Domenico Osella

On the mechanism of the antitumor activity of ferrocenium derivatives

Abstract Contradictory results exist in the literature about the antineoplastic activity of ferrocenes and their ferrocenium salts; additionally, little is known about the mechanism by which such drugs become active towards cancer cells. In the present paper we show that only ferrocenium species are able to inhibit the growth of Ehrlich ascites tumor cells in vivo and we propose that the cytotoxic activity of ferrocenium salts is not based on their direct linking to DNA, but on their ability to generate oxygen active species which induce oxidative DNA damage.

ELECTRONIC INTERACTIONS IN ORGANOMETALLIC DIMERS. AN ELECTROCHEMICAL APPROACH

Abstract A simple electrochemical criterion is employed for an approximate evaluation of the electronic interaction between redox centres in π-conjugated organometallic dimers. This approach allows one to predict the results of the use of such organometallic complexes (and related polymers) as precursors of mixed-valence compounds (in solution) and low-dimensional conducting or non-linear optical materials (in the solid state). Chemical complications following the redox processes often alter the electrochemical response. In such cases, this approach is only useful if the experimental conditions (measurements at high scan rates or sub-ambient temperatures) are chosen carefully.

Radical scavenging abilities of fish MT-A and mussel MT-10 metallothionein isoforms: An ESR study

Metallothioneins (MTs) are cysteine-rich proteins involved in homeostasis of essential metals, detoxification of toxic metals and scavenging of free radicals. Scavenging of the stable 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical was measured by means of ESR spectroscopy for two recombinant MTs from aquatic species: MT-10 from the sea mussel Mytilus galloprovincialis, and MT-A from the fish Oncorhyncus mykiss. Both the zinc- and the cadmium-loaded forms (Zn(7)-MTs and Cd(7)-MTs) were analysed, using the commercial MT-II (Zn(7)-MT-II and Cd(7)-MT-II, respectively) from rabbit liver as a reference. A decrease in the scavenging ability was observed for all the three MTs passing from the Zn- to the Cd-loaded forms, because of the higher stability of the Cd-mercapto complex. The Zn(7)-MTs from aquatic species were more effective in scavenging DPPH signal than the rabbit Zn(7)-MT-II (2.8 and 4-folds, respectively). Similar results were obtained also for the Cd(7)-MTs, thus confirming the stronger antioxidant power of MTs from aquatic organisms compared with the rabbit MT-II. Moreover, mussel MT-10 was more active in DPPH scavenging than fish MT-A. When the complete release of metals from MTs was obtained by lowering the pH to 3 or, alternatively, by adding the chelating agent diethylenetriaminepentaacetic acid (DTPA), an increase in the scavenging ability of MTs was observed.

Revisiting [PtCl2(cis-1,4-DACH)]: An Underestimated Antitumor Drug with Potential Application to the Treatment of Oxaliplatin-Refractory Colorectal Cancer

Although the encouraging antitumor activity of [PtCl(2)(cis-1,4-DACH)] (1; DACH = diaminocyclohexane) was shown in early studies almost 20 years ago, the compound has remained nearly neglected. In contrast, oxaliplatin, containing the isomeric 1(R),2(R)-DACH carrier ligand, enjoys worldwide clinic application as a most important therapeutic agent in the treatment of colorectal cancer. By extending the investigation to human chemotherapy-resistant cancer cells, we have demonstrated the real effectiveness of 1 in circumventing cisplatin and oxaliplatin resistance in LoVo colon cancer cells. The uptake of compound 1 by the latter cells was similar to that of sensitive LoVo cells. This is not the case for all other compounds considered in this investigation. Interaction with double-stranded DNA, investigated by a biosensor assay and by quantum mechanical/molecular mechanical geometry optimization of the 1,2-GG intrastrand cross-link, does not show significant differences between 1 and oxaliplatin. However, the DNA adducts of 1 are removed from repair systems with lower efficiency and are more effective in inhibiting DNA and RNA polymerase.

Electrochemical biosensor evaluation of the interaction between DNA and metallo-drugs

Electrochemical techniques were used to study the interaction between a panel of antiproliferative metallo-drugs and double-stranded DNA immobilized on screen-printed electrodes as a model of the analogous interaction occurring in solution. The propensity of a given metal drug to interact with DNA was measured as a function of the decrease of guanine oxidation signal, which was detected by square wave voltammetry. Estimates of variations in experimental parameters, such as the concentration of complexes, time following dissolution (ageing time) and the presence of chloride, are provided.

