Importance of platinum(II)-assisted platinum(IV) substitution for the oxidation of guanosine derivatives by platinum(IV) complexes

Guanosine derivatives with a nucleophilic group at the 5' position (G-5') are oxidized by the Pt (IV) complex Pt( d, l)(1,2-(NH 2) 2C 6H 10)Cl 4 ([Pt (IV)(dach)Cl 4]). The overall redox reaction is autocatalytic, consisting of the Pt (II)-catalyzed Pt (IV) substitution and two-electron transfer between Pt (IV) and the bound G-5'. In this paper, we extend the study to improve understanding of the redox reaction, particularly the substitution step. The [Pt (II)(NH 3) 2(CBDCA-O,O')] (CBDCA = cyclobutane-1,1-dicarboxylate) complex effectively accelerates the reactions of [Pt (IV)(dach)Cl 4] with 5'-dGMP and with cGMP, indicating that the Pt (II) complex does not need to be a Pt (IV) analogue to accelerate the substitution. Liquid chromatography/mass spectroscopy (LC/MS) analysis showed that the [Pt (IV)(dach)Cl 4]/[Pt (II)(NH 3) 2(CBDCA-O,O')]/cGMP reaction mixture contained two Pt (IV)cGMP adducts, [Pt (IV)(NH 3) 2(cGMP)(Cl)(CBDCA-O,O')] and [Pt (IV)(dach)(cGMP)Cl 3]. The LC/MS studies also indicated that the trans, cis-[Pt (IV)(dach)( (37)Cl) 2( (35)Cl) 2]/[Pt (II)(en)( (35)Cl) 2]/9-EtG mixture contained two Pt (IV)-9-EtG adducts, [Pt (IV)(en)(9-EtG)( (37)Cl)( (35)Cl) 2] and [Pt (IV)(dach)(9-EtG)( (37)Cl)( (35)Cl) 2]. These Pt (IV)G products are predicted by the Basolo-Pearson (BP) Pt (II)-catalyzed Pt (IV)-substitution scheme. The substitution can be envisioned as an oxidative addition reaction of the planar Pt (II) complex where the entering ligand G and the chloro ligand from the axial position of the Pt (IV) complex are added to Pt (II) in the axial positions. From the point of view of reactant Pt (IV), an axial chloro ligand is thought to be substituted by the entering ligand G. The Pt (IV) complexes without halo axial ligands such as trans, cis-[Pt(en)(OH) 2Cl 2], trans, cis-[Pt(en)(OCOCF 3) 2Cl 2], and cis, trans, cis-[Pt(NH 3)(C 6H 11NH 2)(OCOCH 3) 2Cl 2] ([Pt (IV)(a,cha)(OCOCH 3) 2Cl 2], satraplatin) did not react with 5'-dGMP. The bromo complex, [Pt (IV)(en)Br 4], showed a significantly faster substitution rate than the chloro complexes, [Pt (IV)(en)Cl 4] and [Pt (IV)(dach)Cl 4]. The results indicate that the axial halo ligands are essential for substitution and the Pt (IV) complexes with larger axial halo ligands have faster rates. When the Pt (IV) complexes with different carrier ligands were compared, the substitution rates increased in the order [Pt (IV)(dach)Cl 4] < [Pt (IV)(en)Cl 4] < [Pt (IV)(NH 3) 2Cl 4], which is in reverse order to the carrier ligand size. These axial and carrier ligand effects on the substitution rates are consistent with the BP mechanism. Larger axial halo ligands can form a better bridging ligand, which facilitates the electron-transfer process from the Pt (II) to Pt (IV) center. Smaller carrier ligands exert less steric hindrance for the bridge formation.     

Oxidation of guanosine derivatives by a platinum(IV) complex: internal electron transfer through cyclization

