An inverse linear relationship between 73Ge, 119Sn and 207Pb 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 73Ge, 119Sn and 207Pb NMR spectroscopy.

[Pt(N-N)Cl(h1-CH2CH2OR)] complexes were generally considered to be indefinitely stable, both in solution and in the solid state. In a previous work we unexpectedly found that complex [Pt(Me2phen)Cl(1-CH2CH2OR)], 1, Me2phen = 2,9-dimethyl-1,10-phenanthroline, in solution, undergoes spontaneous decomposition to give vinyl-ether together with a Pt(II) hydride species. We demonstrated that this decomposition pathway is mediated by a H- b-shift process promoted by the unbearable steric hindrance introduced by Me2phen in the Pt(II) coordination plane. In this work we found that [Pt(Me2phen)Cl(h1-CH2CH2OR)] complexes can undergo H-D exchange on Me2phen Me’s, when dissolved in protic basic deuterated solvents. Moreover, we observed by 1H NMR that this exchange is considerably slowed down in the analogous complex [Pt(Me2bpy)Cl(h1-CH2CH2OR)], Me2bpy = 6,6’-dimethyl-2,2’-bipyridil, demonstrating the relevant effect of ligand flexibility. Increased acidity of the metal core in the formed T-shaped species reported in the Figure, could be responsible for the observed H-D exchange. An analogous H-D exchange process was observed and investigated by 1H NMR and LC-MS spectroscopy in the related complex [Pt(Me2phen)Cl2]. Further studies demonstrated that this phenomenon is considerably slowed down in the less sterically demanding complexes [Pt(Me2phen)(OR)2] and [Pt(Me2bpy)(OR)2], R = H, Me. It cannot be excluded a role of the H- b-shift process also in the catalysis of the observed H-D exchange process.

The relevant adsorption of cis-[Pt(NH3)2(P2O7)](2-) (phosphaplatin) on hydroxyapatite nanocrystals (nHAP) was observed and studied in water suspension. Phosphaplatin cytotoxicity, which is very low for HeLa, MCF-7 and HS-5 cell lines could be enhanced, reaching that of cisplatin, by interaction with solid nHAP. This effect stems from nHAP ability to catalyze the phosphaplatin hydrolysis, producing the same hydrolytic species responsible for cisplatin antitumor activity.

Complexes of the type [PtCl(N-N)(eta(1)-CH2CH2OR)], N-N = diimine ligand, R = 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(Me(2)phen)(eta(1)-CH2CH2OR)], Me(2)phen 2,9-dimethyl-1,10-phenatroline, R = alkyl, undergo spontaneous decomposition, to give the corresponding vinyl-ether, CH2 = CHOR. Decomposition pathway studies suggest a pseudo-Wacker type mechanism (beta H- shift process) activated by sterical hindrance in the Pt(II) coordination plane, due to the Me(2)phen 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.

Me(4)DABPtG(2) adducts with the bulky C(2)-symmetric chiral diamine, Me(4)DAB (N,N,N',N'-tetramethyl-2,3-diamino-butane 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-PtA(2)G(2) adducts formed by clinically widely used anticancer drugs [A(2) = diaminocyclohexane, (NH(3))(2)] is impeded by the rapid conformer interchange permitted by the low A(2) bulk near the inner coordination sphere. Me(4)DABPtG(2) adducts exist as a mixture of exclusively head-to-tail (HT) conformers. No head-to-head (HH) conformer was observed. The Me(4)DAB chirality significantly influences which HT chirality is favored (Delta HT for S,S and Delta HT for R,R). For simple G ligands, the ratio of favored HT conformer to less favored HT conformer is similar to 2:1. For guanosine monophosphate (GMP) ligands, the phosphate group cis G N1H hydrogen bonding favors the Delta HT and the Delta HT conformers for 5'-GMP and 3'-GMP adducts, respectively. For both HT conformers of cis-PtA(2)G(2) adducts, the G nucleobase plane normally cants with respect to the coordination plane in the same direction, left or right, for a given A(2) chirality. In contrast, the results for Me(4)DABPtG(2) 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 Me(4)DAB ligands have bulk both above and below the coordination plane. These results and ongoing preliminary studies of Me(4)DABPt(2) 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.

