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Reactivity of [PtCl(h2-C2H4)(N-N)]+, N-N = diimine ligand, with phenol derivatives and first comparison between single crystal X-ray structures of syn- and anti-[Pt(N-N)(phenolate)2] rotamers in the solid state
... For the Zeise anion [Pt(C2H4)Cl3] − , analogous reactions have been studied [42][43][44] and the Zeise anion or its dimer [(C2H4)ClPt(µ-Cl2)PtCl(C2H4)] have been used as catalysts in many more important transformations, such as hydroaminations, hydrosilylations or alkoxyarylations [29,[45][46][47]. In the presence of chelate nitrogen ligands, such as diimines (N^N), five coordinate species were discussed in such catalytic processes [42,43,[48][49][50][51][52]. ...
... Indeed, when reacting the Zeise anion with diimine ligands (N^N), five coordinate complexes [Pt(N^N)(η 2 -C2H4)Cl2] were obtained [48][49][50][51][52][53][54][55][56][57][58][59][60]. The mono-olefin complexes of the type [Pt(N^N)(η 2 -olefin)X2] (X = halogens and pseudohalogens) form indeed the main body of the so far reported organometallic pentacoordinate Pt(II) complexes [4,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. ...
... The two other protons on these CH2 groups, the Z protons, exhibit angles of about 80° and no detectable 3 JPt-H coupling. The 1 JPt-C coupling to the two olefin groups of 31 Hz for the axial and 334 Hz for the equatorial position, which were comparable to related five coordinate Pt(II) olefin complexes [15,16,[48][49][50][51][52][53][54][55]71,72,79,105], also reflects the very different binding strength of the two groups and, thus, strongly suggests a trigonal bipyramidal coordination [15,[53][54][55]. Thus, the NMR data are completely in line with the molecular structure from the XRD and are represented by Structure (a) in Scheme 2. As has been pointed out before, relatively high 1 JPt-C for a Pt bound olefin group points to a more pronounced description of the Pt-olefin binding as a metallacyclopropane unit [15]. ...
The five coordinate organoplatinum complex [Pt(bpy)(cod)(Me)][SbF6] (cod = 1,5-cyclooctadiene, bpy = 2,2’-bipyridine) was obtained reacting [Pt(cod)(Me)Cl] with Ag[SbF6] and bpy and characterized by multiple spectroscopy (IR and NMR) and single crystal XRD. Although the application of the τ values for the discrimination between trigonal bipyramidal vs. square pyramidal coordination fails, the molecular structure can be unequivocally described as basally-distorted trigonal bipyramidal. Detailed multinuclear NMR spectroscopy in solution at ambient temperature gives strong evidence for the same structure; corresponding low-temperature measurements down to −70 °C revealed no marked dynamic processes.
... The role of the metal-to-olefin back donation on the stabilization of the metal-olefin bonding interaction was also supported by the enhanced stabilization of anionic square planar Pt(II) complexes bearing η 2 -olefins, with respect to neutral or cationic complexes, which instead exhibit reduced stability and increased reactivity. [11][12][13][14][15][16][17][18][19][20] In previous works we synthesized and characterized complexes with the Me 2 phen ligand, of the type [PtX 2 (Me 2 phen)] (X = halogen), 21 showing considerable distortions from the regular square planar arrangement and an unusual chemical and electrochemical behavior, with respect to analogue complexes in which the phenanthroline has no substituents in the 2,9 positions. 22 Because of steric interactions between ortho substituents of the phenanthroline ligand and halogen ligands in cis positions, the square planar [PtX 2 (Me 2 phen)] complexes have a great tendency to add an external L ligand (L = C≡O, PPh 3 , DMSO, DMS, py, n-PrNH 2 , alkene, alkyne) to give the corresponding addition product. ...
... Calc. for C18 H 18 I 2 N 2 Pt (12): C, 30.4; H, 2.6; N, 3.9; I, 35.7. ...
The reactivity with acetylene of [PtX2(Me2phen)] (X = Cl, Br, I) complexes has been investigated. Whereas the chlorido species [PtCl2(Me2phen)] exhibits negligible reactivity at short reaction times, the bromido and iodido species [PtBr2(Me2phen)] and [PtI2(Me2phen)] lead initially to formation of Pt(ii) five-coordinate complexes, [PtX2(η(2)-CH[triple bond, length as m-dash]CH)(Me2phen)], that evolve to four-coordinate alkenyl complexes of the type [PtX(η(1)-E-CH[double bond, length as m-dash]CHX)(Me2phen)]. The alkenyl complexes, in the presence of excess acetylene, establish an equilibrium with the five-coordinate alkyne-alkenyl species [PtX(η(1)-E-CH[double bond, length as m-dash]CHX)(η(2)-CH[triple bond, length as m-dash]CH)(Me2phen)] (X = Br, I). The π-bonded acetylene can be exchanged with free olefins or C[triple bond, length as m-dash]O, affording the new alkene-alkenyl or carbonyl-alkenyl complexes [PtX(η(1)-E-CH[double bond, length as m-dash]CHX)(η(2)-olefin)(Me2phen)] and [PtX(η(1)-E-CH[double bond, length as m-dash]CHX)(C[triple bond, length as m-dash]O)(Me2phen)]. The five-coordinate geometry of the alkyne-alkenyl and alkene-alkenyl complexes was assessed from NMR data and is fully consistent with that of a previously determined X-ray structure of [PtBr(η(1)-E-CH[double bond, length as m-dash]CHBr)(η(2)-CH2[double bond, length as m-dash]CH2)(Me2phen)].
... bonded to coordinated dinitrogen ligands and the observed 195 Pt NMR frequency for pentacoordinate and square-planar Pt II species. [42,43] To better understand the relationship between the observed NMR chemical shifts and the molecular structures of platinum complexes, we studied the Pt II pentacoordinate complexes of the type [PtXY(η 2 -olefin)(N N)] [44][45][46][47][48][49][50][51][52][53][54] and [PtXY(η 2 -alkyne)(N N)] [55] (X,Y = Cl, Br, I; N N = dinitrogen ligand). In particular, collection of the 1 H, 13 C, 15 N, and 195 Pt NMR spectroscopic data of the considered pentacoordinate complexes allowed the linear correlation of the chemical shift frequencies with both the spatial disposition of the observed nuclei and the ionic radii of the apical halido ligands (Figure 1, A). [54,56] A good linear relationship between the observed 195 Pt NMR chemical shift frequencies and the overall sum of the ionic radii [Σ(r h )] of the coordinated halido ligands was also discovered in octahedral Pt IV complexes of the type [PtX n Y 6-n ] 2-(1 ≤ n ≤ 6; X, Y = F, Cl, Br, I; Figure 1, A). [56] Interestingly, NMR frequencies show similar linear relationships (very similar slope) to the Σ(r h ) (and to the ionic radius of each coordinated halido ligand) in both pentacoordinate Pt II [54] and octahedral Pt IV complexes [33,[56][57][58] (Figure 1, A). Hitherto, this new concept, which we defined as "cooperative effects of single atom ligands on the 195 Pt NMR chemical shift", did not involve square-planar Pt II complexes with coordinated halido ligands. ...
In this work, we show by a simple empirical approach that a linear relationship between observed 195Pt NMR frequencies and the overall sum of the ionic radii of the coordinated halido ligands [Σ(rh)] exists in square-planar PtII complexes of the type [PtXnY4–n]2– (1 ≤ n ≤ 4; X, Y = Cl, Br, I). Another finding was that such square-planar complexes could be empirically described as octahedral complexes, with the two lobes of the 5dz² orbital above and below the coordination plane acting as two pseudo-halido ligands, each showing a constant apparent radius of around 207 pm. According to our approach, the overall apparent radius of around 415 pm produces constant 195Pt NMR shielding for all [PtXnY4–n]2– complexes of about 10450 ppm. This result is 1) consistent with the theoretically calculated overall 5d shell lone-pair shielding observed in square-planar PtII with respect to octahedral PtIV complexes and 2) almost coincident with the already measured chemical shift anisotropy (CSA) of the K2[PtCl4] complex both in solution and in the solid state (single crystal).
... After about fifty years from their discovery, platinum based antitumor drugs remain among the most successful chemotherapeutics, either alone or in combination with other treatments (Fig. 1) [1][2][3][4][5][6]. It is well known that cisplatin, cis-[Pt(NH 3 ) 2 Cl 2 ], which is the most studied platinum based antitumor drug, affects the replication of tumor cells, by bonding the N7 of purines into DNA [6][7][8][9][10][11][12][13][14][15]. Such interactions are considered pivotal for antitumor activity [2][3][4][5][6], explaining why most of studies on the cisplatin action mechanism are centered on a better understanding of the cisplatin-DNA interactions. ...