Many transition-metal complexes mediate DNA oxidation in the presence of oxidizing radiation, photosensitizers, or oxidants. The DNA oxidation products depend on the nature of the metal complex and the structure of the DNA. Earlier we reported trans-d,l-1,2-diaminocyclohexanetetrachloroplatinum (trans-Pt(d,l)(1,2-(NH(2))(2)C(6)H(10))Cl(4), [Pt(IV)Cl(4)(dach)]; dach = diaminocyclohexane) oxidizes 2'-deoxyguanosine 5'-monophosphate (5'-dGMP) to 7,8-dihydro-8-oxo-2'-deoxyguanosine 5'-monophosphate (8-oxo-5'-dGMP) stoichiometrically. In this paper we report that [Pt(IV)Cl(4)(dach)] also oxidizes 2'-deoxyguanosine 3'-monophosphate (3'-dGMP) stoichiometrically. The final oxidation product is not 8-oxo-3'-dGMP, but cyclic (5'-O-C8)-3'-dGMP. The reaction was studied by high-performance liquid chromatography, (1)H and (31)P nuclear magnetic resonance, and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The proposed mechanism involves Pt(IV) binding to N7 of 3'-dGMP followed by nucleophilic attack of a 5'-hydroxyl oxygen to C8 of G and an inner-sphere, 2e(-) transfer to produce cyclic (5'-O-C8)-3'-dGMP and [Pt(II)Cl(2)(dach)]. The same mechanism applies to 5'-d[GTTTT]-3', where the 5'-dG is oxidized to cyclic (5'-O-C8)-dG. The Pt(IV) complex binds to N7 of guanine in cGMP, 9-Mxan, 5'-d[TTGTT]-3', and 5'-d[TTTTG]-3', but no subsequent transfer of electrons occurs in these. The results indicate that a good nucleophilic group at the 5' position is required for the redox reaction between guanosine and the Pt(IV) complex.     

Electrophilic substitution of (diamine)tetrahydroxoplatinum(IV) with carboxylic anhydrides. Synthesis and characterization of (diamine)platinum(IV) complexes of mixed carboxylates

A novel series of (diamine)platinum(IV) complexes of mixed carboxylates have been synthesized by electrophilic substitution of the tetrahydroxoplatinum(IV) complex (dach)Pt(OH)4 (dach = trans-(+/-)-1,2-diaminocyclohexane) with three different carboxylic anhydrides, pivalic, acetic, and trifluoroacetic anhydrides. Consecutive two-step acylations with two different carboxylic anhydrides in acetone or dichloromethane gave the mixed carboxylate complexes (dach)Pt(O2CR)x(O2CR')4 - x (R = C(CH3)3 or CF3, R' = CH3, x = 1-4) including all the possible stereoisomers, which could be separated and identified by means of HPLC, column chromatography, 1H NMR, and X-ray crystallography. From analysis of the reaction products we have found that the positions of electrophilic substitution of (dach)Pt(OH)4 were influenced by the kinds of carboxylic anhydrides exhibiting different electrophilicity or steric effects. The initial substitution by the first reactant occurs more favorably on axial OH, but in the case of pivalic anhydride, equatorial substitution is favored probably because of the bulkiness of the pivalate group. Such a result seems to be related to their stereochemical factors rather than to differences in electrophilicity. The lipophilicity of the title complexes was affected not only by the carbon numbers of substituents but also by the conformation of the resulting compound.     

Oxidation of a guanine derivative coordinated to a Pt(IV) complex initiated by intermolecular nucleophilic attacks

In this study we report that fac-[Pt(IV)(dach)(9-EtG)Cl(3)](+) (dach = d,l-1,2-diaminocyclohexane, 9-EtG = 9-ethylguanine) in high pH (pH 12) or phosphate solution (pH 7.4) produces 8-oxo-9-EtG and Pt(II) species. The reaction in H(2)(18)O revealed that the oxygen atom in hydroxide or phosphate ends up at the C8 position of 8-oxo-G. The kinetics of the redox reaction was first order with respect to both Pt(IV)-G and free nucleophiles (OH(-) and phosphate). The oxidation of G initiated by hydroxide was approximately 30～50 times faster than by phosphate in 100 mM NaCl solutions. The large entropy of activation of OH(-1) (ΔS(?) = 26.6 ± 4.3 J mol(-1) K(-1)) due to the smaller size of OH(-) is interpreted to be responsible for the faster kinetics compared to phosphate (ΔS(?) = -195.5 ± 11.1 J mol(-1) K(-1)). The enthalpy of activation for phosphate reaction is more favorable relative to the OH(-) reaction (ΔH(?) = 35.4 ± 3.5 kJ mol(-1) for phosphate vs. 96.6 ± 11.4 kJ mol(-1) for OH(-1)). The kinetic isotope effect of H8 was determined to be 7.2 ± 0.2. The rate law, kinetic isotope effect, and isotopic labeling are consistent with a mechanism involving proton ionization at the C8 position as the rate determining step followed by two-electron transfer from G to Pt(IV).     

