Geometrical configuration of monomethyl–platinum(II) complexes driven by the size of entering nitrogen ligands

The reaction of the monoalkyl complex trans-[Pt(DMSO)₂Cl(CH₃)] with a large variety of heterocyclic nitrogen bases L, in chloroform solution, leads to the formation of uncharged complexes of the type [Pt(DMSO)(L)Cl(CH₃)], containing four different groups coordinated to the metal center. Only two out of the three different possible isomers were detected in solution. These two trans(C,N) and cis(C,N) species can be unambiguously identified through ¹H NMR spectroscopy. For the trans(C,N) isomers, average values of ²J_PtH=75±4 Hz and ³J_PtH=36±4 Hz have been observed for the coordinated methyl and DMSO ligands, respectively. In the case of the cis(C,N) isomers, these values increase to ²J_PtH=83±2 Hz, and decrease to ³J_PtH=26±3 Hz due to the mutual exchange of ligands in trans position to CH₃ and DMSO. In the case of bulky asymmetric ligands, such as quinoline, 2-quinolinecarboxaldehyde, 2-methylquinoline, 5-aminoquinoline, 2-phenylpyridine and 2-chloropyridine, slow rotation of the hindered group around the Pt---N bond makes the coordinated DMSO ligand prochiral. NMR experiments have shown that the first reaction product is the trans(C,N) isomer as a consequence of the very fast removal of one DMSO ligand by the nitrogen bases from the starting complex trans-[Pt(DMSO)₂Cl(CH₃)]. This trans kinetic product undergoes a geometrical conversion into the more stable cis(C,N) isomer through the intermediacy of fast exchanging aqua-species. The rate of isomerization and the relative stability of the two isomers depends essentially on the rate of aquation and on the steric congestion imposed by the new L ligand on the metal.     

Pt(II) compounds with sulfoxide ligands and crystal structures of complexes of the types I(R2SO)Pt(μ-I)2Pt(R2SO)I and trans-Pt(R2SO)(L)X2 (L = amine,pyridine and pyrimidine)

The crystal structures of several Pt(II) complexes containing sulfoxide ligands are described. The two iodo bridged dimers of the type I(R₂SO)Pt(μ-I)₂Pt(R₂SO)I (where R is ethyl or n-butyl) are twinned structures. The dinuclear species are the trans isomers. Two compounds of the type trans-Pt(DMSO)(amine)X₂ were studied by X-ray diffraction methods. The diiodo MeNH₂ compound forms H-bonded chains, formed by maximizing the H-bonds between the amine group with the O atom of DMSO and one iodo ligand. The H-bonding pattern is quite different in the dichloro t-BuNH₂ complex. In the latter crystal, there are two independent molecules which are H-bonded in pairs. The methyl groups of DMSO and the t-butyl group of the amine are oriented towards the outside of the pairs of molecules, while the H-bonds link the two independent molecules. Again, the amino group forms the maximum H-bonds with the O atom of DMSO and one chloro ligand. The crystal structures of trans-Pt(DMSO)(pyridine)I₂ and of trans-Pt(MeBzSO)(pyrimidine)I₂ (Bz = benzyl) were also studied. In the pyridine complex, the O atom of DMSO is in the Pt(II) plane by symmetry, while in the pyrimidine compound, the C atom of the –CH₃ group is in the Pt(II) plane. The pyridine and the pyrimidine ligands are perpendicular to the Pt(II) square plane. The trans influence of the different ligands is discussed.     