The series of complexes of formula [PtCl(h2-olefin)(N^N)]+, previously investigated for N^N = N,N,N0 ,N0-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(h2-olefin)]-anions (K[PtCl3(h2-styrene)] reported here for the first time) with N^N in basic methanol. The initial [PtCl{h1-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 p-olefin complexes [PtCl(h2-olefin)(N^N)]+. The phenanthroline ligand confers peculiar properties to the new compounds. In particular, by reaction with triethylamine, [PtCl{h2-CH2=CH(Me)}(N^N)]+ species, undergo deprotonation of the olefin and formation of the dimeric species [{PtCl(N^N)}2(m-h1:h2-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 h3-allyl complex [Pt(h3-C3H5)(phen)]ClO4.

Cisplatin, cis-[Pt(NH3)2Cl2], was the first inorganic compound applied in clinics to treat a broad range of malignancies. It is able to bind DNA on the N7 positions of adjacent G/A residues, resulting in the cross-link lesions believed to be responsible for observed antitumor activity. Sometimes N7-metalated purines seem to be characterized by a relevant antitumor activity. This has led us to hypothesize a parallel mechanism of action of platinum drugs, based on free platinated purines, formed after drug administration and incorporated into DNA by DNA polymerases. In order to evaluate this possibility, as a key step to develop new drugs, we performed experiments focused on platinated nucleobases, i.e. [Pt(dien)(N7-G)] and cis-[Pt(NH3)2(py)(N7-G)], dien = diethylenetriamine, py = pyridine, G = 5’-dGTP, cell and mitochondrial uptake and processing. For the first time cell uptake and mobility mechanisms, related to plasmatic cell and/or mitochondrial membrane crossing, has been studied. The results of the present study suggest that nucleotide carriers can be actively implicated in the specific uptake of free cytoplasmic platinum bonded nucleotides. Moreover the possible insertion of metalated nucleobases into nuclear and/or mitochondrial new synthesized DNA/RNA, operated by DNA/RNA polymerases, has been evaluated.

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.

A series of pentacoordinate d8 PtII complexes, of the type [PtCl2(η2-CH2=CH2)(Men∩NN)], where Men∩NN = 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.

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(η2-CHuCH)(Me2phen)], that evolve to four-coordinate alkenyl complexes of the type [PtX(η1 -E-CHvCHX)(Me2phen)]. The alkenyl complexes, in the presence of excess acetylene, establish an equilibrium with the five-coordinate alkyne–alkenyl species [PtX(η1-E-CHvCHX)(η2-CHuCH)(Me2phen)] (X = Br, I). The π-bonded acetylene can be exchanged with free olefins or CuO, affording the new alkene–alkenyl or carbonyl–alkenyl complexes [PtX(η1-E-CHvCHX)(η2-olefin)(Me2phen)] and [PtX(η1-E-CHvCHX)(CuO)(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(η1-E-CHvCHBr)(η2-CH2vCH2)(Me2phen)].

The reactivity of [PtX2(Me2phen)] complexes (X = Cl, Br, I; Me2phen = 2,9-dimethyl-1,10-phenanthroline) with terminal alkynes has been investigated. Although the dichlorido species [PtCl2(Me2phen)] exhibits negligible reactivity, the bromido and iodido derivatives lead in short time to the formation of five-coordinate Pt(II) complexes of the type [PtX2(Me2phen)(η2-CHuCR)] (X = Br, I; R = Ph, n-Bu), in equilibrium with the starting reagents. Similar 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-CHuCR)]+. This latter can further evolve to give an unusual, sparingly soluble square planar product where the former terminal alkyne is converted into a :CvC(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)-N̲1–N10–C̲vC(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 experiments here reported evidence on the importance of the residual charge of a nucleotide derivative, for the adsorption on nHAP (hydroxyapatite nanocrystals), in water solution.We found that the simple presence of phosphates on the nucleotide derivative does not guarantee adsorption on nHAP. On the other hand, we demonstrated that a cationic or neutral charge on a nucleotide derivative produces a strongly reduced chemical adsorption (chemisorption) whereas, in the presence of a net negative charge, relevant adsorption on nHAP is observed. The number of phosphates can only modulate the adsorption efficiency of a molecule provided that this latter bears an overall negative charge. The neutral zwitterionic nucleotide Pt(II) complexes, bearing negatively charged phosphates, are unable to give stable chemisorption. Previous considerations are important to model the binding ability of phosphate bearing nucleotide derivatives or molecules on hydroxyapatite. The findings reported in the present paper could be relevant in bone tissue targeting or nHAP mediated drug delivery.