Thermodynamic and kinetic studies on reactions of Pt(II) complexes with biologically relevant nucleophiles

The effect of different N-N spectator ligands on the reactivity of platinum(II) complexes was investigated by studying the water lability of [Pt(diaminocyclohexane)(H2O)2]2+ (Pt(dach)), [Pt(ethylenediamine)(H2O)2]2+ (Pt(en)), [Pt(aminomethylpyridine)(H2O)2]2+ (Pt(amp)), and [Pt(N,N'-bipyridine)(H2O)2]2+ (Pt(bpy)). Some of the selected N-N chelates form part of the coordination sphere of Pt(II) drugs in clinical use, as in Pt(dach) (oxaliplatin), or are models, regarding the nature of the amines, with higher stability in terms of substitution and hydrolysis of the diamine moiety, as in Pt(en) (cisplatin) and Pt(amp) (AMD473). The effect of pi-acceptors on the reactivity was investigated by introducing one (Pt(amp)) or two pyridine rings (Pt(bpy)) in the system. The pK(a) values for the two water molecules (viz., Pt(dach) (pK(a1) = 6.01, pK(a2) = 7.69), Pt(en) (pK(a1) = 5.97, pK(a2) = 7.47), Pt(amp) (pK(a1) = 5.82, pK(a2) = 6.83), Pt(bpy) (pK(a1) = 4.80, pK(a2) = 6.32) show a decrease in the order Pt(dach) > Pt(en) > Pt(amp) > Pt(bpy). The substitution of both coordinated water molecules by a series of nucleophiles (viz., thiourea (tu), L-methionine (L-Met), and guanosine-5'-monophosphate (5'GMP-) was investigated under pseudo-first-order conditions as a function of concentration, temperature, and pressure using UV-vis spectrophotometric and stopped-flow techniques and was found to occur in two subsequent reaction steps. The following k1 values for Pt(dach), Pt(en), Pt(amp), and Pt(bpy) were found: tu (25 degrees C, M(-1) s(-1)) 21 +/- 1, 34.0 +/- 0.4, 233 +/- 5, 5081 +/- 275; L-Met (25 degrees C) 0.85 +/- 0.01, 0.70 +/- 0.03, 2.15 +/- 0.05, 21.8 +/- 0.6; 5'GMP- (40 degrees C) 5.8 +/- 0.2, 3.9 +/- 0.1, 12.5 +/- 0.5, 24.4 +/- 0.3. The results for k2 for Pt(dach), Pt(en), Pt(amp), and Pt(bpy) are as follows: tu (25 degrees C, M(-1) s(-1)) 11.5 +/- 0.5, 10.2 +/- 0.2, 38 +/- 1, 1119 +/- 22; L-Met (25 degrees C, s(-1)) 2.5 +/- 0.1, 2.0 +/- 0.2, 1.2 +/- 0.3, 290 +/- 4; 5'GMP- (40 degrees C, M(-1) s(-1)) 0.21 +/- 0.02, 0.38 +/- 0.02, 0.97 +/- 0.02, 24 +/- 1. The activation parameters for all reactions suggest an associative substitution mechanism. The pK(a) values and substitution rates of the complexes studied can be tuned through the nature of the N-N chelate, which is important in the development of new active compounds for cancer therapy.     

Reduction of Cisplatin and Carboplatin Pt(IV) Prodrugs by Homocysteine: Kinetic and Mechanistic Investigations

Pt(IV) anticancer active complexes are commonly regarded as prodrugs, and the reduction of the prodrugs to their Pt(II) analogs is the activation process. The reduction of a cisplatin prodrug cis‐[Pt(NH₃)₂Cl₄] and a carboplatin prodrug cis,trans‐[Pt(cbdca)(NH₃)₂Cl₂] by dl ‐homocysteine (Hcy) has been investigated kinetically in a wide pH range in this work. The reduction process follows overall second‐order kinetics: −d [Pt(IV)]/dt = k ′[Hcy]_tot[Pt(IV)], where [Hcy]_tot stands for the total concentration of Hcy and k ′ pertains to the observed second‐order rate constants. The k ′ versus pH profiles have been established for both prodrugs. Spectrohotometric titrations reveal a stoichiometry of Δ[Pt(IV)]:Δ[Hcy]_tot = 1:2; homocystine is identified as the major oxidation product of Hcy by high‐resolution mass spectrometry. A reaction mechanism has been proposed, which involves all the four protolysis species of Hcy attacking the Pt(IV) prodrugs in parallel. Moreover, these parallel attacks are the rate‐determining steps, resulting in a Cl⁺ transfer from the Pt(IV) prodrugs to the attacking sulfur atom. Rate constants of the rate‐determining steps have been derived, indicating that the two prodrugs are reduced with a very similar rate in spite of the difference between the coordination ligands in their equatorial positions. The reactivity analysis in the case of cis,trans‐[Pt(cbdca)(NH₃)₂Cl₂] unravels that one species of Hcy (form III ) is almost exclusively responsible for the reductions at the physiological pH (7.4), although it is existing only 5.2% of the total Hcy. On the other hand, the dominant existing form II of Hcy virtually does not make a contribution to the overall reactivity at pH 7.4.     