... In previous studies we analyzed the NMR properties of pentacoordinate complexes, formed by the interaction of Zeise's anion, [PtCl 3 (η 2 -CH 2 vCH 2 )] − , with N,N-chelate ligands. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] These specific complexes are generally considered to be interesting since platinum bonded unsaturated ligands are useful models in the study of the interaction of alkenes and alkynes with metals. [14][15][16][17][18][19][20][21][22] In particular, in the study of the single crystal X-ray structures and NMR signals of the symmetric pentacoordinate complexes [PtX 2 (η 2 -CH 2 vCH 2 )(Me 2 phen)] (X = Cl, Br, I; Me 2 phen = 2,9-dimethyl-1,10-phenanthroline), we described the evidence of pseudo-ring currents circulating around the Pt-X axes, Fig. 1 and 2. These currents seemed to be modulated by the ionic radii of the halido ligands coordinated at trans positions, above and below the trigonal equatorial plane. ...
An inverse linear relationship between the experimentally observed (195)Pt NMR signals and the overall sum of coordinated halido ligands' ionic radii was discovered in Pt(ii) and Pt(iv) complexes. The reduction of (195)Pt NMR frequencies parallels the increase of coordinated halido ligands' ionic radii sum. This suggests that each halido ligand may act as a conducting ring whose induced electric current shields the (195)Pt NMR signals proportionally to the ionic radius of the coordinated halido ligand.
... We previously extensively studied the reactions of the Zeise's anion, [PtCl 3 (η 2 -CH 2 =CH 2 )] − , with various donor ligands. [1][2][3][4][5][6][7][8][9][10] Indeed the reactivity of platinum bonded olefin in such reaction and in the resulting complexes, [1,4,11] can be a model in the general study of alkenes and alkynes interactions also with other metals. [12][13][14][15][16][17][18][19][20][21][22][23][24][25] Moreover, in these reactions the likely nucleophilic additions on the metal and/or η 2 -ethene, yield a variety of very interesting products, Scheme 1. [1,5,6,10,26] Bidentate dinitrogen donors, can easily form pentacoordinate complexes of the type [PtX 2 (η 2 -CH 2 =CH 2 )(N^N)] (X = Cl, Br, I). ...
The single crystal X-ray structure of the pentacoordinate complex [PtBr2(η2-CH2CH2)(Me2phen)], Me2phen = 2,9-dimethyl-1,10-phenanthroline, is here reported for the first time. Comparison of the complete series of [PtX2(η2-CH2CH2)(Me2phen)] (X = Cl, Br, I) X-ray structures shows a very low variability of the bond lengths and angles, in the trigonal equatorial plane (where η2-olefin and Me2phen are bound), on varying the coordinated axial halogens. In first approximation, this suggests describing as independents and not interacting the two subsystems constituted by the metal bonds with axial (X-Pt-X) and equatorial ligands (Me2phen-Pt-η2-ethene). This means that the electric charge donated to the metal, by the axial ligands, cannot substantially modify the bonds of the metal with the ligands in the trigonal equatorial plane. The 1H, 13C, 15N and 195Pt NMR chemical shifts variations, studied as a function of the ionic radius of the axial halides are here discussed. The NMR data strongly suggest the existence of electric pseudo-ring currents circulating around the Pt-X axes and modulated by the ionic radius of the coordinated halides.
The therapeutic advantages of some platinum complexes as major anticancer chemotherapeutic agents and of nucleoside analogue-based compounds as essential antiviral/antitumor drugs are widely recognized. Red blood cells (RBCs) offer a potential new strategy for the targeted release of therapeutic agents due to their biocompatibility, which can protect loaded drugs from inactivation in the blood, thus improving biodistribution. In this study, we evaluated the feasibility of loading model nucleobase-containing Pt(II) complexes into human RBCs that were highly stabilized by four N-donors and susceptible to further modification for possible antitumor/antiviral applications. Specifically, platinum-based nucleoside derivatives [PtII(dien)(N7-Guo)]2+, [PtII(dien)(N7-dGuo)]2+, and [PtII(dien)(N7-dGTP)] (dien = diethylenetriamine; Guo = guanosine; dGuo = 2′-deoxy-guanosine; dGTP = 5′-(2′-deoxy)-guanosine-triphosphate) were investigated. These Pt(II) complexes were demonstrated to be stable species suitable for incorporation into RBCs. This result opens avenues for the possible incorporation of other metalated nucleobases analogues, with potential antitumor and/or antiviral activity, into RBCs.
Pancreatic cancer is one of the most lethal malignancies with an increasing incidence and a high mortality rate, due to its rapid progression, invasiveness, and resistance to anticancer therapies. In this work, we evaluated the antiproliferative and antimigratory activities of the two organometallic compounds, [Pt(η1-C2H4-OMe)(DMSO)(phen)]Cl (1) and [Pt(η1-C2H4-OEt)(DMSO)(phen)]Cl (2), on three human pancreatic ductal adenocarcinoma cell lines with different sensitivity to cisplatin (Mia PaCa-2, PANC-1, and YAPC). The two cationic analogues showed superimposable antiproliferative effects on the tested cells, without significant differences depending on alkyl chain length (Me or Et). On the other hand, they demonstrated to be more effective than cisplatin, especially on YAPC cancer cells. For the interesting cytotoxic activity observed on YAPC, further biological assays were performed, on this cancer cell line, to evaluate the apoptotic and antimetastatic properties of the considered platinum compounds (1 and 2). The cytotoxicity of 1 and 2 compounds appeared to be related to their intracellular accumulation, which was much faster than that of cisplatin. Both 1 and 2 compounds significantly induced apoptosis and cell cycle arrest, with a high accumulation of sub-G1 phase cells, compared to cisplatin. Moreover, phenanthroline-containing complexes caused a rapid loss of mitochondria membrane potential, ΔΨM, if compared to cisplatin, probably due to their cationic and lipophilic properties. On 3D tumor spheroids, 1 and 2 significantly reduced migrated area more than cisplatin, confirming an antimetastatic ability.
Environmental pollution has become a pressing concern worldwide due to the accumulation of pollutants from industries and agricultural sectors in soil and water environments. Heavy metals pose severe hazards to the environment, plants, and human health. Consequently, an eco-friendly technique is needed to combat environmental pollutants. Vermibiochar, a product prepared through the combined action of earthworms and biochar, demonstrates great potential in reducing heavy metal concentrations in contaminated soil. Its large surface area and high cation exchange capacity enhance the sorption of contaminants onto the vermibiochar surface, reducing their bioavailability. This review highlights the roles played by earthworms and biochar in heavy metal detoxification and immobilization. It discusses the current methods of remediation, vermibiochar production, its effects on soil properties and plant growth, and biochar’s impact on earthworm growth and reproduction. The studies reviewed suggest that vermibiochar is a novel strategy for addressing heavy metal contamination.
In this work, we elucidated some key aspects of the mechanism of action of the cis-platin anticancer drug, cis-[Pt(NH3)2Cl2], involving direct interactions with free nucleotides. A comprehensive in silico molecular modeling analysis was conducted to compare the interactions of Thermus aquaticus (Taq) DNA polymerase with three distinct N7-platinated deoxyguanosine triphosphates: [Pt(dien)(N7-dGTP)] (1), cis-[Pt(NH3)2Cl(N7-dGTP)] (2), and cis-[Pt(NH3)2(H2O)(N7-dGTP)] (3) {dien = diethylenetriamine; dGTP = 5-(2-deoxy)-guanosine-triphosphate}, using canonical dGTP as a reference, in the presence of DNA. The goal was to elucidate the binding site interactions between Taq DNA polymerase and the tested nucleotide derivatives, providing valuable atomistic insights. Unbiased molecular dynamics simulations (200 ns for each complex) with explicit water molecules were performed on the four ternary complexes, yielding significant findings that contribute to a better understanding of experimental results. The molecular modeling highlighted the crucial role of a specific α-helix (O-helix) within the fingers subdomain, which facilitates the proper geometry for functional contacts between the incoming nucleotide and the DNA template needed for incorporation into the polymerase. The analysis revealed that complex 1 exhibits a much lower affinity for Taq DNA polymerase than complexes 2-3. The affinities of cisplatin metabolites 2-3 for Taq DNA polymerase were found to be quite similar to those of natural dGTP, resulting in a lower incorporation rate for complex 1 compared to complexes 2-3. These findings could have significant implications for the cisplatin mechanism of action, as the high intracellular availability of free nucleobases might promote the competitive incorporation of platinated nucleotides over direct cisplatin attachment to DNA. The study's insights into the incorporation of platinated nucleotides into the Taq DNA polymerase active site suggest that the role of platinated nucleotides in the cisplatin mechanism of action may have been previously underestimated.
