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Six enantiomerically pure, oxaliplatin-like, platinum compounds (two platinum(ii) and four platinum(iv)), all containing unsaturated cyclic diaminetrans-1,2-diamino-4-cyclohexene (DACHEX) as a substitute for thetrans-1,2-diaminocyclohexane used in oxaliplatin, were investigated. The complexes were characterized by elemental analyses, ESI-MS, and1H-NMR spectroscopy. For the four Pt(iv) complexes the electrochemical redox behaviour, investigated by cyclic voltammetry, showed that all complexes possess reduction potentials suitable for activationin vivo. The antiproliferative activity was assessedin vitroon human cancer cell lines, also selected for resistance to platinum-based drugs or belonging to the MultiDrug-Resistant (MDR) phenotype. All complexes exhibited antiproliferative activity superior to that of cisplatin and almost equivalent to or better than that of oxaliplatin; moreover, most complexes were also capable of overcoming both the cisplatin- and the oxaliplatin-resistance. By comparing the effectiveness of the enantiomerically pure compounds with the racemic one, theR,Renantiomer emerged as the most effective in the case of Pt(ii) complexes whereas theS,Senantiomer was the most effective in the case of the Pt(iv) derivatives. From the results obtained also against 3D spheroid tumor models,cis,trans,cis-[Pt(OXA)(OBz)2(1S,2S-DACHEX)] (OBz = benzoate) emerged as the most promising candidate for further preclinical investigation.

Here, we investigated the mechanism of antiproliferative action in cancer cells of new compounds structurally derived from oxaliplatin, namely a pair of enantiomers [Pt(OXA)(1R,2R-DACHEX)] (1) and [Pt(OXA)(1S,2S-DACHEX)] (2) (OXA = oxalate, DACHEX = trans-1,2-diamino-4-cyclohexene). While oxaliplatin is used almost exclusively to treat colorectal and other gastrointestinal cancers, new complex 1 shows instead high potency in malignant pancreatic adenocarcinoma PSN1 cells including superior selectivity for pancreatic cancer over noncancerous cells. Utilizing a multi-platform biochemical approach to study the unique features of the mechanism of action of this new platinum-based drug, we show that 1 has a much greater ability to penetrate pancreatic tumors than its S,S enantiomer 2 and oxaliplatin, and to be transported into cells as bound to plasma proteins. Additionally, the mechanism of action of 1 and, to a lesser extent, oxaliplatin in pancreatic cancer cells involves alterations of the lipogenesis pathway, namely inhibition of de novo lipid synthesis, acting by a new mechanism not yet considered for anticancer action of clinically used antitumor platinum drugs. These data highlight the functional diversity of platinum anticancer compounds and the potential benefits of finding new anticancer drugs applying a mechanism-based rationale.

Platinum compounds containing an aromatic diimine (1,10-phenanthroline or 2,9-dimethyl-1,10-phenanthroline; phen and Me 2 phen, respectively) and antiviral guanosine-type ligands (acyclovir or penciclovir; acy and pen, respectively) have been synthesised. These compounds maintain the antiviral activity against Herpes Symplex Virus (HSV) and have greater efficacy than free acyclovir or penciclovir against Cytomegalovirus (CMV); in both cases the species with Me 2 phen are more active. The same complexes are effective against tumor cell proliferation which also results to be dependent upon the nature of the diimine ligand: all compounds containing Me 2 phen being more active than those containing phen. Although in vivo some complexes significantly reduce tumor cell proliferation, nevertheless, they do not appear to significantly affect the life time expectancy of the treated mice. The greater cytotoxicity of compounds with Me 2 phen may result from a higher reactivity towards cellular components, such as glutathione, which could cause release of the diimine, known to be highly cytotoxic.