A kinetic analysis of oxidation of the antioxidant <Emphasis Type="Italic">N</Emphasis>-acetyl-<Emphasis Type="SmallCaps">l</Emphasis>-cysteine (NAC) by Pt(IV) complexes

N-acetyl-l-cysteine (NAC) is an antioxidant and a supplement and has been demonstrated to have protective effects for a variety of toxic effects of heavy metals. Although previous works have shown that NAC can ameliorate the severe toxic effects of cisplatin, there is a lack of understanding of the interactions between NAC and Pt(IV)-based prodrugs. In this work, the oxidation of NAC by a cisplatin prodrug (cis-[Pt(NH₃)₂Cl₄]), by a prototype of Pt(IV) anticancer drug ormaplatin ([Pt(dach)Cl₄]) and by a model compound (trans-[PtCl₂(CN)₄]^2–) was characterized in detail. NAC was oxidized to NAC-disulfide as identified by mass spectrometric analysis. Time-resolved spectral and stopped-flow kinetic measurements were carried out over a wide pH range, demonstrating that the oxidation followed overall second-order kinetics. The observed second-order rate constants k′ versus pH profiles were established. A reaction mechanism was deduced, involving three parallel rate-determining steps; conceivable transition states were also proposed for these steps. Rate constants of the rate-determining steps, obtained from the simulations of rate equation to the k′–pH profiles, were largely correlated with the electron density on the sulfur atom in NAC. The Pt(IV) prodrugs can execute oxidative stress in the biological systems of the human body by direct oxidation of relevant molecules, similar to HOCl/OCl^? and chloroamines. Instead, the oxidative stress involved in the severe toxic effects of cisplatin is produced via a different mode. NAC could be a chemoprotecting agent also for the Pt(IV) anticancer drugs if recent drug delivery technologies are used.     

Reduction of (imine)Pt(IV) to (imine)Pt(II) complexes with carbonyl-stabilized phosphorus ylides

A novel method is reported for generation of the difficult-to-obtain (imine)Pt(II) compounds that involves reduction of the corresponding readily available Pt(IV)-based imines by carbonyl-stabilized phosphorus ylides, Ph3P=CHCO2R, in nonaqueous media. The reaction between neutral (imino)Pt(IV) compounds [PtCl4[NH=C(Me)ON=CR1R2]2] [R1R2 = Me2, (CH2)4, (CH2)5, (Me)C(Me)=NOH], [PtCl4[NH=C(Me)ONR2]2] (R = Me, Et, CH2Ph), (R1 = H; R2 = Ph or C6H4Me; R3 = Me) as well as anionic-type platinum(IV) complexes (Ph3PCH2Ph)[PtCl5[NH=C(Me)ON=CR2]] [R2 = Me2, (CH2)4, (CH2)5] and 1 equiv of Ph3P=CHCO2R (R = Me, Et) proceeds under mild conditions (ca. 4 h, room temperature) to give selectively the platinum(II) products (in good to excellent isolated yields) without further reduction of the platinum center. All thus prepared compounds (excluding previously described Delta4-1,2,4-oxadiazoline complexes) were characterized by elemental analyses, FAB mass spectrometry, IR and 1H, 13C[1H], 31P[1H] and 195Pt NMR spectroscopies, and X-ray single-crystal diffractometry, the latter for [PtCl2[NH=C(Me)ON=CMe2]2] [crystal system tetragonal, space group P4(2)/n (No. 86), a = b = 10.5050(10) A, c = 15.916(3) A] and (Ph3PCH2CO2Me)[PtCl3(NCMe)] [crystal system orthorhombic, space group Pna2(1) (No. 33), a = 19.661(7) A, b = 12.486(4) A, c = 10.149(3) A]. The reaction is also extended to a variety of other Pt(II)/Pt(IV) couples, and the ylides Ph3P=CHCO2R are introduced as mild and selective reducing agents of wide applicability for the conversion of Pt(IV) to Pt(II) species in nonaqueous media, a route that is especially useful in the case of compounds that cannot be prepared directly from Pt(II) precursors, and for the generation of systematic series of Pt(II)/Pt(IV) complexes for biological studies.     