Nucleoside analogues (NAs) are a family of compounds which include a variety of purine and pyrimidine derivatives, widely used as anticancer and antiviral agents. For their ability to compete with physiological nucleosides, NAs act as antimetabolites exerting their activity by interfering with the synthesis of nucleic acids. Much progress in the comprehension of their molecular mechanisms has been made, including providing new strategies for potentiating anticancer/antiviral activity. Among these strategies, new platinum-NAs showing a good potential to improve the therapeutic indices of NAs have been synthesized and studied. This short review aims to describe the properties and future perspectives of platinum-NAs, proposing these complexes as a new class of antimetabolites.
One of the major challenges of drug delivery is the development of suitable carriers for therapeutic molecules. In this work, a novel nano-formulation based on superparamagnetic nanoclusters (MNC) is presented. In order to control the size of the nanoclusters and the density of magnetic cores, several parameters were evaluated and tuned. Then, MNC were functionalized with a polydopamine layer (MNC@PDO) to improve their stability in aqueous solution, to increase density of functional groups and to obtain a nanosystem suitable for drug-controlled release. Finally, cisplatin was grafted on the surface of MNC@PDO to exploit the system as a magnetic field-guided anticancer delivery system. The biocompatibility of MNC@PDO and the cytotoxic effects of MNC@PDO-cisplatin complex were determined against human cervical cancer (HeLa) and human breast adenocarcinoma (MCF-7) cells. In vitro studies demonstrated that the MNC@PDO-cisplatin complexes inhibited the cellular proliferation by a dose-dependent effect. Therefore, by applying an external magnetic field, the released drug exerted its effect on a specific target area. In summary, the MNC@PDO nanosystem has a great potential to be used in targeted nanomedicine for the delivery of other drugs or bio-functional molecules.
The reactivity of [PtX2(Me2phen)] complexes (X = Cl, Br, I; Me2phen = 2,9-dimethyl-1,10-phenanthroline) with terminal alkynes has been investigated. Whereas the dichlorido species [PtCl2(Me2phen)] exhibits negligible reactivity, the bromido and iodido derivatives lead in short time to formation of five-coordinate Pt(II) complexes of the type [PtX2(Me2phen)(η²-CH≡CR)] (X = Br, I; R = Ph, n-Bu), in equilibrium with the starting reagents. Similarly to analogous complexes with simple acetylene, the five coordinate species can also undergo dissociation of an halido ligand and formation of the transient square-planar cationic species [PtX(Me2phen)(η²-CH≡CR)]⁺. This latter can further evolve to give an unusual, sparingly soluble square planar product where the former terminal alkyne is converted into a :C=C(H)(R) moiety with the α-carbon bridging the Pt(II) core with one of the two N-donors of coordinated Me2phen. The final product [PtX2{κ²-N,C-(Z)-text-decoration:underline"N1—N10-text-decoration:underline"C=C(H)(R)}], (N1—N10 = 2,9-dimethyl-1,10-phenanthroline; X = Br, I) contains a Pt-N-C-C-N-C six membered chelate ring in a square planar Pt(II) coordination environment.
The series of complexes of formula [PtCl(η²-olefin)(N^N)]⁺, previously investigated for N^N = N,N,N’,N’-tetramethyl-ethylenediamine (Me4en), has been extended to the case of aromatic diimines 1,10-phenanthroline (phen) and 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4phen) and to a variety of olefins (ethene, propene and styrene). The complexes have been prepared by reaction of the [PtCl3(η²-olefin)]⁻ anions (K[PtCl3(η²-styrene)] reported here for the first time) with N^N in basic methanol. The initial [PtCl{η¹-CH2−CH(R’)−OMe}(N^N)] (R’ = Me, Ph) complexes are formed in quantitative yield and as pure Markovnikov isomer. The reaction of the alkoxylic species with non coordinating acids, results in the quantitative formation of the desired cationic π-olefin complexes [PtCl(η²-olefin)(N^N)]⁺. The phenanthroline ligand confers peculiar properties to the new compounds. In particular, by reaction with triethylamine, [PtCl{η²-CH2=CH(Me)}(N^N)]⁺ species, undergo deprotonation of the olefin and formation of the dimeric species [{PtCl(N^N)}2(μ-η¹:η²-CH2CH=CH2)]⁺ which could be isolated and characterized. Interestingly such product in acetonitrile gives a disproportionation with precipitation of [PtCl2(phen)] and formation in solution of the new η³-allyl complex [Pt(η³-C3H5)(phen)]ClO4.
An inverse linear relationship between (73)Ge, (119)Sn and (207)Pb NMR chemical shifts and the overall sum of ionic radii of coordinated halido ligands has been discovered in tetrahedral [MXnY4-n] (M = Ge, Sn, Pb; 1 ≤ n ≤ 4; X, Y = Cl, Br, I) coordination compounds. This finding is consistent with a previously reported correlation found in octahedral, pentacoordinate and square planar platinum complexes. The effect of the coordinated halido ligands acting on the metal as shielding conducting rings is therefore confirmed also by (73)Ge, (119)Sn and (207)Pb NMR spectroscopy.
A series of pentacoordinate d8 PtII complexes, of the type [PtCl2(η2-CH2=CH2)(MenNN)], where MenNN = bis-nitrogen ligand, with a variable number of Me groups (i.e., 2,2′-bipyridyl; 1,10-phenanthroline; 6-methyl-2,2′-bipyridyl; 2,9-dimethyl-1,10-phenanthroline; 2,9-dimethyl-1,10-phenanthroline; N,N′-trimethyl-ethylenediamine; N,N,N′,N′-tetramethyl-ethylenediamine; N,N,N′,N′-tetramethyl-1,2-diaminocyclohexane) was studied. The compounds are characterized by variable steric hindrance, due to the variable number (n) of Me substituents, on or ortho to the N-donors of aliphatic diamines or aromatic diimines, respectively. This approach was developed to investigate the interaction of substituents with the metal coordination sphere. With this aim, we analyzed the NMR properties of the considered complexes, with respect to modulation of the metal electron density (195Pt NMR signal frequency) by alkyl groups close to the N-donors. 1H and 13C NMR analysis of the η2-olefin signals has revealed, for each kind of bis-nitrogen ligand, a positive or negative chemical shift variation that is proportional to the number of Me groups geminal or vicinal to the N-donors. Interestingly, the 1JPt,C values increase by approximately 45 Hz for each additional Me on the series of diamine or diimine bis-nitrogen ligands. A rationale for the stability changes observed in such pentacoordinate complexes is suggested, based on the NMR spectroscopic data analysis.
In this work we report on the synthesis of new [PtCl(h2-CH2-CH2)(N^N)]+ and [PtCl(h1-CH2
-CH2OCH3)(N^N)] complexes, with different N^N dinitrogen ligands, i.e. ethylenediamine (en), R,R- and S,Sdiaminocyclohexane (R,R- and S,S-chxn), R,R- and S,S-N,N,N',N'-tetramethyl-1,2-diaminocyclohexane
(R,R- and S,S-Me4chxn). In particular, the factors determining complex stability are highlighted, and
discussed in relation to 1H, 13C and 195Pt NMR chemical shifts exhibited by different complexes bearing
hindered or unhindered diamine or diimine ligands.
In this work, the reactivity of the Zeise’s salt, K[PtCl3(h2-C2H4)], with ketones, in the presence of strong bases, has been studied. In these conditions the formation of metastable intermediate complexes of the type trans-[PtCl2{h1-CH2C(O)R}(h2-C2H4)]-, has been demonstrated by NMR spectroscopy. Further reaction with dinitrogen ligands (N-N) gives [PtCl{h1-CH2C(O)R}(N-N)] complexes. This reactivity of the Zeise’s anion can be exploited for the first general synthesis, in a one pot reaction, of s-carbon Pt(II) ketonyl derivatives with aliphatic or aromatic dinitrogen ligands (even if sterically hindered).
The [PtCl(η(1)-CH2CH2OR)(Me2phen)], Me2phen = 2,9-dimethyl-1,10-phenanthroline, complex is indefinitely stable in the solid state; however, when dissolved in protic deuterated solvents at basic pH, it undergoes H-D exchange at the Me2phen Me's. An analogous H-D exchange process takes place in the related [PtCl2(Me2phen)] complex which is sterically strained and very easily can detach one nitrogen of Me2phen yielding a T-shaped species. In contrast, the H-D exchange is considerably slower in the [Pt(OR)2(Me2phen)] complex characterized by smaller size and lower trans-labilizing effect of the oxygen donor ligands. It is suggested that the formation of a T-shaped intermediate could foster the C-H activation via oxidative addition to the metal centre. In accord with this hypothesis, the H/D exchange was found to be considerably slower in analogous complexes with 6,6'-dimethyl-2,2'-bipyridyl (Me2bpy), where the greater flexibility of Me2bpy, as compared to Me2phen, reduces the strain in the four coordinate substrate and hence the propensity to dissociate one end of the bidentate ligand.
