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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.

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.

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)

The effect of bridging with an ethylene chain the two aminic nitrogens cis -coordinated to the metal in a platinum-dichloro-diamine complex has been examined by studying forward mutagenesis in strains of Salmonella typhimurium carrying hisG46 and hisD3052 mutations and differing at the uvrB locus. While the complexes with the monodentate amines NH 3 and α-methylbenzylamine (mba) exhibit strong mutagenic activity, the corresponding species with chelating diamines, 1,2-diaminoethane (en) and N,N ′-bis(α-methylbenzyl)1,2-diaminoethane (mben), show much weaker activity. Moreover, the latter complexes appear to be more active via ‘frame shift’ than ‘base substitution’ mechanisms and do not differentiate appreciably between cells differing in the rfa locus. Complexes with amines bearing alkyl substituents of opposite chirality ( R -mba and S -mba, R,R -mben and S,S -mben) were tested separately and appeared to have comparable activity.