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In this work, we elucidated some key aspects of the mechanism of action of the cisplatin 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.

Pomegranate peel extract is rich of interesting bioactive chemicals, principally phenolic compounds, which have shown antimicrobial, anticancer, and antioxidative properties. The aim of this work was to improve extract’ bioactivity through the adsorption on calcium carbonate nanocrystals. Nanocrystals revealed as efficient tools for extract adsorption reaching 50% of loading efficiency. Controlled release of the contained metabolites under acidic pH has been found, as it was confirmed by quantitative assay and qualitative study through NMR analysis. Specific functionality of inorganic nanocarriers could be also tuned by biopolymeric coating. The resulting coated nanoformulations showed a great antimicrobial activity against B. cinerea fungus preventing strawberries disease better than a commercial fungicide. Furthermore, nanoformulations demonstrated a good antiproliferative activity in neuroblastoma and breast cancer cells carrying out a higher cytotoxic effect respect to free extract, confirming a crucial role of nanocarriers. Finally, pomegranate peel extract showed a very high radical scavenging ability, equal to ascorbic acid. Antioxidant activity, measured also in intracellular environment, highlighted a protective action of extract-adsorbed nanocrystals twice than free extract, providing a possible application for new nutraceutical formulations.

Nanoparticles-based drug delivery systems for cancer therapy offer great promising opportunity as they specifically target cancer cells, also increasing the bioavailability of anticancer drugs characterized by low water solubility. Platicur, [Pt(cur)(NH3)2](NO3), is a cis-diamine-platinum(II) complex linked to curcumin. In this work, an ultrasonication method, coupled with Layer by Layer technology, allows to obtain highly aqueous stable Platicur nanocolloids of about 100 nm. The visible light activated Platicur nanocolloids showed an increased drug release and antitumor activity on HeLa cells, with respect Platicur Nanocolloids in darkness. This occurrence could give very interesting insight for a selective activation of the nano-delivered Pt(II) complex and a possible side effects lowering. For the first time, the metabolic effects of Platicur nanocolloids photoactivation, in Hela cell line, have been investigated using a NMR based metabolomics approach coupled with statistical multivariate data analysis (MVA). The reported results highlight specific metabolic differences between photoactivated and non-photoactivated Platicur NCs treated HeLa cancer cells.

The appearance of new epidemic virus opened new questions on the treatment of viral infections. The expectations in receiving answers and fast solutions from scientists are very high and the search for more effective antiviral drugs is highly desired. The potential of platinum compounds in viral diseases is an unexplored field. In last fifty years, since the discovery of their antitumor activity, platinum drugs were worldwide studied to improve their efficacy, activity and/or selectivity. As a consequence, thousands new platinum compounds were synthesized, even showing interesting antiviral properties. This review is aimed to describe the demonstrated antiviral properties of some platinum drugs. The reported studies suggest to reconsider platinum drugs for a further evaluation as potential antiviral agents.

Nucleos(t)ide analogues (NA) belong to a family of compounds widely used in anticancer/antiviral treatments. They generally exhibit a cell toxicity limited by cellular uptake levels and the resulting nucleos(t)ides metabolism modifications, interfering with the cell machinery for nucleic acids synthesis. We previously synthesized purine nucleos(t)ide analogues N7-coordinated to a platinum centre with unaltered sugar moieties of the type: [Pt(dien)(N7-dGuo)]2+ (1; dien = diethylenetriamine; dGuo = 2'-deoxy-guanosine), [Pt(dien)(N7-dGMP)] (2; dGMP = 5'-(2'-deoxy)-guanosine monophosphate), and [Pt(dien)(N7-dGTP)]2- (3; dGTP = 5'-(2'-deoxy)-guanosine triphosphate), where the indicated electric charge is calculated at physiological pH (7.4). In this work, we specifically investigated the uptake of these complexes (1-3) at the plasma membrane level. Specific experiments on HeLa cervical cancer cells indicated a relevant cellular uptake of the model platinated deoxynucleos(t)ide 1 and 3 while complex 2 appeared unable to cross the cell plasma membrane. Obtained data buttress an uptake mechanism involving Na+-dependent concentrative transporters localized at the plasma membrane level. Consistently, 1 and 3 showed higher cytotoxicity with respect to complex 2 also suggesting selective possible applications as antiviral/antitumor drugs among the used model compounds.