Stable cesium lead bromide perovskite nanocrystals (NCs) showing a near-unity photoluminescence quantum yield (PLQY), narrow emission profile, and tunable fluorescence peak in the green region can be considered the ideal class of nanomaterials for optoelectronic applications. However, a general route for ensuring the desired features of the perovskite NCs is still missing. In this paper, we propose a synthetic protocol for obtaining near-unity PLQY perovskite nanocubes, ensuring their size control and, consequently, a narrow and intense emission through the modification of the reaction temperature and the suitable combination ratio of the perovskite constituting elements. The peculiarity of this protocol is represented by the dissolution of the lead precursor (PbBr2) as a consequence of the exclusive complexation with the bromide anions released by the in situ SN2 reaction between oleylamine (the only surfactant introduced in the reaction mixture) and 1-bromohexane. The obtained CsPbBr3 nanocubes exhibit variable size (ranging from 6.7 ± 0.7 nm to 15.2 ± 1.2 nm), PL maxima between 505 and 517 nm, and near-unity PLQY with a narrow emission profile (fwhm of 17–19 nm). Additionally, the NCs synthesized with this approach preserve their high PLQYs even after 90 days of storage under ambient conditions, thus displaying a remarkable optical stability. Through the rationalization of the obtained results, the proposed synthetic protocol provides a new ground for the direct preparation of differently structured perovskite NCs without resorting to any additional post-synthetic treatment for improving their emission efficiency and stability.

Six platinum(IV) compounds derived from an oxaliplatin analogue containing the unsaturated cyclic diamine trans-1,2-diamino-4-cyclohexene (DACHEX), in place of the 1,2-diaminocyclohexane, and a range of axial ligands, were synthesized and characterized. The derivatives with at least one axial chlorido ligand demonstrated solvent-assisted photoreduction. The electrochemical redox behavior was investigated by cyclic voltammetry, all compounds showed reduction potentials suitable for activation in vivo. X-ray photoelectron spectroscopy (XPS) data indicated an X-ray-induced surface reduction of the Pt(IV) substrates, which correlates with the reduction potentials measured by cyclic voltammetry. The cytotoxic activity was assessed in vitro on a panel of human cancer cell lines, also including oxaliplatin-resistant cancer cells, and compared with that of the reference compounds cisplatin and oxaliplatin, all IC50 values were remarkably lower than those elicited by cisplatin and somewhat lower than those of oxaliplatin. Compared to the other Pt(IV) compounds of the series, the bis-benzoate derivative was by far (5&ndash, 8 times) the most cytotoxic showing that low reduction potential and high lipophilicity are essential for good cytotoxicity. Interestingly, all the complexes proved to be more active than cisplatin and oxaliplatin even in three-dimensional spheroids of A431 human cervical cancer cells.

Here, polyethylene glycol (PEG)-stabilized solid lipid nanoparticles (SLNs) containing Pt(IV) prodrugs derived from kiteplatin were designed and proposed as novel nanoformulations potentially useful for the treatment of glioblastoma multiforme. Four different Pt(IV) prodrugs were synthesized, starting from kiteplatin by the addition of two carboxylate ligands with different length of the alkyl chains and lipophilicity degree, and embedded in the core of PEG-stabilized SLNs composed of cetyl palmitate. The SLNs were extensively characterized by complementary optical and morphological techniques. The results proved the formation of SLNs characterized by average size under 100 nm and dependence of drug encapsulation efficiency on the lipophilicity degree of the tested Pt(IV) prodrugs. A monolayer of immortalized human cerebral microvascular endothelial cells (hCMEC/D3) was used as in vitro model of blood–brain barrier (BBB) to evaluate the ability of the SLNs to penetrate the BBB. For this purpose, optical traceable SLNs were achieved by co-incorporation of Pt(IV) prodrugs and luminescent carbon dots (C-Dots) in the SLNs. Finally, an in vitro study was performed by using a human glioblastoma cell line (U87), to investigate on the antitumor efficiency of the SLNs and on their improved ability to be cell internalized respect to the free Pt(IV) prodrugs.

