Marina Fiallo

Physicochemical studies of the iron(III)-carminomycin complex and evidence of the lack of stimulated superoxide production by NADH deydrogenase

Fe(III) complex of an antitumoral antibiotic carminomycin has been studied. Using potentiometric and spectroscopic measurements we have shown that carminomycin forms with Fe(III) a well-defined species in which three molecules of drug are chelated to one Fe(III) ion. This occurs with the release of one proton per molecule of drug. Magnetic susceptibility measurements suggest that six oxygen atoms are bound to iron. The stability constant is 3 X 10(34). The in vitro inhibition of P 388 leukemia cell growth by this complex compares with that of the free drug. This complex, unlike the free drug, does not catalyze the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase.

Mitomycin antitumor compounds. Part 1. CD studies on their molecular structure.

The UV-Vis and circular dichroism (CD) spectra of several mitomycin antitumor compounds and some of their derivatives were analyzed in order to attribute the proper assignment to their electronic transitions. The lowest energy pi-->pi* transition was found to depend on the effect of the auxochromic group in the aromatic ring, whereas the three n-->pi* transitions, present at around 240, 400 and 560 nm, are related to the C(9)==O of the carbamoyl group and to the C(8)==O and the C(5)==O of the quinone, respectively. The chirality of the C(9) is responsible for the sign of the Cotton effect (CE) at around 240 nm, whereas the substituents of the chromophore for mitosane derivatives and the conformation of the carbamoyloxymethyl group at C(9) determine the CE sign of the (1)A-->(1)L(b) transition. When the aziridine ring was opened and mitosenes derivatives were obtained, CD spectra did not differ significantly among the compounds and the bands associated to the different transitions had similar Cotton effect. Our findings suggest that the differences in the CD spectra, observed between mitosanes and mitosenes, are probably related to the more rigid molecular structure of the mitosene derivatives and the different conformations in solution of the C(9) side chain.

Impact of aluminium ions on adriamycin-type ligands

Potentiometric and spectroscopic measurements have shown that Al3+ ions form 1:1 complexes with adriamycin and its analogues. The major complex at pH > 5 is a tetrahedral species in which the metal ion is co-ordinated to the ligand via two anthracycline oxygens. Two OH– groups complete the co-ordination sphere. Although the complexes are comparatively stable the formation of [Al(OH)4]– at pH > 8.5 excludes adriamycin from the metal ion co-ordination sites. The unusual fluorometric behaviour of the drug molecule is also present in the complex formed at lower pH.

Reaction of elemental sulphur with cobalt(II)-Schiff-base complexes: synthesis of µ-disulphido and µ-tetrasulphido binuclear cobalt(III) complexes. Crystal structures of two binuclear cobalt(III)-Schiff-base complexes

Reaction of elemental sulphur with cobalt(II)–quadridentate Schiff-base complexes is reported. Elemental sulphur reacts with [Co(salphen)][salphen =NN′-o-phenylenebis(salicylideneiminate)],(1), [Co(salen)][salen =NN′-ethylenebis(salicylideneiminate)],(2), [Co{3,3′-(MeO)2-salen}], (3), and [Co(α,α′-Et2-salen)], (4), in co-ordinating solvents to afford binuclear, diamagnetic cobalt(III) complexes containing a tetrasulphido bridging ligand: [{Co(salphen)}2(µ-S4)L2][L = tetrahydrofuran (thf)(5) or pyridine (py)(6)]; [{Co(salen)}2(µ-S4)(thf)], (7); [{Co(salen)}2(µ-S4)(py)2], (8); [(Co)3,3′-(MeO)2-salen]}2(µ-S4)], (9); [{Co(α,α′-Et2-salen)}2(µ-S4)(thf)], (10). Substituents on the quadridentate ligand do not affect the nature of the final compound. Carrying out the reaction of (1) with elemental sulphur in thf containing NaBPh4 results in the formation of a completely different compound, which was isolated and structurally characterized as [{Co(salphen)}2S2Na(thf)2]BPh4, (11). This is a diamagnetic binuclear cobalt(III) complex, in which the two Co(salphen) units are bridged by the S22– ligand and by the Na+ which is bonded to all four oxygen atoms of the Schiff-base ligands [Co–S 2.231(7), 2.249(7); S–S 1.962(9)A]. Both the genesis and the stability of (11) are dependent on Na+. The complex [Co(salphen)] binds Na+ in a thf solution to form a binuclear complex, [{Co(salphen)}2Na(thf)2]BPh4, (12), the structure of which shows two Co(salphen) units arranged around Na+ creating a cavity between the two planar units for the S2 ligand. Attempts to remove Na+ from (11) by using 18-crown-6 ether resulted in decomposition of the Co–S2–Co fragment and the formation of (5) and (1). Complex (11) can transfer a single sulphur atom to [Fe(salen)] and PPh3, or the S2 unit to [V(η-C5Me5)2], resulting in formation of (12). Lithium, potassium, and guanidinium cations affect the reaction of [Co(salphen)] with elemental sulphur much less than the Na+. Crystallographic details for complex (11) are space group P(triclinic), a= 11.816(1), b= 15.949(2), c= 17.437(2)A, α=93.70(1), β= 93.90(1), γ= 94.86(1)°, Z= 2, R 0.059 (R′= 0.058) for 1 479 observed reflections; and for complex (12) are space group Pnna(orthorhombic), a= 20.223(4), b= 29.197(8), c= 20.204(4)A, Z= 8, and R 0.065 (R′= 0.069) for 1 516 observed reflections.

Analysis of Multidrug Transporter in Living Cells. Inhibition of P-glycoprotein-mediated Efflux of Anthracyclines by Ionophores.

One of the major obstacles of chemotherapy is that, after repeated treatments, cellular resistance to the drug appears. The problem is that the tumor cells become resistant not only to the drugs which have been used during the treatment but also to other drugs which are structurally and functionally unrelated. This is termed ‘multidrug resistance’ (MDR). MDR is frequently associated with decreased drug accumulation resulting from enhanced drug efflux. This is correlated with the presence of a membrane protein, P-glycoprotein, which pumps a wide variety of drugs out of cells thus reducing their toxicity. The search for molecules able to reverse MDR is very important. We here report that mobile ionophores such as valinomycin, nonactin, nigericin, monensin, calcimycin, lasalocid inhibit the efflux of anthracycline by P-glycoprotein whereas, channel-forming ionophores such as gramicidin do not. Cyclosporin which is also a strong Ca2+ chelating agent also inhibits the P-glycoprotein-mediated efflux of anthracycline.

Degradation of Anthracycline Antitumor Compounds Catalysed by Metal Ions

The influence of some metal ions on the degradation of anthracyclines was examined. One of the degradation products is the 7,8-dehydro-9,10-desacetyldoxorubicinone, D* (¥), usually formed by hydrolysis at slightly basic pH. D* is a lipophilic compound with no cytostatic properties. Its formation could be responsible for the lack of antitumor activity of the parent compound. The coordination of metal ions to anthracycline derivatives is required to have degradation products. Cations such as Na+, K+, or Ca2+ do not induce the D* formation however metals which can form stable complexes with doxorubicin afford D*. Iron(III) and copper(II) form appreciable amount of D* at slightly acidic pH. Terbium(III) forms D* but its complex is stable only at slightly basic pH. Palladium(II) which does not form D*. The influence of the coordination mode of metal ions to anthracycline on the D* formation is discussed.