Ruthenocenyl Derivatives Research Articles

Metallocenyl derivatives of ebselen are selective and competitive inhibitors of thioredoxin reductase

Ferrocenyl and ruthenocenyl derivatives of ebselen are found to be competitive inhibitors of mammalian TrxR, with IC50 of 4.2 ± 0.3 and 2.5 ± 0.3 µM, respectively. The inhibition of TrxR is selective over GR, and in the presence of excess GSH. They exhibit lower Km values than ebselen and the natural substrate, Trx.

Synthesis, characterization and antiparasitic activity of organometallic derivatives of the anthelmintic drug albendazole.

Helminthiases, a group of neglected tropical diseases, affect more than one billion people mainly in tropical and subtropical regions. Moreover, major intestinal protozoa have a significant impact on global public health. Albendazole (ABZ) is a broad-spectrum anthelmintic recommended by the World Health Organisation (WHO). However, drug resistance is emerging due to its widespread use. In order to tackle this problem, taking into account the spectacular results obtained with ferroquine, an organometallic derivatization of the antimalarial drug chloroquine, we have prepared, in this study, a series of new ferrocenyl and ruthenocenyl derivatives of the organic drug ABZ and assessed their activity against different helminths and protozoans, namely Trichuris muris, Heligmosomoides polygygrus, Schistosoma mansoni, Giardia lamblia, Haemonchus contortus and Toxoplasma gondii. The ferrocene-containing ABZ analogue 2d exhibited over 70% activity against T. muris adults in vitro at 200 μM and no toxicity to mammalian cells (IC50 >100 μM). H. polygyrus adults were not affected by any of the derivatives tested. Against T. gondii, the ferrocene-containing ABZ analogues 1a and 2d showed better in vitro activity than ABZ and low toxicity to the host cells. The activity of the analogous ruthenocenyl compound 2b against S. mansoni and T. gondii in vitro might be attributed to its toxicity towards the host cells rather than a specific antiparasitic activity. These results demonstrate that the derivatives show a species specific in vitro activity and the choice of the organometallic moieties attached to the organic drug is playing a very important role. Two of our organometallic compounds, namely 1b and 2d, were tested in T. muris infected mice. At a 400 mg kg-1 dose, the compounds showed moderate worm burden reductions but low worm expulsion rates. Overall, this work, which is one of the first studies reporting the potential of organometallic compounds on a very broad range of parasitic helminths and protozoan, is a clear confirmation of the potential of organometallic complexes against parasites of medical and veterinary importance.

Metallocenyl-containing and Unsaturated Fulleropyrrolidine Derivatives: Synthesis and Hydrogenation

The possibility of Pd/C-catalyzed hydrogenation of ferrocenyl, cymantrenyl, and ruthenocenyl derivatives of N-methyl-2-(3-chlorovinyl)fulleropyrrolidine and N-methyl-2-(2-styryl)fulleropyrrolidine with hydrogen was elucidated. A new compound, N-methyl-2-(3-chlorovinyl-3-ruthenocenyl)fulleropyrrolidine, was synthesized.

Synthesis, characterization and biological activity of organometallic derivatives of the antimalarial drug mefloquine as new antischistosomal drug candidates.

We present the design, synthesis, characterization and biological evaluation of new ferrocenyl and ruthenocenyl derivatives of the organic antimalarial mefloquine, a drug also known for its antischistosomal activity. The two metallocenyl derivatives prepared (3 and 4) demonstrated comparable activity to mefloquine against adult-stage Schistosoma mansoni in vitro. Importantly, both compounds were found to have lower toxicity in all cell lines than mefloquine itself. Administration of a 200 mg kg-1 oral dose of 3 and 4 to S. mansoni-infected mice did not significantly reduce worm burden, contrary to mefloquine.

Assessment of the nematocidal activity of metallocenyl analogues of monepantel

In this study, we present the design, synthesis, characterization and biological evaluation of structurally new ferrocenyl and ruthenocenyl derivatives of the organic anthelmintic monepantel (Zolvix®). All seven metallocenyl derivatives prepared (4a/b, 5a/b, 6a/b and 7) were isolated as racemates and characterized by 1H, 13C and 19F NMR spectroscopies, mass spectrometry, IR spectroscopy and elemental microanalysis. The molecular structures of four compounds (4a/b, 6a and 7) were further confirmed by X-ray crystallography. The biological activities of the organometallic intermediates (4a/b) and organometallic derivatives of monepantel (5a/b, 6a/b and 7) were evaluated in vitro using parasitic nematodes of major importance in livestock, namely Haemonchus contortus and Trichostrongylus colubriformis. Two ferrocenyl compounds (4a and 6a) showed nematocidal activity, while the analogous ruthenocenyl compounds (4b and 6b) were not active at the highest concentration tested (10 μg mL-1). In order to obtain insight into the difference in activity between ferrocenyl and ruthenocenyl derivatives, the potential of the compounds for reactive oxidative species (ROS) production in live cells was assessed. Interestingly, neither the ferrocenyl nor the ruthenocenyl compounds (4a/b and 6a/b) produced significant ROS in HeLa cells when checked after 22 h, potentially indicating a redox-independent activity of 4a and 6a on the parasites. The selectivity of the compounds on parasites was confirmed by investigating their cytotoxicity profiles. None of these compounds was toxic either to HeLa or MRC-5 cells. Thus, 4a and 6a could be considered as interesting leads for further development of new classes of anti-parasitic agents.