Synthesis, crystal structure, DNA-binding and cytotoxicity in vitro of novel cis-Pt(II) and trans-Pd(II) pyridine carboxamide complexes

In an attempt to establish fundamental structure-activity relationships (SAR) of Pt/Pd-based anti-tumour compounds, we have recently designed monodentate pyridyl amide ligand containing central amide units which possess external metal co-ordinating pyridyl group and internal amide functionality. It was prepared in one step from commercially available compounds in moderate to good yield. Surprisingly, treatment of K(2)[MCl(4)] [M=Pt(II), Pd(II)] with ligand N-(4-chlorophenyl)-3-pyridinecarboxamide (L) in the same reaction condition affords two different hydrogen-bonded polymers: cis-[PtL(2)Cl(2)]·CH(3)OH·DMF (1) and trans-[PdL(2)Cl(2)]·2DMF (2). Fluorescence analysis indicates that the two complexes can bind to fish sperm DNA (FS-DNA) and gel electrophoresis assay demonstrates the ability of the complexes to cleave the pBR322 plasmid DNA. The two complexes exhibit cytotoxic specificity and significant cancer cell inhibitory rate. Furthermore, cytotoxicity values are higher in the case of cis-Pt(II) complex than trans-Pd(II) complex in four different cancer cell lines.     

The platinum complexes with histamine: Pt(II)(Hist)Cl2, Pt(II)(Iodo-Hist)Cl2 and Pt(IV)(Hist)2Cl2

The Pt(II) and Pt(IV) complexes with histamine were calculated by using more than 20 DFT functionals and various basis sets. Based on the comparison between the X-ray and theoretical geometrical parameters of the Pt(II)(Hist)Cl₂ complex the MPW1PW91, OPW91 and SVWN5 functionals combined with the 6-311G^∗∗ basis set for non-metallic and SDD (ECP) basis set for platinum were found to yield the most satisfactory agreement. The structure of the Pt(II) complex with iodohistamine important for pharmacy, so far isolated only in minute amounts, was predicted by using the MPW1PW91 functional. Comparison of the theoretical NMR chemical shifts of the Pt(II)(Hist)Cl₂ complex with those found experimentally have shown that the theoretical ¹H and ¹³C NMR chemical shifts are in plausible agreement with the experimental ones, whereas the theoretical ¹⁹⁵Pt chemical shifts fit the experimental values only when the relativistic approach is applied within the ZORA formalism. We confirmed suitability of the three selected functionals for reproduction of the experimental structure of Pt complexes at fourth oxidation state by using the cis- and ions as models. Finally, with the selected theoretical methods, the structures and stabilities of four Pt(IV)(Hist)₂Cl₂ complex isomers were predicted.     

Synthetic procedures to monomethyl-platinum(II) complexes containing nitrogen ligands of biological relevance

The complex trans-bis(dimethylsulfoxide)chloromethylplatinum(II) (1) is fairly soluble in water, where it undergoes multiple equilibria involving the formation of geometrically distinct [Pt(H(2)O)(DMSO)Cl(CH(3))] aqua-species. On reacting an aqueous solution of 1 with monodentate nitrogen donor ligands L, such as pyridines or amines, two well distinct patterns of behavior can be recognized: (i) a single stage fast substitution of one DMSO by the entering ligand, yielding a complex of the type trans(C,N)-[Pt(DMSO)(L)Cl(CH(3))] which contains four different groups coordinated to the metal and which undergoes a slow conversion into its cis-isomer, (ii) a double substitution affording cationic complex ions of the type cis-[Pt(L)(2)(DMSO)(CH(3))](+). When this latter reaction is carried out using sterically hindered ligands, slow rotation of the bulk ligand around the Pt[bond]N bond allows for the identification of head-to-head and head-to-tail rotamers in solution, through (1)H NMR spectrometry. The addition of chloride anion to 1 leads to the anionic species cis-[Pt(DMSO)Cl(2)(CH(3))](-), where a molecule of DMSO still remains coordinated to the metal center, despite its quite fast rate of ligand exchange (k(exch) with free DMSO=12+/-1 s(-1)). The reaction of complex 1 with bidentate ligands, such as ethylenediamine (en) or simple amino acids, leads to the cationic species [Pt(en)(DMSO)(CH(3))](+) or to the neutral [Pt(DMSO)(N[bond]O)(CH(3))], (where N[bond]-O[double bond]GlyO(-), AlaO(-)).     

