Internalization of Ineffective Platinum Complex in Nanocapsules Renders It Cytotoxic

Anticancer therapy by platinum complexes, based on nanocarrier‐based delivery, may offer a new approach to improve the efficacy and tolerability of the platinum family of anticancer drugs. The original rules for the design of new anticancer platinum drugs were affected by the fact that, although cisplatin (cis‐[PtCl₂(NH₃)₂) was an anticancer drug, its isomer transplatin was not cytotoxic. For the first time, it is demonstrated that simple encapsulation of an inactive platinum compound in phospholipid bilayers transforms it into an efficient cytotoxic agent. Notably, the encapsulation of transplatin makes it possible to overcome the resistance mechanisms operating in cancer cells treated with cisplatin and prevents inactivation of transplatin in the extracellular environment. It is also shown that transplatin delivered to the cells in nanocapsules, in contrast to free (nonencapsulated) complex, forms cytotoxic cross‐links on DNA.     

Peculiarities of interactions between the DNA molecule and different isomers and modifications of binuclear coordination compounds of platinum(II)

A comparison has been made of conformational changes in the DNA molecule during its interaction in solution with different binuclear coordination compounds of platinum [Pt(NH₃)₂Cl-R-Pt(NH₃)₂Cl]Cl₂ in cis and trans conformations, which contain cytosine, pyrazine, and carboxypyrazine as the common ligand (R). The influence of concentration of the components, and in particular, of ionic strength of the solution on the complexation process was studied. The influence of the nature of the common ligand, and of cis and trans conformations of coordination compounds on the character of their interaction with DNA was considered. A comparison was made between the structures of DNA complexes with mono-and binuclear compounds with the same set of ligands in the platinum coordination sphere.     

Electronic structure and vibrational spectra of cis-diammine(orotato)platinum(II), a potential cisplatin analogue: DFT and experimental study

Orotic acid (vitamin B₁₃) is a key intermediate in biosynthesis of the pyrimidine nucleotides in living organisms, moreover, it may serve as the biological carrier for some metal ions. cis-Diammine(orotato)platinum(II), cis-[Pt(C₅H₂N₂O₄)(NH₃)₂] can be considered as a new potential cisplatin analogue. The FT-Raman and FT-IR spectra of the title complex are reported, for the first time. The molecular structure, vibrational frequencies, and the theoretical infrared and Raman intensities have been calculated by the density functional mPW1PW91 method. The detailed vibrational assignment has been made on the basis of the calculated potential energy distribution. The theoretically predicted IR and Raman spectra show very good agreement with experiment. Natural bond orbital (NBO) analyses were performed for cisplatin, carboplatin and the title complex. The results provided new data on the nature of platinum–ligand bonding in these compounds. Strong intramolecular hydrogen bond between the orotate ligand and the coordinated ammonia group stabilizes the structure of the platinum(II) complex. Thus, it is suggested that the orotate ligand in the title complex is more inert to the substitution reactions than the chloride ligands in cisplatin.     

Synthesis, structure, and biological activity of mixed-ligand platinum(II) complexes with aminonitroxides

Mixed-ligand platinum complexescis-Pt^II(R⁶NH₂)(NH₃)X₂ andcis-Pt^II(R⁵NH₂)(NH₃)X₂ (R⁶ is 2,2,6,6-tetramethyl-4-piperidyl-1-oxyl and R⁵ is 2,2,5,5-tetramethyl-3-pyrrolidinyl-1-oxyl) were synthesized by either the reaction of aminonitroxides RNH₂ with Na[Pt^II(NH₃)Cl₂I] generatedin situ (for X₂=ClI) or by replacement of the iodo-chloro ligands incis-Pt¹¹(RNH₂)(NH₃)ClI by dichloro and oxalato ligands. The complexes obtained were characterized by elemental analysis and by IR, UV, and ESR spectra. Forcis-Pt¹¹(R⁵NH₂)(NH₃)Cl₂, crystal and molecular structures were determined by X-ray diffraction analysis. Cisplatin accelerates autooxidation of methyl linoleate and the platinum nitroxide complexes synthesized exhibit antioxidant properties. The rate of isolated DNA binding with the new complexes is almost as high as that for cisplatin.cis-Pt¹¹(R⁶NH₂)(NH₃)Cl₂ exhibits the highest antitumor activity. The high antitumor activity of platinum nitroxide complexes shows that the possible “radical component” is not a crucial factor in the cytotoxic action of cisplatin. Published inIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1624–1630, September, 2000.     