NMR-based metabolomics is a very effective tool to assess the tumor response to drugs by providing insights for their mode of action. Recently, a novel Pt(II) complex, [Pt(ƞ1-C2H4OMe)(DMSO)(phen)]+ (phen = 1,10-phenanthroline), Pt-EtOMeSOphen, was synthesized and studied for its antitumor activity against eight human cancer cell lines. Pt-EtOMeSOphen showed higher cytotoxic effects than cisplatin in most of the cancer cell lines and in particular against the neuroblastoma cell line (SH-SY5Y). In this study, the mechanism of action of Pt-EtOMeSOphen on SH-SY5Y cells was investigated using 1H NMR-based metabolomics and compared with cisplatin. The observed time response of SH-SY5Y cells under treatment revealed a faster action of Pt-EtOMeSOphen compared with cisplatin, with a response already observed after six hours of exposure, suggesting a cytosolic target. NMR-based metabolomics demonstrated a peculiar alteration of the glutathione metabolism pathway and the diacylglycerol expression.

NMR-based metabolomics is a very effective tool to assess the tumor response to drugs by providing insights for their mode of action. Recently, a novel Pt(II) complex, [Pt(ƞ

Pomegranate peel extract is rich of interesting bioactive chemicals, principally phenolic compounds, which have shown antimicrobial, anticancer, and antioxidative properties. The aim of this work was to improve extract' bioactivity through the adsorption on calcium carbonate nanocrystals. Nanocrystals revealed as efficient tools for extract adsorption reaching 50% of loading efficiency. Controlled release of the contained metabolites under acidic pH has been found, as it was confirmed by quantitative assay and qualitative study through NMR analysis. Specific functionality of inorganic nanocarriers could be also tuned by biopolymeric coating. The resulting coated nanoformulations showed a great antimicrobial activity against

We previously demonstrated that the δ NMR chemical shift of central NMR active atoms (A), in simple halido [AXn] (A=C, Si, Ge, Sn, Pb, Pt; Xn = combination of n halides, n = 4 or 6) derivatives, could be directly related to X radii overall sum, Σ(r L ). Further correlation have also been observed for tetrahedral [AX4] (A=C, Si; X4 = combination of four halides) compounds where the X Pauling electronegativities sum, Σ ( χ L Pau ) , $\Sigma (\chi _L^{{\rm{Pau}}}),$ exceeds a specific value (≈12.4). In this work, we focused on these latter systems considering the H vs. X substitution. The analysis of the literature reported δ(13C) and δ(29Si) NMR chemical shift for the mono hydrogenated derivatives and in particular for [CHF3] and [SiHF3], characterized by the lowest Σ(r L ) and the highest Σ ( χ L Pau ) , $\Sigma (\chi _L^{{\rm{Pau}}}),$ suggests a revised value for the H electronegativity ranking with respect to Pauling’s.

Platicur is a cis-diamine-platinum(II) complex linked to curcumin. Previous studies have shown that the photoactivation of Platicur, with visible light, is responsible for the production of active species of platinum(II) and a photoactive curcumin. The active species formed act synergistically causing an interesting anticancer activity. In this work, we tried to improve the antitumor activity of photoactivated Platicur by using a nano delivery system. With this aim, Platicur's aqueous chitosan nanocolloids were synthesized, Figure 1. The preliminary in vitro biological assays on HeLa tumor cell line have demonstrated a significantly higher cytotoxicity (a significantly lower IC50 dose) of the photoactivated nanocolloids with Platicur, compared to the photoactivated Platicur not encapsulated in the nanocolloids. The use of a metabolomic approach based on NMR spectroscopy in the research of the mechanism of action or for the evaluation of the tumor response to the anticancer metal drugs is a new tool of recent growth. The side effects induced by metal based drugs, the prediction of the response to treatment and the key information on the mechanism of action (for known and new compounds) could be easily obtained using NMR-based metabolomics. [2, 3] For this reason, the 1H NMR spectroscopy coupled with multivariate statistical analysis was used to characterize the metabolic variations of intracellular metabolites and the compositional changes of the corresponding culture media of HeLa cells treated with photoactivated Platicur nanocolloids. The metabolomic analysis allowed to highlight specific metabolic differences between the cells treated with photoactivated Platicur nanocoloids compared to non-photoactivated ones. The NMR has once again proved to be a valid tool for the study of the mechanism of action of metal-based drugs.

By studying a model set of square-planar [Pt(NH3)aXb]n (a + b = 4; Xb = combination of b halido ligands; n = 2 – b) complexes, we found that their δ(195Pt) 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 NH3 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 NH3 ligand, affecting the observed δ(195Pt) as previously found for halido ligands. Interestingly, a δ(15N) decrease is observed in Pt bonded NH3 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.