DNA-binding and molecular mechanics modelling studies of the bulky chiral platinum(II) complex [PtCl(2)(mepyrr)] (mepyrr=N-methyl-2-aminomethylpyrrolidine)

Detailed studies were carried out on the binding of the enantiomers of [PtCl₂(mepyrr)] (mepyrr = N-methyl-2-aminomethylpyrrolidine) to dG, d(GpG) and a 52-mer oligonucleotide. The pyrrolidine ligand structure was found to be neither sufficiently rigid nor bulky to enforce a single chirality at the exocyclic amine site in this complex, resulting in the presence of diastereomers that complicated the binding studies. Reaction of the (GpG) dinucleotide with R- and S-[PtCl₂(mepyrr)] resulted in formation of four [Pt{d(GpG)}(mepyrr)] isomers for each enantiomer as a consequence of the existence of two orientational isomers and two diastereomers. These isomers formed in different amounts most likely as a consequence of the unequal formation of the diastereomers together with stereoselectivity induced by interactions between the dinucleotide and the mepyrr ligand. The [PtCl₂(mepyrr)] complexes displayed stereoselectivity and enantioselectivity in their reactions with a 52-mer duplex designed to allow formation of only GpG intrastrand adducts. All four bifunctional adducts formed for each enantiomer, providing further evidence of the lack of directing ability of the ligand in formation of the 1,2-intrastrand adduct. Significant amounts of monofunctional species remained in these assays suggesting that the introduction of the methyl substituent to the exocyclic amine inhibited ring-closure to the bifunctional adduct. This was not sufficient to achieve enantiospecificity, but in the case of the R-enantiomer, one of the bifunctional adducts formed in only small amounts.     

Preparation and crystal structure of bis(acetato)(trans-1,2-diaminocyclohexane)platinum(II)

The structure of the complex [Pt(trans-1,2-di- aminocyclohexane) (acetate)₂]·H₂O has been determined by X-ray diffraction. This racemic compound is orthorhombic, space group Aba2, a = 20.813(9), b = 7.926(5), c = 17.296(8) Å, Z = 8. The structure was refined on 1214 nonzero Cu Kα reflections to R = 0.028. The square planar environment of Pt includes the amino groups of the diamine in cis positions and oxygens from two monodentate acetates. The PtN and PtO distances average 2.00(3) and 2.02(3) Å, respectively. The bite of the diamine ligand imposes a NPtN angle of 85(1)°, whereas the small OPtO angle of 85(1)° probably results from packing effects. The average plane through the puckered cyclohexyl ring makes an angle of 19° with the PtN₂O₂ plane. The molecules are stacked by pairs along the b axis. The two molecules of each pair are 180° apart about the stacking axis, and form altogether four NH···O hydrogen bonds.     

The synthesis and X-ray structural characterization of mer and fac isomers of the technetium(I) nitrosyl complex [TcCl2(NO)(PNPpr)]

The nitrosyl complex H[TcNOCl₄] reacts with the tridentate ligand bis[(2-diphenylphosphino)propyl]amine (PNPpr) to yield a mixture of the mer or fac isomers of [TcCl₂(NO)(PNPpr)]. In acetonitrile, where the ligand is freely soluble, reaction occurs at room temperature to yield mostly the mer isomer with the linear nitrosyl ligand cis to the amine ligand; and the phosphine ligands arranged in a mutually trans orientation. The reaction in methanol requires reflux to dissolve the lipophilic ligand and generates the fac isomer of [TcCl₂(NO)(PNPpr)] as the major product, with the tridentate ligand in a facial arrangement, leaving the chlorides and nitrosyl ligand in the remaining facial sites. The steric bulk of the tridentate ligand’s diphenylphophino-moieties results in a significant distortion from octahedral geometry, with the P-Tc-P bond angle expanded to 99.48(4)°.The infrared spectra display absorptions from these nitrosyl ligands in the 1700 and 1800 cm⁻¹ regions for the fac and mer isomers, respectively. The ESI(+) mass spectra each display the parent ion at 647 m/z.     