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.     

HPLC Method for the Determination of the Purity of K[Pt(NH3)Cl3], a Precursor of the Platinum Complexes with Cytostatic Activity

K[Pt(NH₃)Cl₃], a valuable precursor for the preparation of platinum complexes with cytostatic activity, e.g. satraplatin, picoplatin, LA-12 and cycloplatam, is currently prepared from cis-[Pt(NH₃)₂Cl₂] or K₂[PtCl₄] and these are the usual impurities in the final product. A simple, selective and sensitive HPLC-UV analytical method for the determination of the purity of K[Pt(NH₃)Cl₃] and the quantification of the impurities has been developed and validated. The platinum complexes present in the final product were separated on a strong base ion exchange column by the gradient elution with detection at 213 nm. Intra-assay precisions for the platinum complexes respective to their ions ([PtCl₄]^2?, [Pt(NH₃)Cl₃]^? and cis-[Pt(NH₃)₂Cl₂]) were between 0.1 and 2.0% (relative standard deviation); intermediate precisions were between 1.4 and 2.0% and accuracies were between 98.6 and 101.4%. Limits of detection of [PtCl₄]^2?, [Pt(NH₃)Cl₃]^? and cis-[Pt(NH₃)₂Cl₂] were 6 µg · ml^?1, 13 mg · ml^?1 and 5 µg · ml^?1 respectively, limits of quantification of [PtCl₄]^2?, [Pt(NH₃)Cl₃]^? and cis-[Pt(NH₃)₂Cl₂] were 51 µg · ml^?1, 55 mg · ml^?1 and 20 µg · ml^?1 respectively.     

Immobilization of Platinum(II) and Platinum(IV) Complexes on Oxidized Nanoporous Carbon Material and Evaluation of the Enthalpy of Adsorption

Physicochemical study of cis-[Pt(NH3)2Cl2] and cis-[Pt(NH₃)₂Cl₂(OH)₂] is carried out, and immobilization of platinum complexes on the nanoporous carbon substrate is investigated. The solubility of cis-[Pt(NH₃)₂Cl₂] in 1 M HCl solution is determined, and the average enthalpy of dissolution is calculated: Δ_solH° = 27.3 ± 0.9 kJ/mol. The batch capacity is determined experimentally for cis-[Pt(NH3)2Cl2] and cis- [Pt(NH₃)₂Cl₂(OH)₂] to be 32.9 mg/g (0.17 mg-equiv/g) and 47.6 mg/g (0.24 mg-equiv/g), respectively. Immobilization of platinum complexes on the oxidized carbon surface is found to take place due to interaction between carboxy groups and ammine groups of platinum complexes. The resulting heat capacity curves are used to calculate the enthalpies of adsorption for cis-[Pt(NH₃)₂Cl₂] and cis-[Pt(NH₃)₂Cl₂(OH)₂] on the oxidized carbon surface, equal to 24.46 and 27.46 kJ/mol, respectively.     

Synthesis of a new class of acylplatinum complexes derived from salicylaldehyde

The synthesis of a new class of acylplatinum complexes of composition [Pt(OC₆H₄CO)L_aL_b] L_a = L_b = PR₃, P(OR)₃, Ph₂PCH₂CH₂PPh₂, AsR₃; L_a = 2-picoline, 3-picoline, 4-picoline, ¹⁵NH₂{CH₂}₅CH₃, L_b = DMSO, is described. The complexes are synthesized from o-hydroxybenzaldehyde (salicylaldehyde) and K₂PtCl₄ and contain an organic chelating ligand bound to platinum via the phenolic oxygen and the aldehyde carbon. ¹H, ¹³C, ³¹P and ¹⁹⁵Pt NMR data for the new complexes are reported.     