Among the emerging anti-cancer compounds, phenanthroline derivatives are of high interest. In contrast to cisplatin, phenanthrolines and their metal complexes are potentially intercalant molecules that can interact with DNA by aromatic π-stacking between base pairs. In this study, two new organometallic Pt(II)-complexes containing 1,10-phenantroline (phen), [Pt(phen)(DMSO)(η1CH2CH2OMe)]+, 1, [Pt(phen)(NH3)(η1-CH2CH2OMe)]+, 2, have been taken into consideration in order to evaluate their cytotoxicity in different human cancer cell lines. In addition, maximal intracellular uptake (MIU) was assayed by ICP-AES after incubation of cells with 100 μM 1 and 2 for 0.5-12 hours. Ten different human cancer cell lines (Caco-2, Caki-1, HeLa, Hep-G2, MCF-7, MG-63, SH-SY5Y, Skov-3, ZL-34 and ZL-55) were treated with 1, 2 and cisplatin at increasing concentrations (0.1-200 μM) from 12 to 72 hours to assess their effect on cell viability. While 2 did not show significantly greater cytotoxic effects than cisplatin in any cell line, 1 proved to be highly effective in almost all cell lines and mainly in the first 12-24 hours of treatment (Figure 1). The greater effects were observed in neuroblastoma cells SH-SY5Y (IC50 (12-24 h) between 8.23 ± 1.11 μM and 19.8 ± 3.26 μM) and ovarian adenocarcinoma cells SKOV-3 (IC50 (12-24 h) between 39.8 ± 3.56 μM and 92.13 ± 7.81 μM). ICP-AES in SH-SY5Y and SKOV-3 demonstrated a high intracellular uptake of compound (1) (MIUSH-SY5Y 430.5 ± 40.1 ng Pt/mg protein; MIUSKOV-3 497.6 ± 59.5 ng Pt/mg protein) compared to cisplatin (MIUSH-SY5Y 155.9 ± 31.4 ng Pt/mg protein; MIUSKOV-3 30 ± 10.2 ng Pt/mg protein). Total Pt concentration of compound 2 (MIUSH-SY5Y 300 ± 39.2 ng Pt/mg protein; MIUSKOV-3 140.4 ± 46.3 ng Pt/mg protein) was also higher than cisplatin despite not having significantly greater cytotoxic effects. Further studies are needed in order to evaluate the mechanism of action of both 1 and 2 compounds and therefore understand why compound 1 is more toxic than compound 2. Finally, it is desirable to use healthy cell lines corresponding to the tumor lines used here in order to verify any cellular specificity towards cancer cells of the two compounds.

Since the discovery of the antitumor activity of cisplatin, many studies have been devoted to understanding the relation between structure of platinum compounds and their antitumor activity. Several investigations on cisplatin analogues demonstrated that their effectiveness could be greatly improved by substituting the labile chlorido ligands with other leaving groups, giving a 2nd generation platinum drugs (e.g. carboplatin, nedaplatin, etc.). A 3rd generation could be obtained by replacement of both ammonia and chlorido ligands of cisplatin with different ligands (e.g. oxaliplatin, heptaplatin, etc.). The here studied new organometallic compounds belong to this last category. We synthesized complex precursors of type [PtCl(1-C2H4OMe)(N^N)], 3, by using a previously reported procedure consisting in the reaction of a dinitrogen ligand with the Zeise’s salt in basic methanol. Reaction of the neutral complex 3 with excess NH3 or DMSO in water solution, gave the final [Pt(NH3)(h1-C2H4OMe)(N^N)]+, 4’, or [Pt(DMSO)(h1-C2H4OMe)(N^N)]+, 4’’, complexes, respectively. The citotoxic activity of such complexes were studied in comparison with cisplatin. Preliminary experiments on different cell lines showed a relevant cytotoxic activity for complex 4’’ differently from 4’, when N^N = 1,10-phenanthroline.

The series of complexes of formula [PtCl(η 2 -olefin)( N^N )] + , previously investigated for N^N = N , N , N′ , N′ -tetramethyl-ethylenediamine (Me 4 en), has been extended to the case of aromatic diimines 1,10-phenanthroline (phen) and 3,4,7,8-tetramethyl-1,10-phenanthroline (Me 4 phen) and to a variety of olefins (ethene, propene and styrene). The complexes have been prepared by reaction of the [PtCl 3 (η 2 -olefin)] − anions (K[PtCl 3 (η 2 -styrene)] reported here for the first time) with N^N in basic methanol. The initial [PtCl{η 1 -CH 2 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(η 2 -olefin)( N^N )] + . The phenanthroline ligand confers peculiar properties to the new compounds. In particular, by reaction with triethylamine, [PtCl{η 2 -CH 2 CH(Me)}( N^N )] + species, undergo deprotonation of the olefin and formation of the dimeric species [{PtCl( N^N )} 2 ( μ -η 1 :η 2 -CH 2 CH CH 2 )] + which could be isolated and characterized. Interestingly such product in acetonitrile gives a disproportionation with precipitation of [PtCl 2 (phen)] and formation in solution of the new η 3 -allyl complex [Pt(η 3 -C 3 H 5 )(phen)]ClO 4 .