Reductive elimination/oxidative addition of carbon-hydrogen bonds at Pt(IV)/Pt(II) centers: mechanistic studies of the solution thermolyses of Tp(Me2)Pt(CH3)2H

Reductive elimination of methane occurs upon solution thermolysis of kappa(3)-Tp(Me)2Pt(IV)(CH(3))(2)H (1, Tp(Me)2 = hydridotris(3,5-dimethylpyrazolyl)borate). The platinum product of this reaction is determined by the solvent. C-D bond activation occurs after methane elimination in benzene-d(6), to yield kappa(3)-Tp(Me)2Pt(IV)(CH(3))(C(6)D(5))D (2-d(6)), which undergoes a second reductive elimination/oxidative addition reaction to yield isotopically labeled methane and kappa(3)-Tp(Me)2Pt(IV)(C(6)D(5))(2)D (3-d(11)). In contrast, kappa(2)-Tp(Me)2Pt(II)(CH(3))(NCCD(3)) (4) was obtained in the presence of acetonitrile-d(3), after elimination of methane from 1. Reductive elimination of methane from these Pt(IV) complexes follows first-order kinetics, and the observed reaction rates are nearly independent of solvent. Virtually identical activation parameters (DeltaH(++)(obs) = 35.0 +/- 1.1 kcal/mol, DeltaS(++)(obs) = 13 +/- 3 eu) were measured for the reductive elimination of methane from 1 in both benzene-d(6) and toluene-d(8). A lower energy process (DeltaH(++)(scr) = 26 +/- 1 kcal/mol, DeltaS(++)(scr) = 1 +/- 4 eu) scrambles hydrogen atoms of 1 between the methyl and hydride positions, as confirmed by monitoring the equilibration of kappa(3)-Tp(Me)()2Pt(IV)(CH(3))(2)D (1-d(1)()) with its scrambled isotopomer, kappa(3)-Tp(Me)2Pt(IV)(CH(3))(CH(2)D)H (1-d(1'). The sigma-methane complex kappa(2)-Tp(Me)2Pt(II)(CH(3))(CH(4)) is proposed as a common intermediate in both the scrambling and reductive elimination processes. Kinetic results are consistent with rate-determining dissociative loss of methane from this intermediate to produce the coordinatively unsaturated intermediate [Tp(Me)2Pt(II)(CH(3))], which reacts rapidly with solvent. The difference in activation enthalpies for the H/D scrambling and C-H reductive elimination provides a lower limit for the binding enthalpy of methane to [Tp(Me)2Pt(II)(CH(3))] of 9 +/- 2 kcal/mol.     

First electrogeneration of a platinum(IV) porphyrin: elucidation of the Pt(II/IV) and Pt(IV/II) oxidation-reduction processes in nonaqueous media

The first example for electrogeneration of a Pt(IV) porphyrin from its Pt(II) form is presented and the Pt(II/IV) and reverse Pt(IV/II) oxidation-reduction processes are elucidated by electrochemistry and thin-layer UV-visible spectroelectrochemistry. Three products, [(TPP˙(+))Pt(II)](+), [(TPP)Pt(IV)](2+) and [(TPP˙(+))Pt(IV)](3+), produced by electrooxidation of the Pt(II) porphyrin have been characterized by in situ spectroelectrochemistry and ESR measurements after controlled potential bulk electrolysis. The first definitive evidence for the electrochemical conversion of a Pt(iv) porphyrin to its Pt(II) form is also presented. The potential for this electroreduction is highly dependent upon the nature of the anion, ClO(4)(-) or Cl(-). A mechanism for the reversible conversion between Pt(II) and Pt(IV) tetraphenylporphyrins is proposed.     

Pt(II)- and Pt(IV)-bridged cofacial diporphyrins via carbon-transition metal sigma-bonds

A directly Pt(IV)-bridged cofacial diporphyrin has been synthesized by the cyclometalation reaction of beta-pyridylporphyrin with a Pt(IV) salt. Upon treatment with methylhydrazine, the Pt(IV) bridge is reduced to the Pt(II) center, resulting in a Pt(II)-bridged cofacial dimer with a helicity inversion of the complex as well as change in electronic communication through the metal bridge.     

