Synthesis, characterization and cytotoxic activities of the [RuCl2(NO)(dppp)(L)]PF6 complexes.

The synthesis and characterization of ruthenium compounds of the type [RuCl(2)(NO)(dppp)(L)]PF(6) [dppp=1,3-bis(diphenylphosphino)propane; L=pyridine, 4-methylpyridine, 4-phenylpyridine and dimethyl sulfoxide] are described. The complexes were characterized by elemental analysis, UV/Vis and infrared spectroscopy, cyclic voltammetry, and X-ray crystallography for the complexes with the pyridine and 4-methylpyridine ligands. In vitro evaluation of these nitrosyl complexes revealed cytotoxic activity from 7.1 to 19.0 microM against the MDA-MB-231 breast tumor cells and showed that, in this case, they are more active than the reference metallodrug cisplatin. The 1,3-bis(diphenylphosphino)propane and the N-heterocyclic ligands alone failed to show cytotoxic activities at the concentrations tested (maximum concentration utilized=200 microM).

Slow-onset inhibition of 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis by an inorganic complex.

Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. The reemergence of tuberculosis as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, and the proliferation of multi-drug-resistant strains have created a need for the development of new antimycobacterial agents. Mycolic acids, the hallmark of mycobacteria, are high-molecular-weight alpha-alkyl, beta-hydroxy fatty acids, which appear mostly as bound esters in the mycobacterial cell wall. The product of the M. tuberculosis inhA structural gene (InhA) has been shown to be the primary target for isoniazid (INH), the most prescribed drug for active TB and prophylaxis. InhA was identified as an NADH-dependent enoyl-ACP reductase specific for long-chain enoyl thioesters. InhA is a member of the mycobacterial Type II fatty acid biosynthesis system, which elongates acyl fatty acid precursors of mycolic acids. Although the history of chemotherapeutic agent development demonstrates the remarkably successful tinkering of a few structural scaffolds, it also emphasizes the ongoing, cyclical need for innovation. The main focus of our contribution is on new data describing the rationale for the design of a pentacyano(isoniazid)ferrateII compound that requires no KatG-activation, its chemical characterization, in vitro activity studies against WT and INH-resistant I21V M. tuberculosis enoyl reductases, the slow-onset inhibition mechanism of WT InhA by the inorganic complex, and molecular modeling of its interaction with WT InhA. This inorganic complex represents a new class of lead compounds to the development of anti-tubercular agents aiming at inhibition of a validated target.

Electron transfer kinetics and mechanistic study of the thionicotinamide coordinated to the pentacyanoferrate(III)/(II) complexes: a model system for the in vitro activation of thioamides anti-tuberculosis drugs.

The mechanism of activation thioamide-pyridine anti-tuberculosis prodrugs is poorly described in the literature. It has recently been shown that ethionamide, an important component of second-line therapy for the treatment of multi-drug-resistant tuberculosis, is activated through an enzymatic electron transfer (ET) reaction. In an attempt to shed light on the activation of thioamide drugs, we have mimicked a redox process involving the thionicotinamide (thio) ligand, investigating its reactivity through coordination to the redox reversible [Fe(III/II)(CN)(5)(H(2)O)](2-/3-) metal center. The reaction of the Fe(III) complex with thionicotinamide leads to the ligand conversion to the 3-cyanopyridine species coordinated to a Fe(II) metal center. The rate constant, k(et)=10 s(-1), was determined for this intra-molecular ET reaction. A kinetic study for the cross-reaction of thionicotinamide and [Fe(CN)(6)](3-) was also carried out. The oxidation of thionicotinamide by [Fe(CN)(6)](3-) leads to formation of mainly 3-cyanopyridine and [Fe(CN)(6)](4-) with a k(et)=(5.38+/-0.03) M(-1)s(-1) at 25 degrees C, pH 12.0. The rate of this reaction is strongly dependent on pH due to an acid-base equilibrium related to the deprotonation of the R-SH functional group of the imidothiol form of thionicotinamide. The kinetic results reinforced the assignment of an intra-molecular mechanism for the ET reaction of [Fe(III)(CN)(5)(H(2)O)](2-) and the thioamide ligand. These results can be valuable for the design of new thiocarbonyl-containing drugs against resistant strains of Mycobacterium tuberculosis by a self-activating mechanism.