The study of the NMR chemical shift variations produced by monoatomic halido ligands bonded to NMR active central A atoms, in [AXn] compounds (Xn = combination of n halido ligands) is of wide interest. At this regard, we could previously demonstrate that the NMR chemical shift of a central 13C or 29Si atom, in simple [AX4] (A = C, Si; X4 = combination of four halides) tetrahalido derivatives, can be directly related to both ionic radii and Pauling’s electronegativities overall sums of the coordinated atomic ligands, Σ() and Σ(), respectively. [1,2] In this work, we extended this approach to halomethane and halosilane derivatives of the type [AHmXn] (A = C, Si; Xn = combination of n halido ligands; n+m = 4), by studying the 13C and 29Si NMR chemical shift variations of [AHmXn] compounds, as a function of Σ() and Σ(). In this way, new measurements for the hydrogen electronegativity, based on experimental molecular NMR data (), could be obtained. Remarkably, the hydrogen electronegativity obtained by these NMR data resulted higher than that reported by Pauling in its scale, but similar to that reported by Mulliken (= 2.75; =2.20; = 2.80). The importance of this new finding derives from the use of NMR data, based on molecular rather than atomic properties, in order to obtain a hydrogen electronegativity value similar to that calculated by Mulliken.

Starting from the [PtCl(η1-C2H4OMe)(phen)] (phen = 1,10-phenanthroline, 1) platinum(II) precursor, we synthesized and characterized by multinuclear NMR new [Pt(η1-C2H4OMe)(L)(phen)]+ (L = NH3, 2; DMSO, 3) complexes. These organometallic species, potentially able to interact with cell membrane organic cation transporters (OCT), violating some of the classical rules for antitumor activity of cisplatin analogues, were evaluated for their cytotoxicity. Interestingly, despite both complexes 2 and 3 resulting in greater cell uptake than cisplatin in selected tumor cell lines, only 3 showed comparable or higher antitumor activity. General low cytotoxicity of complex 2 in the tested cell lines (SH-SY5Y, SK-OV-3, Hep-G2, Caco-2, HeLa, MCF-7, MG-63, ZL-65) appeared to depend on its stability towards solvolysis in neutral water, as assessed by NMR monitoring. Differently, the [Pt(η1-C2H4OMe)(DMSO)(phen)]+ (3) complex was easily hydrolyzed in neutral water, resulting in a comparable or higher cytotoxicity in cancer cells with respect to cisplatin. Further, both IC50 values and the uptake profiles of the active complex appeared quite different in the used cell lines, suggesting the occurrence of diversified biological effects. Nevertheless, further studies on the metabolism of complex 3 should be performed before planning its possible use in tissue- and tumor-specific drug design.

One of the major challenges of drug delivery is the development of suitable carriers for therapeutic molecules. In this work, a novel nanoformulation based on superparamagnetic nanoclusters [magnetic nanocrystal clusters (MNCs)] is presented. In order to control the size of the nanoclusters and the density of magnetic cores, several parameters were evaluated and tuned. Then, MNCs 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 biofunctional molecules.

The study of the NMR chemical shift variations produced by mono atomic ligands bonded to NMR active central A atoms, in [ALn] compounds (A = C, Si, Ge, Sn, Pb, Pt; Ln = combination of n halido and/or hydrido ligands; n = 4-6) is of wide interest. In particular, we found that the observed central atoms 13C, 29Si, 73Ge, 119Sn, 195Pt, 207Pb) NMR chemical shifts, are affected by both halido and hydrido ligands ionic radii and electronegativities overall sums, Σ(rL) and Σ(L), respectively. At this regard, we generally observed simple linear correlations between the central atoms  NMR chemical shifts and the Σ(rL), when Σ(rL) results below an onset value (red line in Figure 1A). For instance, this occurs in several [AL4] coordination compounds, where the central A can show different oxidation states and geometries (octahedral, squareplanar and tetrahedral). [1-3] Interestingly, in [CL4] and [SiL4] derivatives, we could determine a dependence of the DΣ(rL) difference (indicated for example by the green double arrow in Figure 1A) on Σ(rL), as also reported in Figure 1B. Indeed, above the indicated onset value the example DΣ(rL)C variations result directly proportional to the increase of Σ(rL) (blue line in Figure 1B). Similar trends were also observed in the analogue Si derivatives.