Targeted single-wall carbon nanotube-mediated Pt(IV) prodrug delivery using folate as a homing device

Most low-molecular-weight platinum anticancer drugs have short blood circulation times that are reflected in their reduced tumor uptake and intracellular DNA binding. A platinum(IV) complex of the formula c, c, t-[Pt(NH 3) 2Cl 2(O 2CCH 2CH 2CO 2H)(O 2CCH 2CH 2CONH-PEG-FA)] ( 1), containing a folate derivative (FA) at an axial position, was prepared and characterized. Folic acid offers a means of targeting human cells that highly overexpress the folate receptor (FR). Compound 1 was attached to the surface of an amine-functionalized single-walled carbon nanotube (SWNT-PL-PEG-NH 2) through multiple amide linkages to use the SWNTs as a "longboat delivery system" for the platinum warhead, carrying it to the tumor cell and releasing cisplatin upon intracellular reduction of Pt(IV) to Pt(II). The ability of SWNT tethered 1 to destroy selectively FR(+) vs FR(-) cells demonstrated its ability to target tumor cells that overexpress the FR on their surface. That the SWNTs deliver the folate-bearing Pt(IV) cargos into FR(+) cancer cells by endocytosis was demonstrated by the localization of fluorophore-labeled SWNTs using fluorescence microscopy. Once inside the cell, cisplatin, formed upon reductive release from the longboat oars, enters the nucleus and reacts with its target nuclear DNA, as determined by platinum atomic absorption spectroscopy of cell extracts. Formation of the major cisplatin 1,2-intrastrand d(GpG) cross-links on the nuclear DNA was demonstrated by use of a monoclonal antibody specific for this adduct. The SWNT-tethered compound 1 is the first construct in which both the targeting and delivery moieties have been incorporated into the same molecule; it is also the first demonstration that intracellular reduction of a Pt(IV) prodrug leads to the cis-{Pt((NH 3) 2} 1,2-intrastrand d(GpG) cross-link in nuclear DNA.     

The crystal structure of tetrakis[trimethylthiomethyl-platinum(IV)], [Pt(CH3)3(SCH3)4

The crystal structure of trimethyl(thiomethyl)platmum(IV), [Pt(CH₃)₃(SCH₃)]₄, has been determined using X-ray diffraction. The compound has three independent but isostructural tetrameric units in the asymmetric unit. The four metal atoms in each tetramer are linked by bridging thiomethyl sulphurs, with three methyl groups completing the octahedral coordination around each platinum. Mean interatomic distances within the tetramer are PtS, 2.48(2), PtC, 2.00(4), PtPt, 3.80(2) Å, with a mean bridge angle SPtS, 79.1(7)°.     

Complexes of Pt(II) and Pt(IV) with disubstituted purines

Mixed-ligand complexes of Pt(II) and Pt(IV) with 2,6-diaminopurine and 6-thioguanine were synthesized and characterised. The complexes were prepared in acidic and basic media. The binding of the ligands to the metal ion varies according to the pH of the medium. Thus, in the complexes of 6-thioguanine, the ligand acts as a monodentate ligand coordinating through the neutral C₆-SH group in the acidic medium and in the basic medium as a bidentate ligand binding to the metal ion through C₆S^? and N₇, forming a five-membered chelate ring. In an acidic medium 2,6-diaminopurine forms mononuclear complexes with Pt(II) and Pt(IV) binding through N₇. In a basic medium binuclear hydroxobridged complexes are formed with Pt(IV) and the ligand is monodentate, coordinating through N₇.     

Encapsulation of Pt(iv) prodrugs within a Pt(ii) cage for drug delivery

This report presents a novel strategy that facilitates delivery of multiple, specific payloads of Pt(iv) prodrugs using a well-defined supramolecular system. This delivery system comprises a hexanuclear Pt(ii) cage that can host four Pt(iv) prodrug guest molecules. Relying on host–guest interactions between adamantyl units tethered to the Pt(iv) molecules and the cage, four prodrugs could be encapsulated within one cage. This host–guest complex, exhibiting a diameter of about 3 nm, has been characterized by detailed NMR spectroscopic measurements. Owing to the high positive charge, this nanostructure exhibits high cellular uptake. Upon entering cells and reacting with biological reductants such as ascorbic acid, the host–guest complex releases cisplatin, which leads to cell cycle arrest and apoptosis. The fully assembled complex displays cytotoxicity comparable to that of cisplatin against a panel of human cancer cell lines, whereas the cage or the Pt(iv) guest alone exhibit lower cytotoxicity. These findings indicate the potential of utilising well-defined supramolecular constructs for the delivery of prodrug molecules.     