An inorganic iron complex that inhibits wild-type and an isoniazid-resistant mutant 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis.

The in vitro kinetics of inactivation of both wild-type and I21V InhA enzymes by [FeII(CN)5(INH)]3- indicate that this process requires no activation by KatG, and no need for the presence of NADH. This inorganic complex may represent a new class of lead compounds to the development of anti-tubercular agents aiming at inhibition of a validated target.

4,4'-dithiodipyridine as a bridging ligand in osmium and ruthenium complexes: the electron conductor ability of the -S-S- bridge.

The compounds [Ru(NH(3))(5)(dtdp)](TFMS)(3), [Os(NH(3))(5)(dtdp)](TFMS)(3), [(NH(3))(5)Os(dtdp)Os(NH(3))(5)](TFMS)(6), [(NH(3))(5)Os(dtdp)Ru(NH(3))(5)](TFMS)(3)(PF(6))(2), and [(NH(3))(5)Os(dtdp)Fe(CN)(5)] (dtdp = 4,4'-dithiodipyridine, TFMS = trifluoromethanesulfonate) have been synthesized and characterized by elemental analysis, cyclic voltammetry, electronic, vibrational, EPR, and (1)H NMR spectroscopies. Changes in the electronic and voltammetric spectra of the ion complex [Os(NH(3))(5)(dtdp)](3+) as a function of the solution pH enable us to calculate the pK(a) for the [Os(NH(3))(5)(dtdpH)](4+) and [Os(NH(3))(5)(dtdpH)](3+) acids as 3.5 and 5.5, respectively. The comparison of the above pK(a) data with that for the free ligand (pK(1) = 4.8) provides evidence for the -S-S- bridge efficiency as an electron conductor between the two pyridine rings. The symmetric complex, [(NH(3))(5)Os(dtdp)Os(NH(3))(5)](6+), is found to exist in two geometric forms, and the most abundant form (most probably trans) has a strong conductivity through the -S-S- bridge, as is shown by EPR, which finds it to have an S = 1 spin state with a spin-spin interaction parameter of 150-200 G both in the solid sate and in frozen solution. Further the NMR of the same complex shows a large displacement of unpaired spin into the pi orbitals of the dttp ligand relative to that found in [Os(NH(3))(5)(dtdp)](3+). The comproportionation constant, K(c) = 2.0 x 10(5), for the equilibrium equation [Os(II)Os(II)] + [Os(III)Os(III)] right harpoon over left harpoon 2[Os(II)Os(III)] and the near-infrared band energy for the mixed-valence species (MMCT), [(NH(3))(5)Os(dtdp)Os(NH(3))(5)](5+) (lambda(MMCT) = 1665 nm, epsilon = 3.5 x 10(3) M(-)(1) cm(-)(1), deltanu(1/2) = 3.7 x 10(3) cm(-)(1), alpha = 0.13, and H(AB) = 7.8 x 10(2) cm(-)(1)), are quite indicative of strong electron delocalization between the two osmium centers. The electrochemical and spectroscopic data for the unsymmetrical binuclear complexes [(NH(3))(5)Os(III)(dtdp)Ru(II)(NH(3))(5)](5+) (lambda(MMCT) = 965 nm, epsilon = 2.2 x 10(2) M(-)(1) cm(-)(1), deltanu(1/2) = 3.0 x 10(3) cm(-)(1), and H(AB) = 2.2 x 10(2) cm(-)(1)) and [(NH(3))(5)Os(III)(dtdp)Fe(II)(CN)(5)] (lambda(MMCT) = 790 nm, epsilon = 7.5 x 10 M(-)(1) cm(-)(1), deltanu(1/2) = 5.4 x 10(3) cm(-)(1), and H(AB) = 2.0 x 10(2) cm(-)(1)) also suggest a considerable electron delocalization through the S-S bridge. As indicated by a comparison of K(c) and energy of the MMCT process in the iron, ruthenium, and osmium complexes, the electron delocalization between the two metal centers increases in the following order: Fe < Ru < Os.