By studying a model set of square‐planar [Pt(NH 3 ) a X b ] n ( a + b = 4; X b = combination of b halido ligands; n = 2 – b) complexes, we found that their δ ( 195 Pt) NMR chemical shift decreases proportionally to the platinum bonded halido ligands' ionic radii overall sum. This confirms also for these systems, the already observed NMR shielding attributed to pseudo ring currents, circulating around the M–X bond axis. Moreover, the present data show that also the NH 3 ligands are characterized by a constant NMR shielding ability toward the central metal. This could be rationalized in term of a “ NMR effective molecular radius ” of the NH 3 ligand, affecting the observed δ ( 195 Pt) as previously found for halido ligands. Interestingly, a δ ( 15 N) decrease is observed in Pt bonded NH 3 ligands if the ionic radius of a cis halido ligand is increased. The opposite occurs if the ionic radius of a trans halido ligand is increased. The two contrasting effects stem from both shielding electric ring currents affecting the cis ligands and prevailing trans ‐influence due to coordinated halido ligands.

In agreement with all authors of this paper the order of the authors and the contribution “Paola Lunetti[+], Alessandro Romano[+], Chiara Carrisi, Daniela Antonucci, Tiziano Verri, Giuseppe E. De Benedetto, Vincenza Dolce, Francesco P. Fanizzi, Michele Benedetti,* and Loredana Capobianco.* [+] These authors contributed equally to this paper. * Corresponding authors: Michele Benedetti and Loredana Capobianco, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce.” is corrected to read the original order of the first submitted version of the paper: “Chiara Carrisi[+], Alessandro Romano[+], Paola Lunetti, Daniela Antonucci, Tiziano Verri, Giuseppe E. De Benedetto, Vincenza Dolce, Francesco P. Fanizzi, Michele Benedetti,* and Loredana Capobianco.* [+] These authors contributed equally to this paper. * Corresponding authors: Loredana Capobianco and Michele Benedetti, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce.” For completeness the following individual contributions of the authors were added in the Supporting Information: “Author contributions: L.C., M.B., C.C., A.R. designed research; C.C., A.R., P.L. and D.A. performed research; L.C., M.B., C.C., A.R., V.D. and P.L. analysed data; F.P.F., A.R., L.C. and M.B. wrote the paper; L.C., M.B., T.V., G.D.B. and F.P.F. active discussion paper revision.”

cis-[PtCl2(NH3)2] (cisplatin) is among the highest effective antitumor drugs used for the chemotherapeutic treatment of a broad range of malignancies. Recently, alongside with the classical direct bond to DNA, an alternative mechanism of action mediated by N7 platinated nucleotides has been suggested for cisplatin. Considering that mitochondria play an important role in cell death activation and in a significant portion of the clinical activity and pharmacological properties associated with cisplatin, aim of this research was to evaluate the possibility that platinated deoxynucleotides, as the model complex [Pt(dien)(N7-5’-dGTP)] (1), dien=diethylenetriamine, could be transported into mitochondria and then incorporated into mtDNA. The kinetic characterization has revealed that the mitochondrial deoxynucleotide carrier (DNC) transports complex 1 with high affinity. Finally, a highly efficient in organello DNA synthesis system, followed by ICP-AES, has demonstrated that [Pt(dien)(N7-5’-dGTP)] is incorporated in the mitochondrial DNA by DNA polymerase γ. These results may have critical implications in the development of new generations of anticancer and/or antiviral nucleotide analogues with more specific cellular targets and fewer side effects.

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.

A series of pentacoordinate d(8) Pt-II complexes, of the type [PtCl2((2)-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 (Pt-195 NMR signal frequency) by alkyl groups close to the N-donors. H-1 and C-13 NMR analysis of the (2)-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 (1)J(Pt,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 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.

In this work we report on the synthesis of new [PtCl(η2-CH2CH2)(NˆN)]+ and [PtCl(η1-CH2–CH2OCH3)(NˆN)] complexes, with different NˆN dinitrogen ligands, i.e. ethylenediamine (en), R,R- and S,S-diaminocyclohexane (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.

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≡CH)(Me2phen)], that evolve to four-coordinate alkenyl complexes of the type [PtX(η(1)-E-CH=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=CHX)(η(2)-CH≡CH)(Me2phen)] (X = Br, I). The π-bonded acetylene can be exchanged with free olefins or C≡O, affording the new alkene-alkenyl or carbonyl-alkenyl complexes [PtX(η(1)-E-CH=CHX)(η(2)-olefin)(Me2phen)] and [PtX(η(1)-E-CH=CHX)(C≡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=CH2)(Me2phen)].

We studied the reactivity of the Zeise’s salt with ketones, in the presence of strong bases, demonstrating the formation of intermediate complexes of the type trans-[PtCl2{η1-CH2C(O)R}(η2-C2H4)]−. Further reaction with dinitrogen ligands (N–N) gives [PtCl{η1-CH2C(O)R}(N–N)] complexes. This reactivity of the Zeise’s anion can be exploited for the general synthesis, in a one pot reaction, of σ-carbon Pt(II) ketonyl derivatives with aliphatic or aromatic dinitrogen ligands.

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.

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)(OC6H4-4-Me)2], N-N=1,10-phenanthroline, (head to tail) and syn-[Pt(N-N)(OC6H4-4-Me)2], N-N=2,2′-bipyridyl, (head to head) rotamers, which were characterized as different rotamers in the solid state by single crystal X-ray diffraction.

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. (C) 2012 Elsevier B. V. All rights reserved.

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.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Complexes of the type [PtCl(N–N)(η1-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(Me2phen)(η1-CH2CH2OR)], Me2phen=2,9-dimethyl-1,10-phenatroline, R=alkyl, undergo spontaneous decomposition, to give the corresponding vinyl-ether, CH2CHOR. Decomposition pathway studies suggest a pseudo-Wacker type mechanism (β 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.

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)(W-G)], then = 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.

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. Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Das Metall hängt schon an der Base: Am Beispiel eines DNA-Polymerase-Modells und N7-metallierter Purintriphosphatnucleotide wird nachgewiesen, dass metallierte Purine bei einer enzymatischen In-vitro-Synthese in DNA inkorporiert werden können (siehe Schema; dNTP=Desoxynucleotidtriphosphat). Mithilfe von DNA-Polymerase lässt sich überdies ortsspezifisch metallierte DNA erzeugen.