Synthesis, crystal structure and comparative electrochemistry of metallocenyldiphenylphosphines of ruthenocene, osmocene, ferrocene and cobaltocenium hexafluorophosphate

The metallocenyldiphenylphosphines [M(C5H5)(C5H4PPh2)] with M = Fe(II) (ferrocenyl = Fc), 1, Ru(II) (ruthenocenyl = Rc), 2, Os(II) (osmocenyl = Oc), 3, and Co(III)+PF6− (cobaltocenium hexafluorophosphate = [Cc][PF6]), 4, were synthesized and the crystal structure of RcPPh2, 2, (Z = 4, monoclinic, space group P21/c) was determined. The differences in reactivity of each metallocenyl derivative were such that 1 could be obtained from a Friedel Crafts reaction between ferrocene and PPh2Cl in the presence of AlCl3 as catalyst. Both the ruthenocene and osmocene derivatives 2 and 3 were obtained by reacting the monolithiated metallocene precursor with PPh2Cl. However, monolithiation of ruthenocene had to be achieved via a stoichiometric amount of tBuLi. For osmocene, monolithiation was achieved by a 20% excess of nBuLi. This was evidenced by the failure to isolate any bisphosphine, Oc(PPh2)2, during workup. Complex 4 could not be obtained via phosphination of free cobaltocenium hexafluorophosphate. Phosphine derivatisation of free cyclopentadiene prior to complexation with CoIII was required to form [CcPPh2][PF6], 4. The electrochemistry of all phosphines was studied by voltammetric techniques in CH2Cl2/0.1 mol dm−3 [N(nBu)4][B(C6F5)4]. A reversible one-electron transfer process for the ferrocenyl group of 1 was observed at 0.078 V vs. FcH/FcH+. The osmocenyl and ruthenocenyl derivatives exhibited irreversible metallocenyl oxidations at 0.355 and 0.476 V respectively. The cobaltocenium complex, 4, exhibited two reversible one-electron transfer reductions to liberate first a neutral CoII cobaltocene species at −1.062 V and then an anionic CoI cobaltocene species at −2.122 V. A single electrochemical irreversible, one-electron oxidation at the phosphorus centre which forms a quickly-decomposing phosphorus radical cation, Mc+Ph2P+, was also observed at Epa > 0.754 V. The newly-formed Mc+Ph2P+ species or its chemical decomposition products can be oxidized at Epa > 1.090 V vs. FcH/FcH+.

Inhibition of carbonic anhydrase isozymes I, II and IX with benzenesulfonamides containing an organometallic moiety

A novel series of benzenesulfonamides that contain ferrocenyl or ruthenocenyl moieties were synthesized and investigated for their ability to inhibit the enzymatic activity of physiologically relevant carbonic anhydrase (CA) isozymes: hCA I, II and tumour-associated IX (h = human). This manuscript describes the regioselective synthesis of both the 1,4- and 1,5-disubstituted-1,2,3-triazole benzenesulfonamides from ethynylmetallocene substrates. This is the first report describing the covalent attachment of organometallic moieties to the arylsulfonamide (ArSO 2NH 2) CA recognition pharmacophore. At hCA I these metallocene derivatives were either nanomolar or low micromolar inhibitors, while against hCA II and IX inhibition in the range of 9.7–80 nM and 10.3–85 nM, respectively, was observed. The ruthenocenyl derivatives gave superior CA inhibition compared to the ferrocenyl compounds across all three CA isozymes. These compounds constitute a new organometallic class of CA inhibitors with promising biological activity.

Second Harmonic Generation and Two-Photon Fluorescence as Nonlinear Optical Properties of Dipolar Mononuclear Sesquifulvalene Complexes