A reflection intensity integration method is presented based upon ab initio calculation of three-dimensional (x, y, ω) reflection boundaries from a few physical crystal and instrument parameters. It is especially useful in challenging circumstances, such as the case of a crystal that is far from spherical, anisotropic mosaicity, α1α2 peak splitting, interference from close neighbours, twin lattices or satellite reflections, and the case of streaks from modulated structures, all of which may frustrate the customary profile-learning and -fitting procedures. The method, called EVAL-14, has been implemented and extensively tested on a Bruker Nonius KappaCCD diffractometer.
A novel case of polymorphism in platinum(H) complexes is reported. Single crystals of [PtBr2(2,9-dimethyl-1,10-phenanthroline)] were obtained at room temperature from a dilute dichloromethane/pentane (1 :3, v/v) solution of the title compound in the presence of guanosine. The space group resulted to be Pbca [a = 20.4024(3), b = 20.3638(3), and c = 13.9522(2) Angstrom, V = 5796.7(l) Angstrom(3), Z = 8]. Crystals of the same compound, obtained in slightly different conditions, had already been investigated by X-ray diffraction and found to have P2(1)/n space group, [a = 12.155(4), b = 7.933(2), and c = 14.522(2) Angstrom, = 93.74(2)degrees, V = 1397.3(6) Angstrom(3), Z = 4]. Comparison of the two polymorphous forms reveals huge differences in the crystal packing and the important role of the stacking interactions between phenanthroline ligands.
Cisplatin, cis-diamminedichloroplatinum (II), is one of the most widely used anticancer drugs. The main cellular target of cisplatin is
DNA, where the platinum atom is able to form covalent bonds with the N7 of purines. It is commonly accepted that there is a direct attack of cisplatin on DNA. But it should be noted that, inside
cells, free purine bases, which can react with cisplatin, are also available. Free bases have many functional roles, not least
the constitution of building blocks for the synthesis of new DNA and RNA molecules. For this reason, under physiological conditions,
the erroneous insertion of platinated bases in the synthesized nucleic acids could compete with direct DNA/RNA platination.
Moreover, due to the lower sterical hindrance offered by single nucleobases with respect to nucleic acids, platination is
expected to be even easier for free purines with respect to DNA and RNA. We have recently shown, for the first time, that
platinated DNA can be formed in vitro by Taq DNA polymerase promoted incorporation of platinated purines. Cytotoxicity tests
with [Pt(dien)(N7-G)], dien = diethylenetriamine, G = 5′-dGTP, 5′-dGDP, 5′-GMP, 5′-dGMP, GUO, dGUO, complexes on HeLa cancer cells support
this hypothesis of the relative cytotoxicity of [Pt(dien)(N7-G)] derivatives being clearly related to their bioavailability. In vivo platination of free purines before their incorporation
in nucleic acids therefore opens new perspectives in platinum based antitumour drugs, for a better understanding of both the
action mechanism and the new molecular design.
KeywordsCisplatin–Platinum–Purine base–DNA–RNA–Cancer–Antitumor drug
To get further insight in the reaction of nucleophilic substitution upon changing the ligand trans to a η(2)-olefin, the reactivity of some monoanionic platinum(II) complexes (trans-[PtCl(2)X(η(2)-C(2)H(4))](-), X = Cl(-), 1, OH(-), 2, and CH(2)NO(2)(-), 3) towards pyridines with different steric hindrance (py, 4-Mepy, and 2,6-Me(2)py) has been tested. All crystallographic (2 and 3 reported for the first time) and spectroscopic data are in accord with a platinum-olefin interaction decreasing in the order 2 > 1 > 3, paralleling the decreasing electronegativity of the donor atom (O > Cl > C). Not only the platinum-olefin bond but also the bond between platinum and the ligand trans to the olefin appear to be strongest in 2 (Pt-O distance at the lower limit for this type of bond). In the reaction with py, the ligand trans to the olefin is displaced in 1 and 2. Moreover the reaction is in equilibrium in the case of sterically hindered 2,6-Me(2)py, the equilibrium being shifted moderately or prevalently toward the reagents in the case of 1 and 2, respectively. In the case of 3, the reaction with pyridines leads to substitution of the olefin instead of the carbanion. This is in accord with the observation that carbanions strongly weaken the trans Pt-olefin bond.
The effect of an extremely bulky carrier ligand, such as N,N,N′,N′-tetramethyl-1,2-diaminocyclohexane (Me4DACH, R,R and S,S configurations of the asymmetric carbon atoms of the chelate ring), upon the rate of formation and stability of Me4DACH–PtG2 derivatives has been investigated (G
= 9-EtG, 3′-GMP, and 5′-GMP). Of the three possible rotamers, two head-to-tail (ΔHT and ΛHT) and one head-to-head (HH), only the former two are found in solution. The very small difference in H8 chemical shifts between ΔHT and ΛHT rotamers indicates that the relationship between the two guanines is very similar in the two conformers which are canted to the same degree but in opposite directions. A smaller interligand steric clash appears to favour the HT rotamer in which the H8 atoms of the guanines are on the same side of pseudo-axial N–Me's with respect to the platinum coordination plane. In the case of 5′-GMP, because of the absence of aminic protons on the carrier ligand, the 5′-phosphate directs its H-bonding potential towards the second ligand in cis-position (the coordinated H2O molecule in the mono adduct, [Me4DACH–Pt(H2O)(5′-GMP)]+, and the cis-G in the bis-adduct). As a consequence the rotamer in which such an interaction is possible, with the nucleotide keeping its favoured anti conformation, is more stable than expected. In contrast with the behaviour of 5′-GMP, 3′-GMP is found to increase the reactivity of the mono adduct in which the phosphate is directed towards the cis-water molecule and to give a negligible contribution to the stability of the HT rotamer in which the 3′-phosphate is directed towards the cis-nucleotide.
The evolution in basic medium ([RO-] = 1 M in methanol, R = H or Me) of five-coordinate platinum(II) compounds, [PtCl2(eta2-C2H4)(N-N)], 2a-c, (N-N = N,N,N',N'-tetramethyl-1,2-ethanediamine, a; 2,2'-bipyridyl, b; 1,10-phenanthroline, c) leads to the formation of [PtCl(eta1-CH2CH2-OCH3)(N-N)], 5a-c. The analogous compound 5d (N-N = 2,9-dimethyl-1,10-phenanthroline, d) can also be prepared, but not via transformation of the five-coordinate species 2d in basic medium where it is quite stable. 5d can instead be prepared by reaction of d with a strongly basic methanol solution of Zeise's anion [PtCl3(eta2-C2H4)](-), 1. In such a medium the di-anionic trans-[PtCl2(OR)(eta1-CH2CH2-OCH3)](2-) species (1") reacts with to form exclusively 5d. Hydrolysis of with acids bearing weakly coordinating anions leads to [PtCl(eta2-C2H4)(N-N)]+, 3a-c, as stable cations; upon the same treatment 5d does not generate 3d, but it reacts with HCl to give 2d in almost quantitative yield. Cationic complexes 3b, 3c, here reported for the first time, were reacted with some nucleophiles and their behaviour compared with that of the already known 3a. In 3b, 3c the metal centre competes with the coordinated ethene for binding to nucleophiles; therefore the acetylacetonate anion can either add to the olefin (affording compounds 6b, 6c ) or to the metal ion replacing the ethene ligand (yielding compounds 7b, 7c). Under similar conditions, 3a gives exclusively 6a. Secondary amines readily add to ethene in 3b, 3c, affording the addition products 8b, 8c, which undergo a ready cyclization to an azaplatinacyclobutane ring (9b, 9c). The remarkable ease of the four-membered ring formation has been related to the high electrophilic character of the metal core in 3b, 3c.
In this article we review the biological activity of analogs of the antitumor drug cisplatin that contain chiral amine ligands. Interaction with DNA and formation of cross-links with adjacent purine bases are considered to be the crucial steps in the antitumor activity of this class of complexes. Because double-helical DNA has a chiral structure, interaction with enantiomeric complexes of platinum should lead to diastereomeric adducts. It has been demonstrated that DNA cross-links of platinum complexes with enantiomeric amine ligands not only can exhibit different conformational features but also can be processed differently by the cellular machinery as a consequence of these conformational differences. These results expand the general knowledge of how the stereochemistry of the platinum-DNA adduct can influence the cell response and contribute to understanding the processes that are crucial for antitumor activity. The steric requirements of the chiral ligands, in terms of configuration and flexibility, are also elucidated.