Isomerisation of pentenes with H4Ru4(CO)12

Abstract Catalytic isomerisation of 1-pentene to 2- cis and 2- trans -pentene with H 4 Ru 4 (CO) 12 in toluene at 70.4 °C is described. Carbon monoxide, hydrogen, weak acids and polar substances, such as ethyl acetate, decrease the isomerisation rate. Reactions of H 4 Ru 4 (CO) 12 with trans -C 2 H 2 D 2 and [1,2-D 2 ] 1-pentene and of D 4 Ru 4 (CO) 12 with 1-pentene suggest the operation of a metal-hydride addition-elimination mechanism involving σ-alkyl intermediates. The active species is supposed to be mainly originated by loss of CO to give H 4 Ru 4 (CO) 11 . Catalytic hydrogenation of the pentene isomers occurs at the approaching of the equilibrium and is largerly enhanced by addition of hydrogen to the reaction system.

Synthesis and characterisation of bis(ferrocenylethynyl) complexes of platinum (II) A re-investigation of their electrochemical behaviour

Abstract We describe herein the synthesis and the electrochemical behaviour of a series of bis(ferrocenylethynyl) complexes of platinum(II). In all complexes, the electronic interaction between the redox-active iron cores of the ferrocenyl termini is small, indicating a moderate electronic delocalisation over the bis(cyclopentadienyl-acetylide)Pt chain.

Relationships between structure and ligand dynamics: II. Alkyne and carbonyl dynamics in Os3(CO)9(alkyne)(L) (L = CO, PR3)

Abstract The synthesis of the phosphine substituted complexes Os3(CO)9(μ3-η2-CH3CH2-CCCH2CH3)L (L = P(C6H5)3 (III), P(CH3)3 (IV)) and Os3(CO)9(μ3-η2-CH3CCCH3)L (L = P(OCH3)3 (V)) are reported. A detailed analysis of the VT-1H and VT-13C NMR of these complexes is presented and compared with the same studies on the parent complexes Os3(CO)9(μ3-η2-RCCR)(μ-CO) (R = CH2CH3 (I), CH3 (II)). In the parent complexes I and II a two stage exchange process is observed: (1) a low energy process involving axial radial exchange at the carbonyl bridged osmium atoms, (2) a higher energy exchange process in which alkyne motion over the face of the metal triangle is coupled with bridge-terminal exchange of the carbonyls, and with axialradial exchange at the unique osmium atom. The phosphine derivatives III–V, all show a three stage exchange process: (1) a localized axial-radial exchange at the unsubstituted osmium atoms; (2) a semibridging terminal carbonyl exchange at the phosphine substituted osmium coupled with a restricted oscillation of the alkyne, pivoted on this osmium atom; (3) free motion of the alkyne and averaging of all the carbonyl groups. The relationship between the differences in the observed dynamic processes are understood by a comparison of the solid state structures of I and III which are also reported. Compound I crystallizes in the triclinic space group P 1 , with unit cell parameters a 9.292(2), b 15.340(3), c 8.391(2) A, α 91.27(2), β 116.70 (1), γ 105.24(2)°, V 1017.3(4) A3, and Z = 2. Compound III belongs to the monoclinic space group P21/c, with a 14.271(4), b 11.370(2), c 21.192(5) A, β 104.43(2)3, V 3330(1) A3, and Z = 4. The structures were refined by full matrix least squares to RF = 0.044, RwF = 0.058 for I, and RF = 0.033, RwF = 0.041 for III, respectively.

Molecular and statistical modeling of reduction peak potential and lipophilicity of platinum(IV) complexes.

We report the results of the quantitative structure–property relationship analysis of 31 Pt(IV) complexes, for three of which the synthesis is reported for the first time. The X-ray structural analysis of one complex of the series was performed to demonstrate that the PM6 semiempirical method satisfactorily reproduces key features of the geometry of the complexes investigated. Molecular properties extracted from such calculations were then used to construct models of experimental data such as electrochemical peak potentials (evaluated by cyclic voltammetry) and the octanol–water partition coefficient (evaluated by a reversed-phase high performance liquid chromatography method), which are key aspects in the design of such Pt(IV) complexes as potential anticancer prodrugs. Statistically accurate models for both properties were found using combinations of surface areas, orbital energies, dipole moments, and atomic partial charges. These models could form the basis of virtual screening of potential drug molecules, allowing the prediction of properties, closely related to the antiproliferative activity of Pt(IV) complexes, directly from calculated data.

ELECTRONIC INTERACTIONS IN DIYNE CO2(CO)6 COMPLEXES

Abstract Electrochemical criteria are used to evaluate the electronic interaction between redox centres in the π-conjugated diyne complexes {RCC[Co 2 (CO) 6 ]CC[Co 2 (CO) 6 ]R} and {RCC[Co 2 (CO) 6 ](S)C[Co 2 (CO) 6 ]} (RPh, Fc) where the aromatic spacer S is phenyl, napthalene or anthracene. Voltammetry at microelectrode, differential pulse techniques and low temperature measurements are used to obviate the chemical complications following the primary redox process. A mechanism is proposed which successfully simulates the electrochemical data.