This study aims at rationalizing the effects of the lead/surfactant ratio on the structural evolution of cesium lead-bromide perovskite nanocrystals (NCs), ascertaining how their shape and surface composition can be modulated by suitably adjusting the ligand amount (an equivolumetric mixture of oleic acid and oleyl amine) relatively to lead bromide. The tailoring of the reaction conditions allows the obtainment of blue-emitting CsPbBr3 nanoplatelets in the presence of ligand excess, while green-emitting nanocubes are achieved under low-surfactant conditions. An insight into the NC's shape evolution dictated by the different reaction conditions suggests that the generation of CsPbBr3 nanoplatelets is controlled by the dimensions of [(RNH3)(2)(PbBr4)](n) layers formed before the injection of cesium oleate. The growth step promoted by preformed layers is concomitant to (but independent from) the nucleation process of lead-based species, leading to centrosymmetric nanocubes (prevalent in low-surfactant regimes) or Cs4PbBr6 NCs (prevalent in high-surfactant regimes). The proposed NC growth is supported by the analysis of the optical properties of non-purified samples, which reveal the selective presence of structures endowed with four cell unit average thickness accompanying larger emissive nanocubes. By combining nuclear magnetic resonance (NMR) and UV-Vis spectroscopy techniques, it is ascertained that the lead/surfactant ratio also controls the relative proportion between lead-based species (PBr2, PbBr3-, PbBr42- and plausibly PbBr53- or PbBr64-) formed before cesium injection, which regulate the size of [(RNH3)(2)(PbBr4)](n) layers as well as the formation of Cs4PbBr6 NCs during the nucleation stage. The surface chemistry of the differently structured perovskite NCs is investigated by correlating the elemental composition of the nanoparticles with specific NMR signals ascribable to the surface ligands. This level of investigation also sheds light on the stability of the time-dependent fluorescence exhibited by differently composed perovskite NCs before the loss of their colloidal integrity. Our findings can bring about a fine tuning of the synthetic methods currently employed for controlling the shape and surface chemistry of perovskite NCs.

Two new Pt(II)-pyrophosphato complexes containing the carrier ligands cis-1,3-diaminocyclohexane (cis-1,3-DACH) and trans-1,2-diamine-4-cyclohexene (1,2-DACHEX), variants of the 1R,2R-diaminocyclohexane ligand present in the clinically used Pt-drug oxaliplatin, have been synthesized with the aim of developing new potential antitumor drugs with high bone tropism. The complexes are more stable at physiological pH than in acid conditions, with Na2[Pt(pyrophosphato)(cis-1,3-DACH)] (1) slightly more stable than [Pt(dihydrogenpyrophosphato)(1,2-DACHEX)] (2). The greater reactivity at acidic pH ensures a greater efficacy at the tumor site. Preliminary NMR studies indicate that 1 and 2 react slowly with 5’-GMP (used as a model of nucleic acids), releasing the pyrophosphate ligand and affording the bis 5’-GMP adduct. In vitro cytotoxicity assays performed against a panel of four human cancer cell lines have shown that both compounds are more active than oxaliplatin. Flow cytometry studies on HCT116 cells showed that the pyrophosphato compounds with the non-classical 1,3- and 1,4-diaminocyclohexane ligands (1 and 4) are the most capable to induce cells’ death by apoptosis and necrosis.

A new family of anticancer compounds has been derived from oxaliplatin by inserting a double-bond between carbons 4 and 5 of the 1,2-diaminocyclohexane ring. Testing against a panel of human tumour cell lines including cervical (A431), ovarian (2008), and colon carcinomas (HCT-15 and LoVo), and two oxaliplatin-resistant clones (LoVo OXP and LoVo MDR) has shown that the new compounds have, in general, equal if not better cytotoxic activity and are able to overcome the oxaliplatin-resistance. Moreover, the oxalato derivative induced lipid droplets increase in LoVo OXP cells thus suggesting the involvement of metabolism stress in its mechanism of action.