Zeise's anion in strongly basic hydroxylated solvents undergoes unprecedented nucleophilic addition of OR- (R = H, Me, Et) to the eta2-ethene giving trans-[PtCl2(eta1-C2H4OR)(OR)]2- which readily reacts with bidentate nitrogen donors N-N to give Cl- and OR- substitution and formation of [PtCl(CH2CH2OR)(N-N)]. Protonolysis of this stable organometallic species offers a versatile route to cationic [PtCl(eta2-C2H4)(N-N)]+ complexes.
We were able, for the first time, to synthesize and characterize Pt derivatives with a structural shape similar to vitamin E, having a metalla-chromane core. The formation reaction mechanism includes an unexpected highly selective ortho aromatic electrophilic substitution on phenol, operated by [PtCl(eta(1)-C(2)H(4)OR)(N-N)], R = Me or Ph, and a final cyclization step. The X-ray structure of one of the new metalla-chromane complexes [Pt(EtPh)(phen)],1a, (EtPh = 2-(ethan-2'-yl-kC(1))-1-phenolato-k0(1), phen = 1,10-phenanthroline) is reported. Cytotoxicity and Pt uptake measurements, performed on HeLa cancer cells, show an interesting structure-activity correlation for the new metalla-chromane analogues 1a and [Pt(MeOEtPh)(phen)], 1b, (MeOEtPh = 2-(ethan-2'-yl-kC(1))-4-(methoxy)-1-phenolato-k0(1)), being the structurally closest to vitamin E and also the most active.
Ab initio calculations using an effective core potential (ECP) have been performed on (π-ethene)palladium complexes with different coordinated nucleophiles, H-, CH3-, OH-, and F-. The calculations show a weak back donation (weak π*-dyz overlap) in all complexes studied. An analysis of the reactivity of the coordinated nucleophiles toward migration to the olefin was done by estimating the bond strength and the energy of the orbital describing the palladium-nucleophile bond. The results indicate that a frontier-controlled cis migration to the olefin would be possible only for coordinated H- and CH3-, whereas OH- and F- would be too unreactive in such a process.
π antibonding interactions result from the overlap of a filled π symmetry ligand orbital with a filled metal d orbital. This antibonding plays an important role in the chemistry of π donor ligands such as oxo and alkoxide. It is in large part responsible for the lack of late transition metal complexes with terminal oxo ligands, and can explain some of the unusual chemistry of late metal alkoxide complexes.
The synthesis of new platinum bipy (bipy = 2,2′-bipyridyl) complexes containing phenoxide ligands is reported, together with kinetic studies of their oxidative addition reactions with MeI to produce phenoxo platinum(IV) complexes. Complexes of the form [(bipy)Pt(OC6H4-4-X)2] (X = OCH3, CH3, H, Br, Cl) are prepared by the reaction of the chloro complex [(bipy)PtCl2] with substituted phenols and KOH in a two phase system of water and chloroform in the presence of benzyl triphenylphosphonium chloride. Platinum(IV) complexes are formed by oxidative addition of MeI to the platinum(II) complexes obtained. The complexes are characterized by elemental analysis, UV–Vis, IR, mass spectrometry and 1H and 13C NMR spectroscopy.The reaction of methyl iodide with [(bipy)Pt(OC6H4-4-OMe)2] to give [(bipy)PtMe(I)(OC6H4-4-OMe)2] follows the rate law rate = k2[(bipy)Pt(OC6H4-4-OMe)2][MeI]. The values of k2 increase with increasing polarity of the solvent, suggesting a polar transition state for the reaction.
Reactions of Zeise’s salt (K[Pt(η2-C2H4)Cl3]) with oxidized phenanthroline ligands (1,10-phenanthroline-5,6-dione, phedon, and 2,9-dimethyl-1,10-phenanthroline-5,6-dione, Me2phedon) are reported. Comparison with analogous reactions involving unoxidized phen (1,10-phenanthroline) and Me2phen (2,9-dimethyl-1,10-phenanthroline) ligands indicates that these latter ligands are less capable to stabilize the five-coordinate species [PtCl2(η2-C2H4)(phenanthroline)] in which the phenanthroline and the olefin share the trigonal plane and two chlorines are in the axial positions. The X-ray structure of the four-coordinate species [PtCl2(Me2phedon)] indicates that the major difference between oxidized and unoxidized phenanthrolines is the loss of aromaticity of the central ring of phenanthroline. As a consequence, the oxidized phenanthroline becomes more flexible and can undergo a bow-like distortion so to reduce steric interaction between ortho substituents of phenanthroline and cis chlorine ligands. The increase in stability of the four-coordinate species with Me2phedon is concomitant with an increase in stability of the five-coordinate precursor complex with ethylene. In the latter case the stabilization is not of sterical origin but stems from reduced electron-donor properties of oxidized phenanthrolines. The balance of the two effects is such that the equilibrium between five- and four-coordinate species is more shifted in favour of the former species in the case of Me2phedon than in the case of Me2phen.
The reactivity of [PtCl(η2-CH2CHR)(tmeda)]+ (R=H, 1a, or Me, 1b; tmeda=N,N,N′,N′-tetramethyl-1,2-diaminoethane) towards some ambident nucleophiles like anilines and phenolate anion has been tested. The reaction of 1a with N-methylaniline gives immediately N-addition to the coordinated ethene (3a), but, in the presence of an inorganic carbonate, a partial rearrangement, with the para carbon of the phenyl ring taking the place of nitrogen, is observed (4a and 5a). Reaction with a tertiary aromatic amine, such as N,N-dimethylaniline, leads exclusively to the C-coupled species. The phenolate anion acts initially as an oxygen donor, however the resulting species (6a), in contact with free phenol, rearranges to C-bonded species (7a). For free phenol/6a ratios⩾5 the rearranged product has an isomeric ortho/para ratio of ≈3. For lower free phenol/6a ratios (⩽1) oligomeric complexes, in which two or three platinum ethanide moieties are bound to the same phenol ring, are also formed. In the case of 1b, the above described reactivity has to compete with the base-induced deprotonation of propene, leading to formation of the allyl-bridged platinum dimer [{PtCl(tmeda)}(μ-η1:η3-CHCHCH2){Pt(tmeda)}]+. The X-ray crystal structure of 1b has also been determined; the structural parameters are very similar to those previously reported for 1a. DFT calculations have shown a similar activation of the two complexes towards nucleophilic addition at the coordinated olefin, although in 1b the electrophilic character of the olefin is masked by the Brønsted acidity of the propene methyl protons.
Whereas much of organic chemistry has classically dealt with the preparation and study of the properties of individual molecules, an increasingly significant portion of the activity in chemical research involves understanding and utilizing the nature of the interactions between molecules. Two representative areas of this evolution are supramolecular chemistry and molecular recognition. The interactions between molecules are governed by intermolecular forces whose energetic and geometric properties are much less well understood than those of classical chemical bonds between atoms. Among the strongest of these interactions, however, are hydrogen bonds, whose directional properties are better understood on the local level (that is, for a single hydrogen bond) than many other types of non-bonded interactions. Nevertheless, the means by which to characterize, understand, and predict the consequences of many hydrogen bonds among molecules, and the resulting formation of molecular aggregates (on the microscopic scale) or crystals (on the macroscopic scale) has remained largely enigmatic. One of the most promising systematic approaches to resolving this enigma was initially developed by the late M. C. Etter, who applied graph theory to recognize, and then utilize, patterns of hydrogen bonding for the understanding and design of molecular crystals. In working with Etter's original ideas the power and potential utility of this approach on one hand, and on the other, the need to develop and extend the initial Etter formalism was generally recognized. It with that latter purpose that we originally undertook the present review.
SIR97 is the integration of two programs, SIR92 and CAOS, the first devoted to the solution of crystal structures by direct methods, the second to refinement via least-squares-Fourier procedures. Several new features have been introduced in SIR97 with respect to the previous version, SIR92: greater automatization, increased efficiency of the direct methods section, and a powerful graphics interface. The program also provides publication tables and CIF files. © 1999 International Union of Crystallography Printed in Great Britain - all rights reserved.