Synthesis, X-ray crystallographic, and NMR characterizations of platinum(II) and platinum(IV) pyrophosphato complexes

A series of mononuclear cis-diamineplatinum(II) pyrophosphato complexes containing ammine (am), trans-1,2-cyclohexanediamine (dach), and 1,2-ethanediamine (en) as the amine ligands were synthesized and characterized by (31)P and (195)Pt NMR spectroscopy. Chemical shifts of (31)P NMR resonances of these completely deprotonated complexes appear at 2.12, 1.78, and 1.93 ppm, indicating a coordination chemical shift of at least 8 ppm. The (195)Pt NMR chemical shifts for the am and dach complexes were observed at -1503 and -1729 ppm. The complexes are highly stable at neutral pH; no aquation due to the release of either phosphate or amine ligands was observed within 48 h. Furthermore, no partial deligation of the pyrophosphate ligand was detected within several days at neutral pH. At lower pH, however, release of a pyrophosphate ion was observed with concomitant formation of a bridged pyrophosphatoplatinum(II) dinuclear complex. The extended crystal structure containing the dach ligand revealed a zigzag chain stacked in a head-to-tail fashion. Moreover, two zigzag chains are juxtaposed in a parallel fashion and supported by additional hydrogen bonds reminiscent of DNA structures where two strands of DNA bases are held by hydrogen bonds. Theoretical calculations support the notion that the two dinuclear units are held together primarily by hydrogen bonds between the amine and phosphate moieties. Platinum(II) pyrophosphato complexes were readily oxidized by hydrogen peroxide to yield cis-diamine-trans-dihydroxopyrophosphatoplatinum(IV) complexes. Two of these complexes, containing am and en, were characterized by X-ray crystallography. Notable structural features include Pt-O (phosphate) bond distances of 2.021-2.086 A and departures from 180 degrees in trans-HO-Pt-OH bond angles, >90 degrees in O-Pt-O, and >90 degrees in cis-N-Pt-N bond angles. The departure in the trans-HO-Pt-OH angle is more pronounced in the 1,2-ethanediamine complex compared to the dach analogue because of the existence of two molecules possessing enantiomeric conformations within the asymmetric unit. (31)P NMR spectra exhibited well-resolved (195)Pt satellites with coupling constants of 15.4 Hz for the ammine and 25.9 Hz for both the 1,2-ethanediamine and trans-1,2-cyclohexanediamine complexes. The (195)Pt NMR spectrum of the ammine complex clearly showed coupling with two equivalent N atoms.     

First metallamacrocyclic complexes of Pt(iv) with 3,3,3',3'-tetraalkyl-1,1'-phenylenedicarbonylbis(thioureas): synthesis by direct or electrolytic oxidative addition of I(2), Br(2) and Cl(2)

Elemental I(2) and Br(2) cleanly react with the 3:3 Pt(ii) metallamacrocycle of 3,3,3',3'-tetra(n-butyl)-1,1'-terephthaloylbis(thiourea)(cis-[Pt(II)(3)(L(p)(1)-S,O)(3)]3), in chloroform at room temperature, to yield oxidative addition products; (195)Pt NMR studies reveal that a stepwise oxidative addition readily occurs to each of the Pt(ii) centres in the metallamacrocycle to yield the mixed valence species cis-[Pt(II)(2)Pt(IV)I(2)(L(p)(1)-S,O)(3)] and cis-[Pt(II)Pt(IV)(2)I(4)(L(p)(1)-S,O)(3)], and the fully oxidised cis-[Pt(IV)(3)I(6)(L(p)(1)-S,O)(3)] in solution, depending on the mole ratio I(2):3. Similar results are obtained on treatment of solutions of 3 with elemental Br(2). Treatment of the corresponding 2:2 Pt(ii) complex of 3,3,3',3'-tetraethyl-1,1'-isophthaloylbis(thiourea)(cis-[Pt(II)(2)(L(m)(1)-S,O)(2)]4) with iodine, results in facile oxidative addition to yield cis-[Pt(IV)(2)(L(m)(1)-S,O)(2)I(4)], with a trans-Pt(iv)-iodo arrangement. Molecules in the crystal structure of 5 have their trans-Pt(iv)-iodo axes essentially aligned, with very close intermolecular iodide contacts (3.775(1)A), resulting in chains of weakly bound metallamacrocycles in the solid. An alternative electrolytic synthesis method, using a simple two-compartment glass cell containing 4 and a chosen halide salt in dichloromethane, led to the formation of cis-[Pt(IV)(2)(L(m)(1)-S,O)(2)Br(4)] 6 and cis-[Pt(IV)(2)(L(m)(1)-S,O)(2)Cl(4)] 7, completing characterization of a series of first-reported trans-Pt(iv)-X (X=I, Br, Cl) metallamacrocyclic complexes.     