The reactivity of [PtX

In carbon and silicon tetrahalide compounds, the experimental

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.

Thanks to recent advances in analytical technologies and statistical capabilities, the application field of metabolomics has increased significantly. Currently, this approach is used to investigate biological substrates looking for metabolic profile alterations, diseases markers, and drug effects. In particular, NMR spectroscopy has shown great potential as a detection technique, mainly for the ability to detect multiple (10s to 100s) metabolites at once without separation. Only in recent years has the NMR-based metabolomic approach been extended to investigate the cell metabolic alterations induced by metal-based antitumor drug administration. As expected, these studies are mainly focused on platinum complexes, but some palladium and ruthenium compounds are also under investigation. The use of a metabolomics approach was very effective in assessing tumor response to drugs and providing insights into the mechanism of action and resistance. Therefore, metabolomics may open new perspectives into the development of metal-based drugs. In particular, it has been shown that NMR-based, in vitro metabolomics is a powerful tool for detecting variations of the cell metabolites induced by the metal drug exposure, thus offering also the possibility of identifying specific markers for in vivo monitoring of tumor responsiveness to anticancer treatments.

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, 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).

The relevant adsorption of cis -[Pt(NH 3 ) 2 (P 2 O 7 )] 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.

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.

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.

NMR-based metabolomic analysis of cells, tissues and biological fluids represents a helpful technique to assess drugs’ tumour response and to explore the mechanism of action and resistance of drugs. The novel Pt(II) complex, [Pt(O,O′-acac)(γ-acac)(DMS)], Ptac2S, has recently gained increasing attention as potential anticancer agent for its pharmacological activity shown in different in vitro cultured tumoral cell lines, and in vivo. In this work, an 1H NMR metabolomic approach was used to evaluate the pharmacological activity of on Epithelial Ovarian Carcinoma (EOC) cisplatin resistant cultured cell line (i.e. SKOV-3 cell line). The multivariate spectroscopic NMR data of both intracellular cell extracts (aqueous and lipidic fractions) and extracellular medium, recover of Ptac2S treated cells, as made by using chemo-metric and pattern recognition techniques. These metabolic profiles were compared to those of untreated and cisplatin treated (at the IC50 dose) SKOV-3 cells, following the same cells for a range of culture times (6-24 h) to evidence variations. The multivariate data analysis revealed the ability of the considered complex to act already 6h after treatment. In particular, it was observed a fast decreasing of succinate (a Krebs’ cycle intermediate) and phosphocholine (an intermediate in the synthesis of phosphatidylcholine, a major component of biological membranes), with respect to untreated and cisplatin treated cells. Similar effects were observed in cisplatin treated cell samples only 24h after treatment. Furthermore, Ptac2S samples showed a decrease of the relative content of cholesterol, triglycerides and polyunsaturated fatty acids. On the contrary, controls and cisplatin treated cells showed an increase of these latter metabolites, which is often associated to proliferation and/or apoptosis phenomena. Finally, the analysis of recovered culture media revealed a preferential release of pyruvate from Ptac2S treated cells, with respect to the cisplatin treated and control cells, characterized by a higher release of lactate. This suggests a possible inhibition of both pyruvate entrance, in the Krebs cycle, and/or pyruvate conversion into lactate. Last condition seems typical of cancer cells (Warburg Effect). In conclusion, these results confirm that Ptac2S limits the proliferation of cancerous cells with a mechanism very different from that of cisplatin.

The novel [Pt (O,O′-acac)(γ-acac)(DMS)], Ptac2S, Pt(II) complex, has recently gained increasing attention as potential anticancer agent for its pharmacological activity shown in different tumour cell lines, studied both in vitro and in vivo. Such studies evidenced that the mechanism of action of Ptac2S, although not completely clarified, involves non-genomic targets. In this study, we describe the application of 1H NMR based metabolomic approaches to evaluate the pharmacological activity of Ptac2S, on the cisplatin resistant Epithelial Ovarian Carcinoma (EOC), SKOV-3 cell line. The metabolic variations of cellular metabolites, in aqueous and lipophilic extracts, and the composition of the corresponding extracellular culture media have been compared to those of cisplatin. Interestingly, based on our results, differently from cisplatin, the Ptac2S is able to act already at 6h after cells treatment, through synergistic effects. These include the decrease of several metabolites involved in membrane modification, Kreb’s cycle and catabolism of carbohydrates and proteins. These results fully confirm the presence of a different mechanism of action of Ptac2S with respect to cisplatin, involving the specific here considered markers.