Cisplatin, cis-diamminedichloroplatinum(II), is one of the most widely used antitumor drugs in cancer chemotherapy, as a critical component against a broad range of malignancies. Platinum anticancer drugs are generally known to target DNA, where they can bind to the N7 of purine bases. Cisplatin, as other bifunctional agents, is able to bind to adjacent purines, resulting in crosslink lesions believed to be responsible for the observed antitumor activity. N7-metalated purines, in some cases, seem to be characterized by a relevant antitumor activity. This has led us to hypothesize a cisplatin parallel mechanism of action: based on free platinated purines formation, directly in tissues, after drug administration. In order to evaluate this possible mechanism, as a key path to develop new drugs, we performed a series of experiments focused on platinated nucleobases cell and mitochondrial uptake and processing. For the first time cell uptake and mobility mechanisms, related to plasmatic cell and/or mitochondrial membrane crossing, has been studied. Moreover the possible insertion of metalated nucleobases into nuclear and/or mitochondrial new synthesized DNA/RNA, operated by DNA/RNA polymerases was evaluated. At this scope model metalated nucleosides/nucleotides, with nitrogen carrier ligands, have been synthesized, isolated and characterized. The possible development of new drugs based on this new rational drug design will be discussed.

To get further insight in the reaction of nucleophilic substitution upon changing the ligand trans to a eta(2)-olefin, the reactivity of some monoanionic platinum(II) complexes (trans-[PtCl2X(eta(2)-C2H4)](-), X = Cl-, 1, OH-, 2, and CH2NO2-, 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-Me2py, 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.

In this work, we assessed the capacity of RNA polymerases to use platinated ribonucleotides as substrates for RNA synthesis by testing the incorporation of the model compound [Pt(dien)(N7-5'-GTP)] (dien=diethylenetriamine; GTP=5'-guanosine triphosphate) into a natural RNA sequence. The yield of in vitro transcription operated by T7 RNA polymerase, on the LacZ (Escherichia coli gene encoding for β-galactosidase) sequence, decreases progressively with decreasing the concentration of natural GTP, in favor of the platinated nucleotide, [Pt(dien)(N7-5'-GTP)]. Comparison of the T7 RNA polymerase transcription activities for [Pt(dien)(N7-5'-GTP)] compound incorporation reaction test, with respect to the effect of a decreasing concentration of natural GTP, showed no major differences. A specific inhibitory effect of compound [Pt(dien)(N7-5'-GTP)] (which may pair the complementary base on the DNA strand, without being incorporated in the RNA by the T7 RNA polymerase) was evidenced. Our findings therefore suggest that RNA polymerases, unlike DNA polymerases, are unable to incorporate N7-platinated nucleotides into newly synthesized nucleic acids. In this respect, specifically designed N7-platinated nucleotides based compounds could be used in alternative to the classical platinum based drugs. This approach may offer a possible strategy to target specifically DNA, without affecting RNA, and is potentially able to better modulate pharmacological activity.

In this work it is described a new synthetic pathway for the synthesis of bis-cresolate Pt(II) complexes with (N-N) dinitrogen ligands. In particular, we were able, for the first time, to isolate, in the solid state, both anti-[Pt(N-N)(4-Me-C6H4O)2], N-N = 1,10-phenanthroline, (Head to Tail, HT) and syn-[Pt(N-N)(4-Me-C6H4O)2], N-N = 2,2’-bipyridile, (Head to Head, HH) rotamers, which were also characterized by single crystal X-ray diffraction

The reactivity of the Zeise’s anion with bidentate dinitrogen ligands (N-N) has been the main subject of several studies on the Pt(II) coordination and organometallic chemistry. The chemistry of Pt(II) organometallic ketonyl derivatives it is recognized to be important for many potential applications. For these reasons we exploit the possible extension of Zeise’s anion reactivity, in basic media, to the general synthesis, of organometallic ketonyl derivatives of the type [PtCl{h1-CH2C(O)R}(N-N)], even in the case of aliphatic diamines and sterically hindered diimine ligands. In these conditions we observed the formation of methastable intermediate complexes of the type trans-[PtCl2{h1-CH2C(O)R}(h2-C2H4)]-. Further reaction with dinitrogen ligands (N-N) gives [PtCl{h1-CH2C(O)R}(N-N)] complexes. In particular this new simple pathway results interesting from the synthetic point of view for the possibility to synthesize ketonyl complexes with several ketones and dinitrogen ligands not suitable for other methods.