In order to investigate nonlinear optical properties, in particular second harmonic generation (SHG) of organometallic complexes, numerous dipolar monocationic sesquifulvalene complexes of the general form [Mc–Z–C7H6]+ have been synthesised (Mc = metallocenyl), wherein the metallocenyl moiety Mc acts as an electron donor, and the tropylium cation C7H6+ as an electron acceptor. The mutual electronic influence of the donor and the acceptor groups is warranted by a linking spacer Z, which is a single bond [Mc = CpFeC5H4 (4a); Mc = CpRuC5H4 (4b)], an unsaturated bridge containing olefins [Z = (E-CHCH)n: n = 1, Mc = CpFeC5H4 (25a), Mc = CpRuC5H4 (25b); n = 2, Mc = CpFeC5H4 (26); n = 3, Mc = CpFeC5H4 (27)], or thiophene units [Z = 2,5-C4H2S, Mc = CpFeC5H4 (28); Z = 5,5′-(2,2′-C4H2S)2, Mc = CpFeC5H4 (29); Z = 2-(5-E-CHCH)C4H2S, Mc = CpFeC5H4 (30)]. For the salts of 4a·BF4, 4b·PF6 and 25a·PF6 X-ray structure determinations have been performed [4a·BF4: orthorhombic, Pnma, = 21.75(2), b = 9.900(2), c = 6.881(3) A, V = 1482.0(15) A3, Z = 4; 4b·PF6: monoclinic, P2(1)/c, a = 8.104(3), b = 18.206(14), c = 11.228(4) A, β = 107.59(3), V = 1579.1(15) A3, Z = 4; 25a·PF6: triclinic, P1bar, a = 10.067(6), b = 10.496(6), c = 11.418(6) A, α = 94.07(4), β = 110.96(4), γ = 102.88(5)°, V = 1083.1(11) A3, Z = 2]; the solid state structures indicate an almost coplanar arrangement of the organic π-system. Cyclic voltammetry studies reveal an irreversible one-electron reduction and an electrochemically reversible one-electron oxidation step for the ferrocenyl derivatives, whereas the ruthenocenyl derivatives demonstrate an irreversible two-electron oxidation. The redox potentials clearly indicate that the oxidation occurs at the metallocene unit, and the reduction is localised on the tropylium entity. In the electronic absorption spectra two intense bands are observed in the region 400 < λ < 900 nm which undergo strong negative solvatochromic shifts. The origin of the high-energy absorption band is assumed to be an interligand charge-transfer (LL–CT) transition, and the low-energy absorption band is assigned to a donor-acceptor charge-transfer (DA–CT) transition. Whereas the LL–CT is continuously shifted to lower energy with increasing spacer length, the energy of the DA–CT approaches a limiting value. A comparable phenomenon is also observed for the difference between the oxidation and reduction potentials obtained from electrochemical studies. Investigations concerning the nonlinear optical properties of the dipolar cationic sesquifulvalene complexes by means of hyper-Rayleigh scattering (HRS) indicate that the ferrocenyl derivatives fluoresce due to two-photon absorption whereas the ruthenocenyl congeners exhibit second harmonic generation with considerably larger first hyperpolarizability which is partly resonance-enhancement based.

Comparing Chiral Ferrocenyl and Ruthenocenyl Ligands: How Subtle Structural Changes Influence Their Performance in Asymmetric Catalysis

A route to enantiopure heteroleptic ruthenocenyl derivatives has been found; the diastereoselective addition of MeLi to (R)-CyCH(Me)N(Me)CHC5H4 (de = 74%), followed by a transmetalation reaction with either [Cp*Ru(μ3-Cl)]4 or [(p-cymene)RuCl2]2/KPF6, afforded the heteroleptic complexes (S,R)-[Cp*Ru(η5-C5H4CH(Me)N(Me)CH(Me)Cy)], 6, or (S,R)-[(p-cymene)Ru(η5-C5H4CH(Me)N(Me)CH(Me)Cy)]+PF6-, 5, in 93% and 72% yields, respectively. Whereas 5 displayed a somewhat inert behavior, 6 reacted with NHMe2, in acetic acid, to afford its dimethylamino congener (S)-7 in 93% yield. The latter was converted in two steps into the bis(phosphine) derivatives (S)-(R)-Cp*RuC5H3CH(Me)PCy2PPh2-2, (S)-(R)-9, and (S)-(R)-Cp*RuC5H3CH(Me)PC8H14PPh2-2, (S)-(R)-10, and into the P,N derivative (S)-(R)-Cp*RuC5H3CH(Me){N2C3HMe2-3,5)PPh2}-1,2, (S)-(R)-11. These products were obtained in >99% ee after recrystallization. The ruthenocenyl derivatives were probed for their use as chiral ligands for the palladium-catalyzed enantioselective allylic alkylation and the rhodium catalyzed hydroboration reactions. By employing the ruthenocenylpyrazole (S)-(R)-11, styrene was converted to (S)-1-phenylethanol with 87% ee, whereas its isostructural ferrocenyl congener (S)-(R)-16 afforded 94% ee. The following compounds were characterized by X-ray diffraction: (S,R)-5, (S)-(R)-9, (S)-(R)-10, [((S*)-(R*)-14)Pd(η3-C3H5)]+[OTf]- ((S*)-(R*)-12), and [((S*)-(R*)-9)Pd(η3-C3H5)]+[OTf]- ((S*)-(R*)-13).