HPLC Method for Monitoring of Degradation Products in Picoplatin Stability Study

An analytical method combining high-performance liquid chromatography (HPLC) with UV detection was developed for an easy and rapid assay determination of the anticancer drug picoplatin (=cis-[Pt(NH₃)(2-methylpyridine)Cl₂]) and its degradation products. An ion exchanger was used as the stationary phase with an aqueous solution of NaH₂PO₄ with pH adjusted to 3.0 with H₃PO₄ as the mobile phase. The calibration curve was linear within the concentration range of 0.10–0.50 g L^?1 (R ² ≥ 0.998). The limit of detection was 0.05 g L^?1 and limit of quantification was 0.09 g L^?1. The developed method was characterized with a high precision (≤6.0%, determined as RSD), an acceptable accuracy (the values of recovery were from intervals 98–103%). The developed method was used for assessing the stability of picoplatin during a stability study.     

Ligand substitution reaction at a binuclear organoplatinum(II) complex

The ligand substitution reactions of the N-donor ligand in the binuclear dimethylplatinum(II) complex of formula cis,cis-[Me₂Pt(μ-NN)(μ-dppm)PtMe₂], 1, in which dppm = bis(diphenylphosphino)methane and NN = phthalazine, by different nucleophilic phosphorous-donors L, L = P(O-ⁱPr)₃ or PPh₃ and L₂ = dppm, to form the dinuclear complexes 2, cis,cis-[Me₂LPt(μ-dppm)PtLMe₂] and cis,cis-[Me₂Pt(μ-dppm)₂PtMe₂], respectively, are studied. Complex 1 has a MLCT band in the visible region which was used to easily follow the kinetics of its ligand substitution reactions. These reactions which involve diplatinum(II) complex 1 containing cis Pt-C bonds, proceeded by the normal associative mechanism. In associative reactions of the present work, as expected, the rate of the reactions was depended on the concentration and the nature of the entering group. The nucleophilicity of PPh₃ is stronger than P(O-ⁱPr)₃ on the basis of its stronger σ-donor ability and its lower solvation and is responsible for the observed 3-fold increase of its rate as compared to that of P(O-ⁱPr)₃. Also, the solvation energy involved is suggested to be responsible for the observation of higher rates in benzene than in acetone. The ΔH^‡/ΔS^‡ compensation plot gives a straight line which suggests the operation of the same mechanism for all entering nucleophiles.     

Quantum chemical modeling of nucleophilic substitution reactions in the complexes cis-Pt(NH3)2Cl2 and cis-Pd(NH3)2Cl2

The B3LYP/6-31G** method was used for the study of nucleophilic substitution reaction in platinum and palladium square-planar cis-diaminate complexes. The processes under consideration take place in two steps through pentacoordinated transition states. Activation barriers for both steps of these processes in gaseous phase and aqueous solution were calculated. A major role in the increase in the activation energies is played by the formation of the intermediate electrostatic Van der Waals’ complexes. For the complex cis-[Pd(NH₃)₂Cl₂], the activation barriers in the nucleophilic substitution reaction are considerably lower than those for the complex cis-[Pt(NH₃)₂Cl₂].     

Platinum(II) Diaquadiammine Complexes. Stable Hydrolysis Products by DFT Quantum-Chemical Calculations

The most stable hydrolysis products of cis-[Pt(NH₃)₂(H₂O)₂]^{2 +} were revealed by means of DFT quantum-chemical calculations of this complex and its deprotonated forms with full geometry optimization. The resulting force fields and normal mode vibrations were used to calculate thermodynamic characteristics for possible hydrolysis stages and equilibrium constants for proton-transfer processes in the gas phase and in aqueous solutions. The hydroxo-bridged dimers [Pt(NH₃)₂(-OH)]₂ ^{2 +} with short Pt+++Pt distances are the hydrolysis products of platinum(II) cis-diaquadiamminates in the aqueous medium.     