Preparation and multinuclear NMR and IR spectroscopic characterization of some complexes of acetyldiphenylphosphine,diphenyl(2-thienyl)phosphine,bis(2-thienyl)phenylphosphine and cyanodiphenylphosphine

The syntheses and multinuclear NMR and IR spectroscopic characterizations of some mononuclear Mo, Pd and Pt complexes of acetyldiphenylphosphine, diphenyl(2-thienyl)phosphine, bis(2-thienyl)phenylphosphine and cyanodiphenylphosphine are presented. The NMR and IR spectra of the Mo carbonyl complexes indicate that the electron-donor ability of the P substituents increases in the order CN < C(O)Me < 2-thienyl < Ph. The reactions of free and coordinated acetyldiphenylphosphine with amines and borohydrides are reported. These reactions do not lead to the desired imino and hydroxymethyl complexes but rather result in PC bond cleavage. Attempts to form dinuclear complexes with bridging 2-thienylphosphine ligands from mononuclear complexes with P-coordinated ligands have not been successful. The products of the reactions result from ligand exchange between the mononuclear precursors and contain only P-coordinated ligands .The structure suggested for a previously reported homodinuclear complex containing a bridging cyanophenylphosphine ligand, [(CO)₅Mo(Ph₂PCN)]₂, has been confirmed by multinuclear NMR and IR spectroscopic studies. An attempt to form a heterodinuclear MoPt complex with bridging cyanophosphine ligands has not been successful. The products of this reaction result from ligand exchange between the mononuclear precursors.     

Characterization and DNA interaction of the Pt(II)(pq)(bdt) complex: A theoretical and experimental research

A mononuclear complex Pt(pq)(bdt) (1) (where pq = 2-(2′pyridyl)quinoxaline and bdt = benzene-1,2-dithiolate) has been prepared and characterized by NMR spectroscopy, ES mass spectroscopy and elemental analysis. Furthermore, its molecular and electronic structure has been fully elucidated by means of the density functional theory (DFT) and time-dependent density functional theory (TDDFT). The former reveals an extensive distortion of the planarity of complex 1, while the latter an intense mixed metal ligand to ligand charge transfer (MM′LLCT) transition in the visible region of the spectrum. Interactions of complex 1, the free ligands pq and bdt with double stranded calf thymus DNA before and after illumination were studied by UV-spectrophotometric (melting curves) and circular dichroism (CD) measurements, indicating that complex 1 is able to form adducts with DNA and to distort the double helix by changing the base stacking. Under our experimental conditions, it is unclear that complex 1 can photocleave DNA. Viscosity changes of calf thymus DNA (CT-DNA) in the presence of an incremental amount of complex 1 demonstrate that in very low ratios, [1]/[DNA]  0.02, this complex binds intercalatively to the DNA, while in higher ratios a partial or a non-classical interacalation should occur due to the tetrahedral distortion of the molecule and the existence of the dithiolato-ligand.     

Ring-substituted diaqua(1,2-diphenylethylenediamine)platinum(II) sulfate reacts with DNA through a dissociable complex.