A study of four late-transition metal fluoroaryloxide (OArF or OAr′) complexes is presented including X-ray crystallography, polynuclear solution NMR spectroscopy, UV–Vis spectroscopy and elemental analyses. The study includes three new compounds: [(Ph3P)2Ni(OArF)2] (1a), [(Ph3P)2Ni(OAr′)2] (1b), [(COD)Pt(OArF)2] (2) and one compound whose synthesis and elemental analysis were reported previously: [(Ph3P)Au(OArF)] (3). These compounds represent the common L2MX2 (1a, 1b, 2) and LMX (3) ligand classes in Groups 10 and 11, respectively, but with an uncommon ligand type, the monodentate phenoxide. In the solid state, compounds 1a and 1b exhibit square-planar geometry at nickel with trans phosphines in each case. In solution, these nickel compounds slowly decompose in CH2Cl2. Compound 2 is quite stable in solution at room temperature with the two phenoxide ligands cis to one another in the solid state. Compound 3 has a virtually linear geometry at the gold center and is stable in the solid state in the dark but decomposes slowly in solution in the light. Comparison of these four fluoroaryloxide compounds with the protio analogs (or attempts to make such compounds) demonstrate the greater stability to reduction of late-metal aryloxide complexes with highly electron-withdrawing substituents on the phenoxide rings.
Complexes of the type [PtCl(NeN)(h1-CH2CH2OR)], NeN¼ diimine ligand, R ¼ alkyl, were generally
considered to be indefinitely stable, both in solution and in the solid state. Unexpectedly we found that
complexes of the type [PtCl(Me2phen)(h1-CH2CH2OR)], Me2phen ¼ 2,9-dimethyl-1,10-phenatroline,
R¼ alkyl, undergo spontaneous decomposition, to give the corresponding vinyl-ether, CH2]CHOR.
Decomposition pathway studies suggest a pseudo-Wacker type mechanism (b H� shift process) activated
by sterical hindrance in the Pt(II) coordination plane, due to the Me2phen ligand sterically induced
distortions in the Pt(II) coordination plane. A new useful synthetic pathway to access valuable and low
toxic alkyl-vinyl-ethers is here reported.
Synthesis and characterization of the new pentacoordinate [PtCl2(h2-C2H4)(Mebpy)] and square planar
[PtCl2(Mebpy)] complexes both containing the asymmetrically hindered nitrogen donor chelate
Mebpy ¼ 6-Methyl-2,20-bipyridil are reported. By nucleophilic addition of MeO� to the coordinated
ethene of [PtCl2(h2-C2H4)(Mebpy)], syn-[PtCl(h1-CH2CH2OMe)(Mebpy)] and anti-[PtCl(h1-CH2CH2OMe)(
Mebpy)] complexes have been obtained as the kinetic and thermodynamic product, respectively.
The mechanism for selective formation of both stereoisomers is also reported. This synthetic route opens
new perspectives for the stereospecific synthesis of syn- and anti-square planar organometallic
complexes.
In recent years a number of chelating ligands, when combined with a π-acid such as an alkene, have been found to stabilize five-coordination in palladium(II) and platinum(II) chemistry. The complexes have invariably a trigonal bipyramidal geometry with the bidentate ligand and the alkene in the equatorial plane. The π-acceptor capacity of the alkene and a small bite of the chelate ligand (between 70 and 85°) are both required for accommodating them in the equatorial plane where the dz electron concentrations (which in the square planar d complexes are located above and below the coordination plane) are also confined. Two mono-dentate ligands, in place of one chelate, do not stabilize the five-coordination since for entropic reasons the dissociation of one of them is strongly favored. A great bulk of the chelate ligand is also found to stabilize five-coordination since interligand steric interactions are smaller in the trigonal plane of a five-coordinate complex than in the square-plane of a four-coordinate species. Moreover the same steric factors that destabilize four- versus five-coordination can also destabilize four-versus three-coordination, and T-shaped ML3 species appear to provide a low energy path for the interconversion between four- and five-coordinate complexes. The alkene is strongly bound to the metal, the metal-carbon bond distances are shorter, and the bending back of the alkene substituents is greater than those found in four-coordinate compounds. The activation energy for alkene rotation is also greater in five-coordinate species, and in a number of cases atropisomers are generated. The chelate dinitrogen ligand also lying in the equatorial plane is, on the other hand, loosely bound to the metal, and dissociation of one end of this ligand appears to be the preliminary step in all substitution processes involving the alkene, the axial ligands, and the bidentate ligand itself. These processes should therefore occur through a mechanism analogous to that operating in four-coordinate complexes. The dissociation of one end of the bidentate ligand also provides a low energy path to proton exchange and inversion of configuration at coordinated nitrogens. Other aspects related to the conformation of the alkene and of the chelate ligand as well as to the preparation and reactivity of this class of compounds are discussed.
The topic discussed in this article is the synthesis of cationic complexes of plati-num(I1) containing η−olefins, their reaction with nucleophiles, and the cleavage, under acidic conditions, of the platinum-carbon bond of the addition productsobtained therefrom. Some general features related to the electrotl distribution and bonding, the structural and conformational preferences, the reaction mechanisms and reactivity are discussed.
Several palladium and platinum phenoxides, [Pd(OPh)2L2] (L2 = tmeda (1), (pyrrolidine)2 (2), (N-methylpyrrolidine)2 (3)) and [M(OPh)(NCN)] (NCN = C6H3{CH2NMe2}2-2,6); M = Pd (5), Pt (6)) have been synthesized and characterized with special emphasis on the role of both N-H-0 and 0-H-0 hydrogen bonding in the resulting structures of these metal phenoxides. The [Pd(OPh)2L2] (1-3) complexes were obtained from the reaction of Pd(OAc)2 with 2 equiv of sodium phenoxide in the presence of the neutral ligand. The terdentate N-C-N-bound arylmetal complexes, [M(OPh)(NCN)], 5 and 6, were synthesized by reacting [M(C6H3{CH2NMe2}2-2,6)(H2O)]BF4 With sodium phenoxide. Both 2,5, and 6 react with excess phenol to form the corresponding phenol adducts, 4, 7, and 8, respectively. The structures of the phenoxides 2 and 5 and the phenol adducts 4 and 7 were studied by X-ray diffraction methods to establish their stereochemistry as well as the nature and structural details of the hydrogen bonding in the phenol adducts. Crystals of trans-[Pd(OPh)2(Pyrrolidine)2] (2) are tetragonal with a = b = 18.6615 (15) angstrom, c = 10.7713 (6) angstrom, space group I4(1)/a, Z = 8, and R = 0.026 for 1774 reflections with I greater-than-or-equal-to 2.5sigma(I); crystals of trans-[Pd-(OPh)2(pyrrolidine)2]-HOPh (4) are monoclinic with a = 6.4039 (3) angstrom, b = 15.497 (1) angstrom, c = 15.085 (1) angstrom, beta = 99.832 (4)-degrees, space group P2(1)/c, Z = 2, and R = 0.032 for 2224 reflections with I greater-than-or-equal-to 2.5sigma(I); crystals of [Pd(OPh)(C6H3{CH2NMe2}2-2,6)] (5) are monoclinic with a = 6.1490 (2) angstrom, b = 12.0595 (6) angstrom, c = 23.1829 (10) angstrom, beta = 97.251 (3)-degrees, space group P2(1)/c, Z = 4, and R = 0.0223 for 3387 reflections with I greater-than-or-equal-to 2.5sigma(I); and crystals of [Pd(OPh)(C6H3{CH2NMe2}2-2,6)]-HOPh (7) are monoclinic with a = 8.5400 (5) angstrom, b = 12.0445 (7) angstrom, c = 22.4473 (14) angstrom, beta = 100.779 (5)-degrees, space group P2(1)/n, Z = 4, and R = 0.0428 for 3081 reflections with I greater-than-or-equal-to 2.5sigma(I). Palladium phenoxide 2 has a unique dimeric structure consisting of two trans-Pd-(OPh)2(pyrrolidine)2 monomers being held together by four identical (pyrrolictine)N-H ... 0(phenoxide) hydrogen bonds (N...O = 2.866 (3) angstrom). The Pd atoms are in close proximity of each other, but the resulting Pd ... Pd distance (3.0960 (3) angstrom) points to some repulsion between the metal centers. In the corresponding phenol adduct, 4, the dimeric structure is broken down by interaction of two phenol molecules resulting in two (phenol)O-H...O(phenoxide) hydrogen bonds (2.638 (4) angstrom). The structural features of the NCN-bound palladium phenoxides, 5 and 7, reflect the effect of changing the trans ligand from phenoxide to aryl on the Pd-phenoxide bonding. In 5 a very short (phenoxide)C-O bond of 1.305 (3) angstrom is observed which lengthens to 1.330 (6) angstrom in the phenol adduct 7. The strong hydrogen bonding in 7 is indicated by the short (phenoxide)O ... 0 (phenol) bond distance of 2.567 (6) angstrom (cf. 2.638 (4) angstrom in 4). These results have been used to synthesize new monodentate N-C-N-metal catecholate complexes, [M(C6H3{CH2NMe2}2-2,6)-(OC6H4OH-2)] (9 (M = Pd), 10 (M = Pt)), which contain an intramolecular O-H...O hydrogen bond. H-1 NMR studies show that 2 is monomeric in solution. Exchange between coordinated phenoxide and associated phenol in 4 remains slow on the NMR time scale (up to 97-degrees-C) but occurs on the laboratory time scale (experiments with pentadeuteriophenol). The arylpalladium phenoxide complex 7 undergoes fast exchange between phenoxide and associated phenol indicating the large trans effect of the aryl ligand (cf. long Pd-O bond in 5). This exchange is slow on the H-1 NMR time scale in the corresponding platinum complex 8. Similarly, intramolecular phenol/phenoxide exchange is fast on the H-1 NMR time scale in the Pd-catecholate 9 but slow in the Pt-catecholate 10. Thermodynamic parameters for the association of phenol with the palladium diphenoxide complexes 2 and 3 have been determined by means of H-1 NMR spectroscopy.