A bromine analogue of picoplatin: a new substance from the group of platinum‐based chemotherapeutics

A new substance, cis‐amminedibromido(2‐methylpyridine‐κN)platinum(II), cis‐[PtBr₂(C₆H₇N)(NH₃)], which is a potential platinum‐based antineoplastic agent for the treatment of patients with solid tumors, has been synthesized and structurally characterized. There is one molecule in the asymmetric unit and molecules are linked via two symmetry‐independent N—H...Br hydrogen bonds into zigzag chains running parallel to the c axis. C—H...Br hydrogen bonds crosslink these chains to give a layer parallel to (010). N—H...Br hydrogen bonds and π–π stacking interactions between pairs of pyridine rings stack the layers along b.     

Complexes of platinum and palladium with 4-nitrobenzoic hydrazide: synthesis and cytotoxic activity

New complexes of platinum and palladium were isolated with 4-nitrobenzoic hydrazide (4-NH) and characterized by spectroscopic techniques. Results show that the ligand is coordinated to metallic ions by the basic nitrogen of NH₂ group and have the general structure cis-[M(4-NH)₂X₂] where M= Pt or Pd and x = Cl or I. The compound III, [Pt(4-NH)₂I₂], was found to display cytotoxicity (IC₅₀ = 0.96 μmol L^?1) against the K562 tumoral cell line. This complex is significantly more cytotoxic than cisplatin.      

Mixed metal PtxMyLz complexes of L = 1-methyluracil and 1-methylthymine: Preparation and spectroscopic studies

The reactions of cis-(NH₃)₂PtL₂ (L = 1-MeT or 1-MeU, the anions of 1-methylthymine or 1-methyluracil respectively) in water with various salts of Fe(II), Fe(III), Co(II), Ni(II), Cu(II) or Ag(I) have produced 14 new heteronuclear complexes of the general types: cis-[(NH₃)₂PtL₂ML₂Pt(NH₃)₂]X_n·mH₂O or cis-(NH₃)₂PtL₂MX_n·mH₂O, and also with silver(I) perchlorate a complex of stoichiometry cis-{(NH₃)₂Pt(1-MeU)₂}₂· 3AgClO₄·6H₂O. Comparisons are made with previously reported heteronuclear species derived from cis-(NH₃)₂PtL₂ and factors influencing the type of heteronuclear complex formed are discussed, particularly the versatility of binding patterns with Ag(I). A tetranuclear structure is suggested for the compound of stoichiometry cis-(NH₃)₂Pt(1-MeU)₂·FeSO₄·3H₂O involving iron(II) ions linked by sulphate bridges. The electronic spectra of the trinuclear complexes cis-[(NH₃)₂Pt(1-MeU)₂M(1-MeU)₂Pt(NH₃)₂] (NO₃)₂·mH₂O (M = Fe, Co or Ni) are reported. They show that the trans-MO₄Pt₂ geometry results in a very severely trans-elongated ligand field about the central metal ion, M. This conclusion is supported by the Mössbauer spectrum in the case of the iron(II) complex. The X- and Q-band EPR spectra of the Fe(III) analogue are also reported.     

