Concepción de Haro

Novel bis-C,N-cyclometalated iridium(III) thiosemicarbazide antitumor complexes: interactions with human serum albumin and DNA, and inhibition of cathepsin B.

A series of new organoiridium(III) complexes [Ir(N-C)(2)(N-S)]Cl (HN-C = 2-phenylpyridine (Hppy), N-S = methyl thiosemicarbazide (1), phenyl thiosemicarbazide (2) and naphtyl thiosemicarbazide (3)) have been synthesized and characterized. The crystal structure of (1) has been established by X-ray diffraction, showing the thiosemicarbazide ligand bound to the iridium atom as N,S-chelate. The cytotoxicity studies show that they are more active than cisplatin (about 5-fold) in T47D (breast cancer) at 48 h incubation time. On the other hand, very low resistance factors (RF) of 1-3 in A2780cisR (cisplatin-resistant ovarian carcinoma) at 48 h were observed (RF ≈ 1). Ir accumulation in T47D cell line after 48 h continuous exposure for complexes 1-3 are higher than that corresponding to cisplatin (about 10 times). The complexes 1-3 bind strongly to HSA with binding constants of about 10(4) M(-1) at 296 K, binding occurring at the warfarin site I for 2. Complexes 2 and 3 are also capable of binding in the minor groove of DNA as shown by Hoechst 33258 displacement experiments. Furthermore, complex 2 is also a good cathepsin B inhibitor (an enzyme implicated in a number of cancer related events), being the enzyme reactivated by cysteine.

Synthesis and Antiproliferative Activity of a C,N-Cycloplatinated(II) Complex with a Potentially Intercalative Anthraquinone Pendant

The synthesis of the novel anthraquinone platinum derivate [Pt(ppy)Cl(1C3)] (2) [Hppy = N,C-chelating 2-phenylpyridine; 1C3 = 1-[(3-aminopropyl)amino]-anthracene-9,10-dione] and its values of IC(50) against a panel of human tumor cell lines representative of ovarian (A2780 and A2780cisR) and breast cancers (T47D) are reported. At 24 h incubation time, complex 2 was more active than cisplatin (about 9-fold) and the free ligand 1C3 (about 2-fold) in T47-D. The observation that the cisplatin IC(50) falls by about 10-fold from 24 to 72 h, whereas that for 2 changes little, suggests substantial differences in the mode of action. Complex 2 also showed high cytotoxicity against A2780 (about 3-fold greater than cisplatin at 24 h). On the other hand, very low resistance factors (RF) of 2 in A2780cisR at 24-72 h (RF = 1.3) were observed. The interaction of 2 with DNA was followed by electrophoretic mobility and UV-visible spectroscopy, and its reaction with the model nucleobase 9-EtG was studied by (1)H NMR and ESI-MS. Theoretical calculations at the B3LYP/def2-TZVPP//BP86/def2-TZVP level of theory on complex 2 show a labile Pt-Cl bond that allows easy replacement of Cl by N-nucleophiles such as 9-EtG, which forms a stronger Pt-N bond.

New Dimetallic Palladium and Platinum Complexes Containing the Tetrakis(1-pyrazolyl)borate Ligand − Crystal Structures of [{(C6F5)2Pd}2(μ-pz)2B- (μ-pz)2]−, [{(C6F5)(tBuNC)Pd}2(μ-pz)2B(μ-pz)2]+ and [(C6F5)2Pd(μ-pz)2B(μ-pz)2Pd(η3-C4H7)]

New dimetallic palladium and platinum complexes containing the tetrakis(pyrazol-1-yl)borate ligand of the type [{(C6F5)2M}2(μ-pz)2B(μ-pz)2]− (M = Pd, Pt), [{(C6F5)(L)Pd}2(μ-pz)2B(μ-pz)2]+ (L = CNtBu, NCPh, PR3, AsR3) and [{(C6F5)(Cl)Pd}2(μ-pz)2B(μ-pz)2]− have been prepared using the benzonitrile complexes cis-[(C6F5)2M(NCPh)2] (M = Pd, Pt) or the halide bridged complexes [{(C6F5)LPd(μ-X)}2] (L = CNtBu, NCPh, PR3, AsR3, tht; X = Cl or Br), and [B(pz)4]− as starting materials. The monometallic [(C6F5)(tBuNC)Pd(μ-pz)2B(pz)2] and the asymmetric dinuclear [(C6F5)2Pd(μ-pz)2B(μ-pz)2Pd(η3-C4H7)] complexes have also been prepared. The crystal structures of [{(C6F5)2Pd}2(μ-pz)2B(μ-pz)2]−, [{(C6F5)(tBuNC)Pd}2(μ-pz)2B(μ-pz)2]+ and [(C6F5)2Pd(μ-pz)2B(μ-pz)2Pd(η3-C4H7)] have been established by X-ray diffraction. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

New Acridine Thiourea Gold(I) Anticancer Agents: Targeting the Nucleus and Inhibiting Vasculogenic Mimicry

Two new 1-acridin-9-yl-3-methylthiourea Au(I) DNA intercalators [Au(ACRTU)2]Cl (2) and [Au(ACRTU) (PPh3)]PF6 (3) have been prepared. Both complexes were highly active in the human ovarian carcinoma cisplatin-sensitive A2780 cell line, exhibiting IC50 values in the submicromolar range. Compounds 2 and 3 are also cytotoxic toward different phenotypes of breast cancer cell lines MDA-MB-231 (triple negative), SK-BR-3 (HER2+, ERα-, and ERβ-), and MCF-7 (ER+). Both complexes induce apoptosis through activation of caspase-3 in vitro. While inhibition of some proteins (thiol-containing enzymes) seems to be the main mechanism of action for cytotoxic gold complexes, 2 and 3 present a DNA-dependent mechanism of action. They locate in the cell nucleus according to confocal microscopy and transmission electronic microscopy. The binding to DNA resulted to be via intercalation as shown by spectroscopic methods and viscometry, exhibiting a dose-dependent response on topoisomerase I mediated DNA unwinding. In addition, 2 and 3 exhibit potent antiangiogenic effects and are also able to inhibit vasculogenic mimicry of highly invasive MDA-MB-231 cells.