Ring-substituted diaqua(1,2-diphenylethylenediamine)platinum(II) sulfate shows unusual kinetics in its reaction with salmon testis DNA. The mechanism for diaqua[meso-1,2-bis(2,6-dichloro-4- hydroxyphenyl)ethylenediamine]platinum(II) sulfate, [Pt(H2O)2(meso-6)]2+SO4(2-), a representative of this series, has been investigated and compared with that for cis-[Pt(NH3)2(H2O)2]2+. Reactions were followed by atomic absorption, analytical HPLC of Pt-DNA digests, arrest of enzymatic DNA synthesis/degradation, ultraviolet and fluorescence spectrophotometry. Except for the formation of monofunctional DNA adducts, the kinetics of the platinum(II) complexes are comparable. The pseudo-first-order rate constant for the attack of DNA by [Pt(H2O)2(meso-6)]2+ follows the concentration of DNA in a hyperbolic fashion, which is in contrast to the linear dependence for cis-[Pt(NH3)2(H2O)2]2+. The hyperbolic dependence is typical for a dissociable DNA/drug complex preceding the coordination reaction. By studying the binding of free ligand to DNA, and by correlating ligand structures and electrostatic charges with effects on adduct formation, both the phenyl residues and the positive charge of the platinum(II) complex are shown to be crucial for the stability of the dissociable complex. A non-intercalative mode of binding to the DNA backbone is suggested. At the high concentrations of DNA found in cell nuclei, the reaction of the dissociable complex can, principally, become rate-limiting in the attack of DNA and thus reduce the cytotoxic efficiency of a drug.     

Preparation,characterization, and antitumor activity of new cisplatin analogues with 1-methyl-4-(methylamino)piperidine: crystal structure of [PtII(1-methyl-4-(methylamino) piperidine)(oxalate)

A series of new platinum(II) complexes of the type [Pt(II)(mmap)X] (where mmap, 1-methyl-4-(methylamino)piperidine and X, 1,1-cyclobutanedicarboxylato (CBDCA), oxalato, malonato, methylmalonato, dimethylmalonato, ethylmalonato, diethylmalonato or 2,3-naphthalene dicarboxylato (NDCA)) have been synthesized and characterized by elemental analysis, infrared (IR), and 13C and 195Pt nuclear magnetic resonance (NMR) spectroscopy. The crystal structure of the analogue [Pt(II)(mmap)(oxalate)] was determined using the single crystal X-ray diffraction method. Based upon a total of 4964 collected reflections, we determined that the compound crystallizes in the monoclinic space group P2(1)/c (with a=11.890(2) A, b=9.6695(19) A, c=9.875(2) A, beta=102.03(3) degrees, Z=4, and R=0.0428). In this complex, platinum has a slightly distorted square planar geometry with the two adjacent corners being occupied by two nitrogen atoms of the mmap ligand, whereas the remaining cis positions are occupied by two oxygen atoms of the oxalate molecule. The mmap ligand is in a boat conformation and forms six-membered chelating rings as well as the oxalate molecule forms five-membered chelating rings with platinum. The complexes were evaluated for their cytotoxic potential against the sensitive A2780 tumor model and cisplatin-resistant clone derived in vitro from potential cells.     

Effect of the amine non-leaving group on the structure and stability of DNA complexes with cis-[Pt(R-NH2)2(NO3)2]

The antitumor compound cis-[Pt(NH3)2Cl2] (cisplatin), conserves two ammine ligands during the reaction with its cellular target DNA. Modifications of these non-leaving groups change the antineoplastic properties of this compound and its genotoxic effects. It is therefore of interest to determine the influence of non-leaving groups on the structure and stability of DNA in vitro. We have investigated platinum-DNA adducts formed by cis-[Pt(R-NH2)2(NO3)2] (where R-NH2 = NH3, methylamine, cyclobutylamine, cyclopentylamine and cyclohexylamine) as a function of DNA binding. All compounds quantitatively reacted with DNA in less than 1 h at 37 degrees C. They formed bifunctional adducts with adjacent nucleotides judging from the displacement of the intercalating molecule ethidium bromide, ultraviolet absorption spectroscopy and circular dichroism. Substitution of a H on the NH3 ligand by alkyl groups dramatically destabilized the platinum-DNA complex. Thermal stability decreased progressively with an increasing number of carbon atoms, delta tm = -4.4 degrees C for 3 cyclohexylamine-platinum-DNA adducts/1000 nucleotides, conditions where cisplatin had no effect. DNA adducts with cyclobutylamine and cyclohexylamine ligands inhibited the hydrolysis of platinum-DNA complexes by S1 nuclease. Km for the digestion of DNA containing these lesions was 2.3 times greater than for cisplatin, indicating steric inhibition of enzyme-substrate complex formation. These results show that the non-leaving groups of substituted cis-Pt(II) compounds may destabilize DNA and interfere with protein-DNA interactions. These perturbations may have consequences for the genotoxic and antitumor activities of platinum compounds.     