Ab initio calculations using an effective core potential (ECP) have been performed on complexes Pd(Nu)2 with Nu- = CH3-, H-, Br-, Cl-, F-, CN-, -CH(CHO)2, OOH-, OCH3-, and OH-. An analysis of the reactivity of the coordinated nucleophiles was carried out on the basis of the bond strength and the energy of the Pd-Nu bond orbital.
The selective oxidation of 3,5-di-tert-butylcatechol (DTBCH2) to 3,5-di-tert-butyl-omicron-benzoquinone (DTBQ) by molecular oxygen is catalyzed by the Ir(III) catecholate complex [(triphos)Ir(DTBC)]+ through its dioxygen adduct [(triphos)Ir(OO)(DTBSQ)]+ [triphos = MeC(CH2PPh2)3; DTBC = 3,5-di-tert-butylcatecholate; DTBSQ = 3,5-di-tert-butylsemiquinonate]. The following overall stoichiometric equation is suggested by analysis of the oxidation products and H2O2: DTBCH2 + 02 --> DTBQ + H2O2. The rates of reaction of the substrate as well as the formation of products are shown to be first order with respect to catalyst and substrate concentrations and zero order with respect to the partial pressure of O2 in the range 15-725 psi. The kinetic parameters for the oxidation reaction are estimated in the temperature range 38-60-degrees-C. Kinetic and thermodynamic data are consistent with a rate-determining step involving the attack of free catechol to the 02 adduct. For partial pressures of O2 higher than 725 psi, the oxygenation of DTBCH2 to 3,5-di-tert-butyl-1-oxacyclohepta-3,5-diene-2,7-dione competes with DTBQ formation.
Intermolecular van der Waals radii of the nonmetallic elements have been assembled into a list of "recommended" values for volume calculations. These values have been arrived at by selecting from the most reliable X-ray diffraction data those which could be reconciled with crystal density at 0°K. (to give reasonable packing density), gas kinetic collision cross section, critical density, and liquid state properties. A qualitative understanding of the nature of van der Waals radii is provided by correlation with the de Broglie wave length of the outermost valence electron. Tentative values for the van der Waals radii of metallic elements - in metal organic compounds - are proposed. The paper concludes with a list of increments for the volume of molecules impenetrable to thermal collision, the so-called van der Waals volume, and of the corresponding increments in area per molecule.
potassium trichloro(ethene)platinate(II);hydrochloric acid;ethene;potassium chloride;water
The reaction of the diamino-ligated dimethylplatinum(II) complex [ Pt(Me)_,(bpy) I (bpy = 2,2'-bipyridyl) with phenol affords the new complex [ Pt(Me 1 (OPh) (bpy) I (!). The X-ray crystal structure of square-planar ! is reported: orthorhombic, space ~oup P2_t2t2 ~ (No. 19), a = 9.1625(12), b = 12.3922(12), c = 13.3181 (13) ,~,, Z = 4. Reaction of complex 1 with Mel or benzyl bromide affords the novel six-coordinate platinum (IV) aryloxide complexes [ Pt (Me)_, (1) (OPh) (bpy) 1 (2) and [ Pt(Me) (CH2Ph) (Br) (OPh) (bpy) 1 (31. respective|y. The X-ray crystal structure of octahedral 2 is reported: monoclinic, space group P2_~/c INo. 141, a= 10.0194(6L b= 10.5126(101, c = 17.6596(14) ,~. ,8 = 104.159(6)°, Z= 4. The iodide complex 2 exists as a mixture of two isomers in solution (the major one correspor~,; to that of trans oxidative addition), whereas the bromide complex 3 is found only as the trans oxidative addition product. '~ 1997 El~vier Science S.A.
The highly distorted Pt(d(G*pG*)) (G* = N7-platinated G) 17-membered macrocyclic ring formed by cisplatin anticancer drug binding to DNA alters the structure of the G*G* base pair steps, canting one base, and increases dynamic motion, complicating solution structural studies. However, the ring appears to favor the HH1 conformation (HH1 denotes head-to-head guanine bases, 1 denotes the normal direction of backbone propagation). Compared to cisplatin, analogues with NH groups in the carrier ligand replaced by bulky N-alkyl groups are more toxic and less active and form less dynamic adducts. To examine the molecular origins for the biological effects of steric bulk, we evaluate Me 4DABPt(d(G*pG*)) models; the bulk and chirality of Me 4DAB (N,N,N′,N′-tetramethyl-2,3- diaminobutane with S,S or R,R configurations at the chelate ring carbons) impede dynamic motion and enhance the utility of NMR methods for identifying and characterizing conformers. Unlike past studies of adducts with such bulky carrier ligands, in which no HH conformer was found, the Me 4DABPt(d(G*pG*)) adducts did form the HH1 conformer, providing compelling evidence that the sugar-phosphate backbone can impose constraints sufficient to overcome the alkyl-group steric effects. The HH1 conformer exhibits no significant canting. The (S,S)-Me 4DABPt(d( G*pG*)) adduct has the least amount of the "normal" HH1 conformer and the greatest amount of the ΔHT1 conformer (ΔHT1 = head-to-tail G* bases with Δ chirality) ever observed (88% under some conditions). Thus, our results lead us to hypothesize that the low activity and high toxicity of analogues of cisplatin having carrier ligands with N-alkyl groups arise from the low abundance and minimal canting of the HH1 conformer and possibly from the adverse effects of an abundant ΔHT1 conformer. The new findings advance our understanding of the chemistry of the Pt(d(G*pG*)) macrocyclic ring and of the effects of carrier-ligand steric bulk on the properties of the ring.
Me4DABPtG2 adducts with the bulky C 2-symmetric chiral diamine, Me4DAB (N,N,N′,N′- tetramethyl-2,3-diaminobutane with R,R and S,S configurations at the chelate ring C atom, G = guanine derivative), exhibit slow conformer interchange and are amenable to characterization by NMR methods. The investigation of the cis-PtA2G2 adducts formed by clinically widely used anticancer drugs [A2 = diaminocyclohexane, (NH3) 2] is impeded by the rapid conformer interchange permitted by the low A2 bulk near the inner coordination sphere. Me 4DABPtG2 adducts exist as a mixture of exclusively head-to-tail (HT) conformers. No head-to-head (HH) conformer was observed. The Me4DAB chirality significantly influences which HT chirality is favored (ΔHT for S,S and ΛHT for R,R). For simple G ligands, the ratio of favored HT conformer to less favored HT conformer is ∼2:1. For guanosine monophosphate (GMP) ligands, the phosphate group cis G N1H hydrogen bonding favors the ΛHT and the ΔHT conformers for 5′-GMP and 3′-GMP adducts, respectively. For both HT conformers of cis-PtA 2G2 adducts, the G nucleobase plane normally cants with respect to the coordination plane in the same direction, left or right, for a given A2 chirality. In contrast, the results for Me 4DABPtG2 adducts provide the first examples of a change in the canting direction between the two HT conformers; this unusual behavior is attributed to the fact that canting always gives long G O6 to N-Me distances and that these Me4DAB ligands have bulk both above and below the coordination plane. These results and ongoing preliminary studies of Me 4DABPt adducts with G residues linked by a phosphodiester backbone, which normally favors HH conformers, all indicate that a high percentage of HT conformer is present. Collectively, these findings advance fundamental concepts in Pt-DNA chemistry and may eventually help define the role of the carrier-ligand steric effects on anticancer activity.