Mechanism of two-electron oxidation of deoxyguanosine 5'-monophosphate by a platinum(IV) complex

Many transition metal complexes mediate DNA oxidation in the presence of oxidizing radiation, photosensitizers, or oxidants. The final DNA oxidation products vary depending on the nature of metal complexes and the structure of DNA. Here we propose a mechanism of oxidation of a nucleotide, deoxyguanosine 5'-monophosphate (dGMP) by trans-d,l-1,2-diaminocyclohexanetetrachloroplatinum (trans-Pt(d,l)(1,2-(NH(2))(2)C(6)H(10))Cl(4), [Pt(IV)Cl(4)(dach)]; dach = diaminocyclohexane) to produce 7,8-dihydro-8-oxo-2'-deoxyguanosine 5'-monophosphate (8-oxo-dGMP) stoichiometrically. The reaction was studied by high-performance liquid chromatography (HPLC), (1)H and (31)P nuclear magnetic resonance (NMR), and electrospray ionization mass spectrometry (ESI-MS). The proposed mechanism involves Pt(IV) binding to N7 of dGMP followed by cyclization via nucleophilic attack of a phosphate oxygen at C8 of dGMP. The next step is an inner-sphere, two-electron transfer to produce a cyclic phosphodiester intermediate, 8-hydroxyguanosine cyclic 5',8-(hydrogen phosphate). This intermediate slowly converts to 8-oxo-dGMP by reacting with solvent H(2)O.     

Kinetic characterization of the interactions of trans-dichloro-platinum(IV) anticancer prodrugs and a model compound with thiosulfate

Sodium thiosulfate has been utilized as a rescuing agent for relief of the toxic effects of cisplatin and carboplatin. In this work, we characterized the kinetics of reactions of the trans-dichloro-platinum(IV) complexes cis-[Pt(NH₃)₂Cl₄], ormaplatin [Pt(dach)Cl₄] and trans-[PtCl₂(CN)₄]^2? (anticancer prodrugs and a model compound) with thiosulfate at biologically important pH. An overall second-order rate law was established for the reduction of trans-[PtCl₂(CN)₄]^2? by thiosulfate, and varying the pH from 4.45 to 7.90 had virtually no influence on the reaction rate. In the reactions of thiosulfate with cis-[Pt(NH₃)₂Cl₄] and with [Pt(dach)Cl₄], the kinetic traces displayed a fast reduction step followed by a slow substitution involving the intermediate Pt(II) complexes. The reduction step also followed second-order kinetics. Reductions of cis-[Pt(NH₃)₂Cl₄] and [Pt(dach)Cl₄] by thiosulfate proceeded with similar rates, presumably due to their similar configurations, whereas the reduction of trans-[PtCl₂(CN)₄]^2? was about 1,000 times faster. A common reduction mechanism is suggested, and the transition state for the rate-determining step has been delineated. The activation parameters are consistent with transfer of Cl⁺ from the platinum(IV) center to the attacking thiosulfate in the rate-determining step.     

Kinetic and Mechanistic Investigations on Some N,N‐Chelated Pt(II) Oxalate Complexes with Some “S” Containing Biorelevant Ligands at Physiological Condition

The substitution of the chelating oxalate group by a group of nucleophiles, viz. thiourea (L₁), 2‐thiouracil (L₂), diethyldithiocarbamate (L₃), dl ‐penicillamine (L₄), and thiosemicarbazide (L₅) was studied under pseudo–first‐order conditions as a function of concentration and temperature using UV–vis spectrophotometry and stopped‐flow technique. π‐Accepting effects are often used to account for the unusual high lability of Pt(bipy) complexes. The complexes [Pt(dach)(oxalate)] (1) (dach = cis‐1,2‐diaminocyclohexane) and [Pt(bipy)(oxalate)] (2) (bipy = 2,2'‐bipyridine) and substituted products were isolated and characterized by FTIR and ESI‐MS spectroscopic analysis. The negative entropies of activation support a strong contribution from bond making in the transition state of the substitution processes.