In this paper we report the synthesis and characterization of the complex c,t,c-[Pt(dihydrogenpyrophosphate)(OH)2(cis-1,4-DACH)] (2), a Pt(IV) derivative of kiteplatin, which could be characterized by high bone tropism (due to the pyrophosphate ligand), enough stability to be administered orally, and activatable at the tumor site where the strong reduction conditions can promote its reduction to the corresponding Pt(II) counterpart with known cytotoxic activity. The new complex was characterized by ESI-MS, multinuclear NMR, X-Ray photoelectron spectroscopy (XPS), and cyclic voltammetry (CV). 2 is very soluble in aqueous environment, very stable at physiological pH and quite stable also in acidic conditions with the possibility of oral administration. The in vitro cytotoxicity assays, performed against a panel of four human cancer cell lines, have shown that complex 2 has a cytotoxic activity comparable to that of cisplatin and slightly lower than that of kiteplatin and the pyrophosphate Pt(II) precursor. This behavior can be attributed to its reduced ability to enter cancer cells. However, the cytotoxic activity of 2 is very promising considering that generally Pt(IV) complexes have IC50 values greater than those of the Pt(II) counterparts.

The compounds [Pt(Me(2)phen)(acy)(2)](NO(3))(2) (1), [Pt(Me(2)phen)(pen)(2)](NO(3))(2), [Pt(phen)(acy)(2)](NO(3))(2) (2), and [Pt(phen)(pen)(2)](NO(3))(2), containing the bidentate 1,10-phenanthroline (phen) or 2,9-dimethyl-1,10-phenanthroline (Me(2)phen, neocuproine) and the antiviral agents acyclovir (acy) or penciclovir (pen), show different in vitro toxicity, the Me(2)phen complexes being appreciably more toxic than the phen complexes. To explain the different behavior, we investigated the reaction of complexes 1 and 2 with glutathione (gamma-glutamylcysteinylglycine, GSH), a peptide believed to play an important role in driving the cellular effects of platinum drugs. The reaction led to different products, the phen complexes forming a stable binuclear mu-thiol-bridged species still containing the phenanthroline and the Me(2)phen complexes releasing the neocuproine ligand and forming an insoluble material. In vitro tests confirmed that the greater cell toxicity of complex 1 is due to the displacement of the neocuproine ligand by GSH. The results highlight the great dependence of the glutathione reactivity upon relatively small changes in the platinum coordination sphere.

A method is proposed for the direct measurement of the π-acidity of ligands coordinated to a metal center. The four-coordinate complex [PtI2(Me2-phen)] (Me2-phen = 2,9-dimethyl-1,10-phenanthroline) is unique since it behaves as a molecular trap and, in the presence of a nucleophile (L), one end of it dissociates to allow the L ligand to coordinate trans to the monocoordinated diamine. The coordination of the free end of the phenanthroline is impeded by the filled d orbitals of the metal lying in the same plane as the phenanthroline (dyz and d electrons assuming as x-axis that of the I−Pt−I vector). However, if the L ligand is a π-acid able to remove electron charge from the yz plane, the second end of the phenanthroline will also be able to interact with platinum. A linear correlation is found between the crystallographic N−Pt−L angle (180° in ideal square-planar species and 143° in a trigonal bipyramid with a bite angle for bidentate Me2-phen of 74°) and the π-acceptor capacity of the L ligand as estimated by ab initio calculations. Alkenes and alkynes are found to be among the best π-acids and lead to a regular trigonal-bipyramidal five-coordinate species. CO appears to be only halfway in between the best π-acceptor ligands and those with smallest π-acidity. P-, S-, and N-donor ligands follow in that order without significant differences between sulfides and sulfoxides or between aliphatic amines and pyridine. The very small difference between aliphatic amines and pyridine has been confirmed by investigation of the rate of exchange between the two ends for monocoordinated phenanthroline by 1H NMR spectroscopy. The activation energy (ΔG‡) was found to be equal, within the experimental error, for the two types of trans ligands. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)