Circular dichroism spectra of the individual rotamers of [Pt(N,N-dmen)(GpG)]+ (N,N-dmen=N,N-dimethylethylenediamine) indicate that the base-base oscillator coupling is not the main source of ellipticity in cis-PtG2L2 head-to-head complexes

The asymmetrical platinum complex [PtCl2(N,N-dmen)] (N,N-dmen = N,N-dimethylethylenediamine) reacts with the dinucleotide GpG to form two isomeric chelates of the formula [Pt(N,N-dmen)(GpG)]+ [9]. One of the isomers forms two stable rotamers separable by HPLC, whereas the other apparently prefers one single rotameric form. The favored conformations of these three forms were elucidated by means of molecular mechanics and dynamics techniques. In parallel, we have prepared the adduct, isolated the three rotamers, and recorded their solution circular dichroism (CD) spectra. For the first time we were thus able to correlate the CD features of individual rotamers of a cis-Pt(GpG) chelate with their structures. We show here that the two forms labeled in Inagaki's paper 1'e and 2e have the same right-handed helicoidal arrangement of the guanine bases but display different CD spectra in which the prominent bands have inverted signs. Thus, base-base interactions cannot be the principal cause of the CD of these compounds.     

Influence of pyridine versus piperidine ligands on the chemical, DNA binding and cytotoxic properties of light activated trans,trans,trans-[Pt(N3)2(OH)2(NH3)(L)

The photocytotoxicity and photobiochemical properties of the new complex trans,trans,trans-[Pt(N₃)₂(OH)₂(NH₃)(piperidine)] (5) are compared with its analogue containing the less basic and less lipophilic ligand pyridine (4). The log P (n-octanol/water) values were of −1.16 and −1.84 for the piperidine and pyridine complexes, respectively, confirmed that piperidine increases the hydrophobicity of the complex. Density Functional Theory (DFT) and time-dependent density functional theory (TDDFT) calculations indicate that 5 has accessible singlet and triplet states which can promote ligand dissociation when populated by both UVA and visible white light. When activated by UVA or white light, both compounds showed similar cytotoxic potencies in various human cancer cell lines although their selectivity was different. The time needed to reach similar antiproliferative activity was noticeably decreased by introducing the piperidine ligand. Neither compound showed cross-resistance in three oxoplatin-resistant cell lines. Furthermore, both compounds showed similar anticlonogenic activity when activated by UVA radiation. Interactions of the light-activated complexes with DNA showed similar kinetics and levels of DNA platination and similar levels of DNA interstrand cross-linking (ca. 5%). Also the ability to unwind double stranded DNA were comparable for the piperidine analogue (24°, respectively), while the piperidine complex showed higher potency in changing the conformation of DNA, as measured in an ethidium bromide binding assay. These results indicate that the nature of the heterocyclic nitrogen ligand can have subtle influences on both the phototoxicity and photobiochemistry of this class of photochemotherapeutic agents.     

