(pp 3)] + with Br − and I − in chloroform approached the respective limiting values as concentrations of the entering halide ions are increased. These kinetic results confirmed the preassociation mechanism in which the square pyramidal intermediate with a dissociated phosphino group and an apically coordinated halide ion is present in the rapid pre-equilibrium.

Comparison of structural effects in 1,4 DNA–DNA interstrand cross-links formed by dinuclear and trinuclear platinum complexes

The novel anticancer drug ([{ trans-PtCl(NH 3) 2} 2-μ-{ trans-Pt(NH 3) 2(NH 2(CH 2) 6NH 2) 2}](NO 3) 4) (BBR3464, 1,0,1/t,t,t, TPC) forms a 1,4-interstrand cross-linked adduct with the self-complementary DNA octamer 5′-d(ATG*TACAT) 2-3′, with the two platinum atoms coordinated in the major groove at N7 positions of guanines four base pairs apart on opposite DNA strands [Y. Qu, N.J. Scarsdale, M.-C. Tran, N. Farrell, J. Biol. Inorg. Chem. 8 (2003) 19–28]. The structure of the identical cross-link formed by the dinuclear [{ trans-PtCl(NH 3) 2} 2-μ-NH 2(CH 2) 6NH 2}](NO 3) 2 (BBR3005, 1,1/t,t, DPC) was examined for comparison. The adduct was characterized and analyzed by MS, UV and NMR spectroscopy. NMR analysis of the adduct shows platination of the unique guanine residues. The strong H8/H1′ intraresidue cross-peaks observed for all purine residues (A1, G3, A5 and A7) are consistent with a syn-conformation of the nucleoside unit in all cases. Thus, the structure resembles closely that formed by the trinuclear compound. Further confirmation of this similarity comes from the increase in melting temperature (66° for DPC, 60° for TPC, 22° for free oligonucleotide). Since DNA is the principal target in vivo for these Pt cross-linking agents, the unique structural perturbations induced by these cross-links may be related to the increased cytotoxicity and antitumor activity of polynuclear platinum compounds as compared to cisplatin ( cis-DDP). The similarity in the structures suggests opportunities to “deliver” the cross-link in a more efficient manner than the current clinically tested drug.