Pt prodrugs: We synthesized new cationic complexes [PtCl(η2- C2H4) (R,R-chxn)]Cl (1) and [PtCl(η2-C 2H4) (S,S-chxn)] Cl (2), which are organometallic analogues of the drug oxaliplatin. Complexes 1 and 2 can be considered antitumor prodrugs, as we demonstrate that they can decompose to give the same metabolites as those of oxaliplatin. (Figure Presented)
Complexes containing bonds between heteroatoms such as nitrogen and oxygen and "late" transition metals (i.e., those located on the right side of the transition series) have been implicated as reactive intermediates in numerous important catalytic systems. Despite this, our understanding of such M-X linkages still lags behind that of their M-H and M-C analogues. New synthetic strategies have now made possible the isolation and study of a variety of monomeric late-metal alkoxide, aryloxide, and amide complexes, including parent hydroxide and amide species. The heteroatoms in these materials form surprisingly strong bonds to their metal centers, and their bond energies do not necessarily correlate with the energies of the corresponding H-X bonds. The M-X complexes typically exhibit nucleophilic reactivity, in some cases form strong hydrogen bonds to proton donors, and even deprotonate relatively weak acids. These observations, as well as thermodynamic investigations, suggest that late metal-heteroatom bonds are strongly polarized and possess significant ionic character, properties that play an important role in their interactions with organic compounds.
Bacteria have aggressive acquisition processes for iron, an essential nutrient. Siderophores are small iron chelators that facilitate cellular iron transport. The siderophore enterobactin is a triscatechol derivative of a cyclic triserine lactone. Studies of the chemistry, regulation, synthesis, recognition, and transport of enterobactin make it perhaps the best understood of the siderophore-mediated iron uptake systems, displaying a lot of function packed into this small molecule. However, recent surprises include the isolation of corynebactin, a closely related trithreonine triscatechol derivative lactone first found in Gram-positive bacteria, and the crystal structure of a ferric enterobactin complex of a protein identified as an antibacterial component of the human innate immune system.
The use of a sterically hindered diamine ligand (Me(4)DACH) has allowed for the first time, the isolation and characterization, both in the solid state (X-ray crystallography) and in solution (circular dichroism), of pure DeltaHT rotamers of [Pt(Me(4)dach)(5'-GMP)(2)] (compounds 1 and 2 for R,R and S,S configurations of the Me(4)DACH ligand, respectively). Comparison of the CD spectra obtained for each rotamer, which differ only in the chirality of the Me(4)DACH ligand (R,R or S,S) or in the chirality of the HT conformation (Delta or Lambda), allowed us to conclude that, in the 200-350 nm range, the contributions to the overall CD spectrum that stem from diamine chirality and diamine-induced chirality of platinum d--d transitions or from sugar chirality are negligible relative to the exciton chiral coupling that occurs for pi-pi* transitions of the cis guanines. Accurate molecular structures of 1.10 D(2)O and 2.14 D(2)O (conventional crystallographic agreement indexes R(1) convergent to 2.07 % and 2.18 %, respectively) revealed that the crystallized rotamers have a DeltaHT conformation that is in agreement with all previously reported X-ray structures of [Pt(diamine)(nucleos(t)ide)(2)] complexes. This conformation allows the 5'-phosphate to be located in proximity to the Me(4)DACH ligand so that (P)O...HC(N) hydrogen-bond interactions exists in both complexes. For both structures, the canting of the guanine planes on the coordination plane is right-handed (R; canting angle (Phi) of 80.9 degrees and 73.2 degrees, respectively); this indicates that the canting direction is driven by the HT conformation chirality (Delta for both compounds) and not by the chirality of the carrier ligand (different for the two compounds). Density functional theory analysis of the conformational space as a function of Phi indicated a good agreement between the computed and experimental structures. The increase in energy for Phi values below 65 degrees and 55 degrees (for 1 and 2, respectively) is mainly due to the short intramolecular contacts between C(8)H and the cis N-Me groups on the same side of the platinum coordination plane.
The mechanism by which copper complexes bind and activate dioxygen was analyzed. The kinetic and thermodynamic information was obtained through cryogenic stopped-flow studies of the oxygenation of Cu(I) compounds. It was shown that protonation or acylation of peroxo copper species appears to enhance their O-atom transfer reactivity. It was concluded that O-O homolysis or heterolysis in CuOOH(R) complexes is energetically disfavored because of thermodynamic instability of the resulting Cu(III/IV)-oxo species.
For Abstract see ChemInform Abstract in Full Text.
Cisplatin, carboplatin and oxaliplatin are platinum-based drugs that are widely used in cancer chemotherapy. Platinum-DNA adducts, which are formed following uptake of the drug into the nucleus of cells, activate several cellular processes that mediate the cytotoxicity of these platinum drugs. This review focuses on recently discovered cellular pathways that are activated in response to cisplatin, including those involved in regulating drug uptake, the signalling of DNA damage, cell-cycle checkpoints and arrest, DNA repair and cell death. Such knowledge of the cellular processing of cisplatin adducts with DNA provides valuable clues for the rational design of more efficient platinum-based drugs as well as the development of new therapeutic strategies.
Extensive investigations of cis-[Pt(diA)G2] complexes (in which G = a guanine ligand; diA = a single diamine ligand) revealed the types of interactions between the two G ligands and between the G and the cis-amine substituents when diA is a diamine ligand with substituents on each nitrogen atom being a small hydrogen atom and a bulky group able to slow the rotation about the Pt-G bond. All these interactions are shown to apply also when diA = dach (1,2-diaminocyclohexane), even though this chiral primary diamine has only small N-H atoms on each side of the coordination plane. However, a slight difference in the stereochemistry of the two protons (one N-H has "quasi axial" and the other "quasi equatorial" character) is sufficient to induce a significant change in the relative stabilities of the [Pt(dach)G2] deltaHT and lambdaHT rotamers (HT = head-to-tail). The new results show that at acidic and neutral pH the induction of asymmetry from the dach ligand to the HT rotamers is governed by the G-to-G dipole-dipole interaction, which is greater for the six-membered ring of each guanine leaning towards the cis-G. Such a "six-in" canting of the two guanine ligands can be hampered by the steric interaction between the H8 of each guanine and the substituent on the cis-amine that is on the same side of the coordination plane. Such a repulsion is greater for a "quasi equatorial" N-H than for a "quasi axial" N-H. Under basic pH conditions, deprotonation of the guanine N1-H renders the O6 atom a much better hydrogen-bond acceptor; therefore, the stability of the HT rotamers is governed by the hydrogen-bond interaction of guanine O6 and the cis-amine N-H group. Such a guanine O6/N-H cis-amine interaction is stronger for a "quasi axial" than for a "quasi equatorial" N-H group. In the head-to-head (HH) rotamer, in which the electrostatic repulsion between electron-rich O6 atoms, both on the same side of the platinum coordination plane, tends to place the six-membered rings of each guanine further from the cis-guanine and closer to the cis-amine, we can expect better N-H...O6 hydrogen bonding for the "quasi equatorial" N-H groups.
cis-[PtA2(nucleotide)2] complexes (A2 stands for two amines or a diamine) have been extensively investigated as model compounds for key cisplatin-DNA adducts. All cis-[metal(nucleotide/nucleoside)2] complexes with guanine and related purines characterized in the solid state thus far have the DeltaHT conformation (head-to-tail orientation of the two bases and right-handed chirality). In sharp contrast, the LambdaHT conformation (left-handed chirality) dominates in acidic and neutral aqueous solutions of cis-[PtA2(5'-GMP)2] complexes. Molecular models and solution experiments indicate that the LambdaHT conformer is stabilized by 5'-phosphate/N1H hydrogen-bond interactions between cis nucleotides with the normal anti conformation. However, this evidence, while compelling, is indirect. At last, conditions have been defined to allow crystallization of this elusive conformer. The structure obtained reveals three unique features not present in all other cis-[PtA2(nucleotide)2] solid-state structures: a LambdaHT conformation, very strong hydrogen-bond interactions between the phosphate and N1H of cis nucleotides, and a very small dihedral angle between the planes of the two guanines lying nearly perpendicular to the coordination plane. These new results indicate that, because there are no local base-base repulsions precluding the LambdaHT conformer, global forces rather than local interactions account for the predominance of the DeltaHT conformer over the LambdaHT conformer in the solid state and in both inter- and intrastrand HT crosslinks of oligonucleotides and DNA.
(Figure Presented) Metal bearing nucleobase: A model DNA polymerase and N7-metalated purine triphosphate nucleotide are used to show that metalated purines can be inserted into DNA during an enzymatic in vitro synthetic process (see scheme; dNTP = deoxynucleotide triphosphate). The possibility of site-specific metalation of DNA mediated by DNA polymerase is demonstrated.
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