Asymmetric homo- and hetero-bimetallic complexes of the nickel group elements. Crystal structure of [(C6F5)2Pd(µ-Cl)2Pt(PEt3)2]

By reaction between cis-[Pd(C6F5)2(PhCN)2] and cis-[MX2L2] in dichloromethane, the asymmetric homo- and hetero-bimetallic complexes [R2Pd(µ-X)2ML2] are formed (M = Ni, Pd or Pt; X = Cl, Br, I or SCN; R = C6F5 or C6H2F3-2,4,6; L = PEt3, PBu3, PPh2Me or C5H5N; L2= Ph2PCH2CH2PPh2). In chloroform solution all the gem derivatives are binuclear. The crystal structure of [(C6F5)2Pd(µ-Cl)2Pt(PEt3)2] has been solved and refined to R= 0.042 for 4241 observed reflections, confirming the existence of binuclear molecules where the Pd and Pt atoms have square-planar co-ordination [Pd–Cl 2.449(2) and 2.402(2) and Pt–Cl 2.430(2) and 2.386(2)A].

A route for the synthesis of novel asymmetric binuclear pentafluorophenyl derivatives of palladium(II)

Abstract Binuclear halogen-bridged complexes of the type (C5F5)2Pd(μ-Cl)2ML2 (M  Ni, Pd (L2  dpe), Pt (L  PEt3)] have been prepared by reaction of cis-Pd(C6F5)2(PhCN)2 with the corresponding halo complexes, MCl2L2, in dichloromethane, IR and NMR structural data are discussed.

Understanding the interaction of an antitumoral platinum(II) 7-azaindolate complex with proteins and DNA

AbstractThe reactivity of the [Pt(dmba)(aza-N1)(dmso)] complex 1, (a potential antitumoral drug with lower IC50 than cisplatin in several tumoral cell lines) with different proteins and oligonucleotides is investigated by means of mass spectrometry (ESI-TOF MS). The results obtained show a particular binding behaviour of this platinum(II) complex. The interaction of 1 with the assayed proteins apparently takes place by Pt-binding to the most accessible coordinating amino acids, presumably at the surface of the protein -this avoiding protein denaturation or degradation- with the subsequent release of one or two ligands of 1. The specific reactivity of 1 with distinct proteins allows to conclude that the substituted initial ligand (dmso or azaindolate) is indicative of the nature of the protein donor atom finally bound to the platinum(II) centre, i.e. N- or S-donor amino acid. Molecular modeling calculations suggest that the release of the azaindolate ligand is promoted by a proton transfer to the non-coordinating N present in the azaindolate ring, while the release of the dmso ligand is mainly favoured by the binding of a deprotonated Cys. The interaction of complex 1 with DNA takes always place through the release of the azaindolate ligand. Interestingly, the interaction of 1 with DNA only proceeds when the oligonucleotides are annealed forming a double strand. Complex 1 is also capable to displace ethidium bromide from DNA and it also weakly binds to DNA at the minor groove, as shown by Hoechst 33258 displacement experiments. Furthermore, complex 1 is also a good inhibitor of cathepsin B (an enzyme implicated in a number of cancer related events). Therefore, although compound 1 is definitely able to bind proteins that can hamper its arrival to the nuclear target, it should be taken into consideration as a putative anticancer drug due to its strong interaction with oligonucleotides and its effective inhibition of cat B. Graphical AbstractReactivity of a Pt complex: The interaction of a potential antitumoral drug, [Pt(dmba)(aza-N1)(dmso)], with distinct proteins and oligonucleotides has been studied by means of ESI-TOF MS. The particular reactivity of this complex in front of the assayed biomolecules required the use of spectroscopic techniques and theoretical calculations to elucidate its mechanism. This information will contribute to its consideration as a putative anticancer drug.

DFT Simulation of Structural and Optical Properties of 9-Aminoacridine Half-Sandwich Ru(II), Rh(III), and Ir(III) Antitumoral Complexes and Their Interaction with DNA

In this work, we use DFT-based methods to simulate the chemical structures, optical properties, and interaction with DNA of a recently synthesized chelated C^N 9-aminoacridine arene Ru(II) anticancer agent and two new closely related Rh(III) and Ir(III) complexes using DFT-based methods. Four chemical models and a number of theoretical approaches, which representatively include the PBE0, B97D, ωB97X, ωB97X-D, M06, and M06-L density functionals and the LANL2DZ, def2-SVP, and def2-TZVP basis sets, are tested. The best overall accuracy/cost performance for the optimization process is reached at the ωB97X-D/def2-SVP and M06/def2-SVP levels of theory. Inclusion of explicit solvent molecules (CHCl3) further refines the geometry, while taking into account the crystal network gives no significant improvements of the computed bond distances and angles. The analysis of the excited states reveals that the M06 level matches better the experimental absorption spectra, compared to ωB97X-D. The use of the M06/def2-SVP approach is therefore a well-balanced method to study theoretically the bioactivity of this type of antitumoral complexes, so we couple this TD-DFT approach to molecular dynamics simulations in order to assess their reactivity with DNA. The reported results demonstrate that these drugs could be used to inject electrons into DNA, which might broaden their applications in photoactivated chemotherapy and as new materials for DNA-based electrochemical nanodevices.