In the [ABrnIm] (A = C, Si, Ge, Sn; n + m = 4) compounds, with the heavier halides bonded to the central IV group elements, the experimental 13C, 29Si, 73Ge and 119Sn NMR chemical shifts of the central atoms were found to be strictly linearly proportional to the bonded halides ionic radii overall sum Σ(rh). Based on this, calibration lines relating the chemical shifts to Σ(rh) could be built for the considered subgroup of [ABrnIm] compounds. Using such calibration lines we could calculate the equivalent NMR radius, NMRrH–A, attributable to each of the bonded hydrogens in [AH4] species, according to the overall NMR shielding produced on the central A atom. Interestingly, the calculated NMRrH–A value resulted to be almost constant in all [AH4] examined systems (A = 13C, 29Si, 73Ge, 119Sn) with an average NMRrH–A value equal to 194.6 ± 1.6 pm. Based on this approach, we could calculate the 207Pb NMR chemical shift of the unstable [PbH4] complex using the value of 192.7 pm calculated for NMRrH–Sn in the stable closest hydride [SnH4]. The obtained unprecedented NMR value is in accord with the 207Pb NMR chemical shift estimation, independently calculated for [PbH4] from the [SnH4] data, using the Pb/Sn chemical shift correlation defined in the Mitchell equation.

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 Me4DABPt(d(G*pG*)) models; the bulk and chirality of Me4DAB (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 Me4DABPt(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)-Me4DABPt(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.

Synthesis and characterization of the new pentacoordinate [PtCl2(eta(2)-C2H4)(Mebpy)] and square planar [PtCl2(Mebpy)] complexes both containing the asymmetrically hindered nitrogen donor chelate Mebpy = 6-Methyl-2,2'-bipyridil are reported. By nucleophilic addition of MeO- to the coordinated ethene of [PtCl2(eta(2)-C2H4)(Mebpy)], syn-[PtCl(eta(1)-CH2CH2OMe)(Mebpy)] and anti-[PtCl(eta(1)-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.

PON 254/Ric. Potenziamento del “Centro Ricerche per la Salute dell’Uomo e dell’Ambiente” Cod. PONa3_00334;Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici (CIRCMSB), Bari (Italy).

In this work, we studied the reactivity of the Zeise’s salt, K[PtCl3(h2-C2H4)], with ketones in the presence of strong bases. In these conditions we demonstrated, by NMR, the formation of metastable intermediate complexes of the type trans-[PtCl2{h1-CH2C(O)R}(h2-C2H4)]-. 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 Zeise’s salt, K[PtCl3(h2-C2H4)], is a paradigmatic example of the olefin to metal bond and still an important starting material for the synthesis of platinum-based organometallic compounds. The great reactivity of Zeise’s anion, essentially related to the lability of the chlorido ligand trans to the olefin, which can be easily substituted by any ligand having a reasonable affinity for platinum. To get further insights in the reaction of nucleophilic substitution upon changing the ligand trans to the h2-olefin, we tested the reactivity of three monoanionic platinum(II) substrates (Zeise’s anion itself, [PtCl3(h2-C2H4)]-, 1, trans-[PtCl2(OH)(h2-C2H4)], 2, and trans-[PtCl2(h1-CH2NO2)(h2-C2H4)]-, 3), towards aromatic imines with different steric requirements (pyridine, 4-methylpyridine, and 2,6-dimethylpyridine). We also performed a X-ray crystal structure characterization of the tetraphenylphosphonium salts of 2 and 3. Our data have highlighted the nature of the Pt-Cl Pt-OH, and Pt-C s bonds. Cl– is the only one of the three trans-to-olefin ligands which can have a h-acceptor capacity towards the metal. The s-donor capacity of the ligands can be ranked in the order: CH2NO2 C- >> Cl– > OH–. The carbanion has an unexpectedly high weakening effect on the bond between platinum and the trans-olefin. As a consequence the olefin is displaced in preference not only by another olefin but also by h-donors such as pyridines. In the light of the present results, the series ranking the trans-effect, which were set up in the 1980’s, needs to be reconsidered in view of the importance for synthetic chemistry of trans-directing 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).