A new [(1R,2R)‐1,2‐diaminocyclohexane]platinum(II) complex: formation by nitrate–acetonitrile ligand exchange

The title compound, cis‐diacetonitrile[(1R,2R)‐1,2‐diaminocyclohexane‐κ²N,N′]platinum(II) dinitrate monohydrate, [Pt(C₂H₃N)₂(C₆H₁₄N₂)](NO₃)₂·H₂O, is a molecular salt of the diaminocyclohexane–Pt complex cation. There are two formula units in the asymmetric unit. Apart from the two charge‐balancing nitrate anions, one neutral molecule of water is present. The components interact via N—H...O and O—H...O hydrogen bonds, resulting in supramolecular chains. The title compound crystallizes only from acetonitrile with residual water, with the acetonitrile coordinating to the molecule of cis‐[Pt(NO₃)₂(DACH)] (DACH is 1,2‐diaminocyclohexane) and the water forming a monohydrate.     

Inelastic Neutron Scattering Study of PtII Complexes Displaying Anticancer Properties

The well‐known platinum(II) chemotherapeutic drugs cisplatin [cis‐(NH₃)₂PtCl₂] and carboplatin [Pt(NH₃)₂C₆O₄H₆], as well as the analogous transplatin [trans‐(NH₃)₂PtCl₂], were studied by inelastic neutron scattering (INS) spectroscopy, coupled to quantum mechanical methods, and some ancillary work with X‐ray diffraction on powders. An assignment of the experimental spectra was carried out based on the calculated INS transition frequencies and intensities (at the DFT level), thereby achieving a good correspondence between the calculated and observed data. Unusually good‐quality INS spectra were obtained from about 250 mg, which is the smallest sample of a hydrogenous compound for which a successful INS interpretation has been reported. The knowledge of the local configuration of this kind of complexes is essential for an accurate understanding of their activity, which will pave the way for the rational design of novel third‐generation drugs comprising cisplatin‐ and carboplatin‐like moieties.     

Solid-Phase “Self-Hydrolysis” of [Zn(NH3)4MoO4@2H2O] Involving Enclathrated Water—An Easy Route to a Layered Basic Ammonium Zinc Molybdate Coordination Polymer

An aerial humidity-induced solid-phase hydrolytic transformation of the [Zn(NH₃)₄]MoO₄@2H₂O (compound 1@2H₂O) with the formation of [(NH₄)_xH_(1−x)Zn(OH)(MoO₄)]_n (x = 0.92–0.94) coordination polymer (formally NH₄Zn(OH)MoO₄, compound 2) is described. Based on the isostructural relationship, the powder XRD indicates that the crystal lattice of compound 1@2H₂O contains a hydrogen-bonded network of tetraamminezinc (2+) and molybdate (2−) ions, and there are cavities (O₄N₄(μ-H₁₂) cube) occupied by the two water molecules, which stabilize the crystal structure. Several observations indicate that the water molecules have no fixed positions in the lattice voids; instead, the cavity provides a neighborhood similar to those in clathrates. The @ symbol in the notation is intended to emphasize that the H₂O in this compound is enclathrated rather than being water of crystallization. Yet, signs of temperature-dependent dynamic interactions with the wall of the cages can be detected, and 1@2H₂O easily releases its water content even on standing and yields compound 2. Surprisingly, hydrolysis products of 1 were observed even in the absence of aerial humidity, which suggests a unique solid-phase quasi-intramolecular hydrolysis. A mechanism involving successive substitution of the ammonia ligands by water molecules and ammonia release is proposed. An ESR study of the Cu-doped compound 2 (2#dotCu) showed that this complex consists of two different Cu²⁺(Zn²⁺) environments in the polymeric structure. Thermal decomposition of compounds 1 and 2 results in ZnMoO₄ with similar specific surface area and morphology. The ZnMoO₄ samples prepared from compounds 1 and 2 and compound 2 in itself are active photocatalysts in the degradation of Congo Red dye. IR, Raman, and UV studies on compounds 1@2H₂O and 2 are discussed in detail.     