Complexes formed from 2,4,6-trimercaptotriazine (H3TMT): synthesis and structural characterization of [M(PhP(CH2CH2P(Ph)2)2(HTMT)], M=Ni(II), Pd(II), Pt(II)

Na₃TMT · 9H₂O (H₃TMT=2,4,6-trimercaptotriazine) reacts with M(PPP)Cl₂, PPP=PhP(CH₂CH₂PPh₂)₂, M=Ni, Pd, Pt, to give the compounds [M(PPP)(HTMT)]. The nickel and palladium complexes have been characterized by single-crystal X-ray diffraction analysis. PPP is tridentate in both complexes. The nickel complex has an irregular trigonal bipyramidal configuration in which the triazine is bidentate, coordinating through one sulfur and one nitrogen donor atom. The palladium complex has an approximately square planar geometry in which the triazine forms a strong Pd-S bond in the plane and also a very weak Pd-N interaction above the plane. The ³¹P NMR spectrum of the platinum complex is similar to that of the palladium complex, which is consistent with the Pt complex also having an approximately square-planar structure. Variable temperature NMR spectra show that two conformational isomers of the nickel complex are present in solution at low temperatures, though exchange is fast at room temperature. DFT calculations have confirmed the possible existence of two five-coordinate isomers of comparable stability.     

Studies on the anti-proliferative effects of novel DNA-intercalating bipyridyl-thiourea-Pt(II) complexes against cisplatin-sensitive and -resistant human ovarian cancer cells

Six bipyridyl complexes of platinum(II) with thiourea, with different substituents on thiourea moiety [Pt(bipy)(R,R'NCSNR',R')(2)]Cl(2) (bipy=2,2'-bipyridine: R=R'=R'=R' =H; R=Me, R'=R'=R'=H; R=n-Bu, R'=R'=R'=H; R=Et, R'=H, R'=Et, R'=H; R=p-tolyl, R'=R'=R'=H; R=phenyl, R'=H, R'=phenyl, R'=H), rationally designed to intercalate into DNA, have been tested against a cisplatin (cDDP)-sensitive human ovarian carcinoma cell line (2008) and its -resistant variant (C13( *)). We show here that the anti-proliferative efficacy of these drugs was dependent on molecular structure, since it increased with ancillary ligand bulkiness and hydrophobicity of substituents on thiourea moiety. In particular, the presence of two phenyl groups on thiourea moiety confers an outstanding cytotoxicity. The increasing cell growth inhibition along the series of complexes partially paralleled with drug accumulation, particularly in resistant cells, but not with drug intercalation into DNA since all compounds exerted comparable ethidium bromide displacement ability. The cDDP-resistant phenotype seems, at least in part, to be involved in the action of these compounds, since the level of cross-resistance established for most complexes appeared to be in agreement with the observed impairment of drug accumulation in the resistant subline. These findings indicate that resistance to alkylating agents such as cDDP confers low level of cross-resistance to this class of DNA intercalators, which, however, depending on substituents on thiourea moiety may present remarkable cell growth inhibition even of resistant cells.     

Fixing the conformations of diamineplatinum(II)-GpG chelates: NMR and CD signatures of individual rotamers

The bulky, asymmetric analog of the antitumor drug cisplatin, [PtCl(2)(tmen)] (tmen = N,N,N'-trimethylethylenediamine), was used to produce crosslinks with the dinucleotide d(GpG), modeling the most frequent lesions that cisplatin and its analogs cause to DNA. The ligand tmen was chosen because it is expected to constrain the guanine cis to the NMe(2) group in the adduct [Pt(tmen){d(GpG)}](+) to an orientation perpendicular to the coordination plane and to stabilize the other guanine in an oblique orientation, thus maintaining a head-to-head geometry typical of cisplatin-d(GpG) crosslinks within single- and double-stranded DNA. Of the four possible combinations of tmen chirality (R or S symmetry of the coordinated NHMe group) and crosslink direction (5'-G bound cis to the secondary or the tertiary amino group of tmen), two isomers were preponderantly formed, [Pt(R-tmen){d(GpG)}](+) with 5'-G bound cis to NMe(2) and [Pt(S-tmen){d(GpG)}](+) with 5'-G bound cis to NHMe. The former was shown to have a right-handed R2 orientation of guanines similar to that found in duplex DNA, whereas the latter had a left-handed L1 orientation that modeled cisplatin-d(GpG) adducts within single-stranded DNA. The R2 rotamer was found to be in an equilibrium (as observed using EXSY spectroscopy) with a minor fraction (< or =4%) of a Delta-HT rotamer related to R2 by rotation of the 3'-G about the Pt-N7 bond. The major rotamers R2 and L1 were isolated using reverse-phase HPLC, and their NMR and CD signatures were compared to those of the corresponding rotamers of the less hindered adduct [Pt(dmen)(GpG)](+) (dmen = N,N-dimethylethylenediamine). From this and other comparisons with previously reported platinum dinucleotide complexes, and from molecular modeling, it could be concluded that both steric repulsion between guanine and substituents of the cis amino group and N-H...O6 hydrogen bonding are significant effects favoring the oblique orientation of one guanine base typical of the HH rotamers of [Pt(diamine){d(GpG)}](+) and [Pt(diamine)(GpG)](+) complexes.     