Cisplatin, cis-diamminedichloroplatinum(II), is an effective antitumor drug known to exert its action by binding to the N7 of purine bases in nuclear DNA, consequently impairing replication, transcription and repair processes. Recently we have demonstrated, by the model complex [Pt(dien)(N7-5'-dGTP)] (dien = diethylenetriamine) the possible existence of an alternative mechanism for cisplatin antitumor activity, in which the metal is bonded to free purine bases, before incorporation in the newly synthesized DNA. This evidence suggests a new possible approach for the development of N7-platinated purines, as new antitumor drugs, for the treatment of cancer diseases. However, it is known that the efficacy of a new drug it is strictly related upon the transport across the cells plasma membrane barrier which strongly condition the drug pharmacokinetic and the targeted cells bioavailability. In particular in this study, we tested the possibility that N7-platinated purines could be transported into cells. At this scope we synthesized model Pt(II) coordination compounds, of the type [Pt(dien)(N7-G)] (G = Guanine derivative) and analysed the uptake of each single platinated nucleoside/nucleotide into Hela cells, by measuring Pt accumulation, by Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES). The quantitative analysis of Pt has provided a strong evidence for transport of the N7 platinated nucleoside [Pt(dien)(N7-dGuo)] into Hela cells (see figure). Moreover, the observed intracellular Pt accumulation was strictly sodiumdependent suggesting a carrier-mediated uptake for the [Pt(dien)(N7-dGuo)]. Overall, these results suggest that N7-platination does not compromise cellular uptake of nucleosides and may have important implications in the development of new potential nucleoside analogues in cancer treatment.

The results of the present study suggest that DmTpc1 is actively implicated in the specific uptake of free cytoplasmic Pt bonded nucleotides, and therefore could be linked to the mechanism of action of some platinum-based antitumor drugs. Although DmTpc1 has a low affinity for model [Pt(dien)(N7-5′-dGTP)] and cis-[Pt(NH3)2(py)(N7-5′-dGTP)] compared to dATP it's well known that DNA platination level of few metal atoms per double-stranded molecule may account for the pharmacological activity of platinum based antitumor drugs. This is the first investigation where it has been demonstrated that a mitochondrial carrier is directly involved in the transport of metalated purines related with the cisplatin mechanism of action. Moreover it is shown as a lower hindrance of nucleotide bonded platinum complexes could strongly enhance mitochondrial uptake. Furthermore, a new application of ICP-AES addressed to measure the transport of metalated nucleobases, by using a recombinant protein reconstituted into liposomes, has been here, for the first time, developed and compared with a standard technique such as the liquid scintillation counting.

Pt prodrugs: We synthesized new cationic complexes [PtCl(η2-C2H4)(R,R-chxn)]Cl (1) and [PtCl(η2-C2H4) (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.

Abstract The single crystal X-ray structure of the pentacoordinate complex [PtBr2(η2-CH2double bond; length as m-dashCH2)(Me2phen)], Me2phen = 2,9-dimethyl-1,10-phenanthroline, is here reported for the first time. Comparison of the complete series of [PtX2(η2-CH2double bond; length as m-dashCH2)(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.

L’invenzione si riferisce alla produzione di un sistema di biorecettore di ioni metallici applicabile allo sviluppo di dispositivi di sensing per monitoraggio ambientale,agroalimentare e sanitario. Il dispositivo e costituito da un supporto in vetro o silicio, necessario al fissaggio della componente proteica capace di legare in maniera specifica ioni metallici, in particolare nichel.Si compone di una serie di strati molecolari utili covalentemente alla superficie inorganica, realizzati per autoassemblaggio. La soluzione di analita posta in contatto col sistema permette alla proteina di legare il nichel, con alta specificità. Le capacita di legame sono state testate in range di concentrazioni compresi fra gli 0,01 μg/ml e i 100 μg/ml. Legame e rilascio dello ione possono essere gestiti variando il pH. I principi su cui si basa il dispositivo sono quelli della cromatografia per affinità, in cui si sfrutta la naturale propensione della proteina Hpn a legare il metallo di transizione, nichel.