Crystal structure of three solvates of 1,1′-binaphthyl-2,2′-bicarboxylic acid with 2-picoline

From solutions in 2-picoline (2-methylpyridine), depending on the temperature of crystallization, the universal clathratogen — 1,1′-binaphthyl-2,2′-bicarboxylic acid (BBA) — precipitates as crystals of three types with different composition and structure. Under normal conditions (room temperature), the precipitate is crystals of BBA disolvate with 2-picoline; a temperature reduction of 20°C results in the crystallization of monosolvate dihydrate; and a temperature increase of the same level results in the precipitation of monosolvate. That is, as the temperature of crystallization rises, the number of included guest molecules gradually decreases and the space where they are located becomes more closed. In 1:1:2 BBA/2-picoline/H₂O solvate (space group P2₁/n, a = 11.991(2) Å, b = 9.317(2) Å, c = 22.283(5) Å, β = 99.77(3)○, V = 2453.3(9) ų, Z = 4), the carboxyl groups of the BBA molecule at the C21 atom are deprotonated and the released proton goes to the nitrogen atom of 2-picoline. BBA molecules interact with those of 2-picoline and water via H bonds to form infinite chains in direction [111], which, in their turn, join together into infinite two-dimensional sheets parallel to plane (?101). 2-Picoline molecules are located in the channels. In BBA/2-picoline disolvate (space group C ₂/c, a = 11.7523(11) Å, b = 13.8563(13) Å, c = 17.9615(13) Å, β = 108.044(9)○, V = 2781.1(4) ų, Z = 4), one BBA molecule and two H bond 2-picoline molecules form a 0-dimensional associate of the type G-H-G. The solvent molecules are also located in the channels. In BBA/2-picoline monosolvate (space group P2₁/c, a = 9.299(5) Å, b = 12.727(5) Å, c = 19.011(5) Å, β = 95.248(5)○, V = 2240.5(16) ų, Z = 4), each BBA molecule is H-bonded with a 2-picoline molecule to form a 0-dimensional associate of the type H-G. Guest molecules are located in closed cavities.     

Reactivity of cyclopalladated compounds: VIII. Synthesis of cyclometallated compounds with an oxygen as the donor atom. Crystal and molecular structure of (8-methylquinoline-C,N)-(1-methoxynaphthalene-8-C,O)palladium(II)

Treatment of 1-methoxynaphthalene (MXNH) with n-butyllithium in a diethyl ether/n-hexane solution gives 1-methoxynaphthalene-8-lithium (MXNLi) in 30% yield as an insoluble material. This compound reacts with PdCl₂(SEt₂)₂ to give bis(1-methoxynaphthalene-8-C,O)palladium(II) (I)_and with PtCl₂(SEt₂)₂ to give cis- and trans-(1-methoxynaphthalene-8-C,O)(1-methoxynaphthalene-8-C)(diethylsulfide)platinum(II) (II), which are non-rigid molecules in solution. With the cyclopalladated dimers [{$\text{Pd(CN}$)Cl₂}₂], MXNLi gives the palladobicyclic compounds: ($\text{N∩C)P}$$\text{d(C∩O}$) (III). An X-ray diffraction study of compound IIIa where N∩N = 8-methylquinoline-C,N reveals the planarity of the molecule, shows that it has a cis configuration with respect to the PdC bonds, and confirms that the oxygen atom of MXN is bonded to palladium: PdO 2.236(4) Å. The geometry of IIIa is maintained in solution, whereas the corresponding compounds IIIb and IIIc in which N∩C is benzo[h]quinoline-9-C,N and N,N-dimethyl-1-naphthylamine-8-C,N, respectively, appear to be mixtures of cis and trans isomers in solution. With PMe₂Ph I and II give trans-Pd(MXN)₂(PMe₂Ph)₂ and cis-Pt(MNX)₂(PMe₂Ph)₂, respectively, in which the methoxynaphthalene is bound to the metals via the 8-carbon of the naphthalene ring. Only one phosphine ligand adds to compounds IIIb and IIIc with displacement of the O → Pd bond. One carbon monoxide ligand can be added to the platinum compound II to give Pt(MXN)₂(SEt₂)CO which in solution exists as two isomers in equilibrium.