Ligand induced P---H bond formation and a comparison of the reactivity of two isomers of the carbonyl hydride [Pt2(μ-PBu2)2(H)(CO)(PBu2H)]CF3SO3

The Pt₂ ^(II) isomeric terminal hydrides [(CO)(H)Pt(μ-PBu^t ₂)₂Pt(PBu^t ₂H)]CF₃SO₃ (1a), and [(CO)Pt(μ-PBu^t ₂)₂Pt(PBu^t ₂H)(H)]CF₃SO₃ (1b), react rapidly with 1 atm of carbon monoxide to give the same mixture of two isomers of the Pt₂ ^(I) dicarbonyl [Pt₂(μ-PBu^t ₂)(CO)₂(PBu^t ₂H)₂]CF₃SO₃ (3-Pt); the solid state structure of the isomer bearing the carbonyl ligands pseudo-trans to the bridging phosphide was solved by X-ray diffraction. A remarkable difference was instead found between the reactivity of 1a and 1b towards carbon disulfide or isoprene. In both cases 1b reacts slowly to afford [Pt₂(μ-PBu^t ₂)(μ,η²,η²-CS₂)(PBu^t ₂H)₂]CF₃SO₃ (4-Pt), and [Pt₂(μ-PBu^t ₂)(μ,η²,η²-isoprene) (PBu^t ₂H)₂]CF₃SO₃ (6-Pt), respectively. In the same experimental conditions, 1a is totally inert. A common mechanism, proceeding through the preassociation of the incoming ligand followed by the P---H bond formation between one of the bridging P atoms and the hydride ligand, has been suggested for these reactions.     

Interaction of N-acetylmethionine with a non-C2-symmetrical platinum diamine complex

The reaction of N-acetylmethionine (N-AcMet) with the complex [Pt(Et(2)en)(D(2)O)(2)](2+) (Et(2)en=N,N-diethylethylenediamine) was studied by NMR spectroscopy and molecular mechanics calculations. Complexes containing two methionine residues coordinated to the platinum atom were calculated to be relatively high in energy unless the bulk of the methionine residues was directed away from the diethyl group of the Et(2)en ligand. In contrast, sulfur-oxygen chelates were found to be relatively free of steric clashes. Experimentally, two sets of NMR resonances were observed when [Pt(Et(2)en)(D(2)O)(2)](2+) was reacted with N-AcMet; variable temperature experiments indicated intermediate chemical exchange between the two sets of resonances. NMR studies indicated that the resonances corresponded to [Pt(Et(2)en)(N-AcMet-S,O)](+) complexes with the sulfur atom trans to the diethyl group of the Et(2)en ligand. No product with the sulfur atom cis to the diethyl group was observed experimentally even though molecular mechanics calculations suggested that such forms have few steric clashes. The NMR results suggested that the chemical exchange was a result of sulfur chirality inversion. In early stages of the reaction, a [Pt(Et(2)en)(N-AcMet-S)(D(2)O)](+) complex was observed, indicating that coordination of the oxygen to form the chelate is relatively slow.