Heterometallic titanium-gold complexes inhibit renal cancer cells and .

Following recent work on heterometallic titanocene-gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = S-CH-COO) bound to gold(I)-phosphane fragments through a thiolate group ([(-CH)TiMe(-mba)Au(PR)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest.

Titanocene-Gold Complexes Containing N-Heterocyclic Carbene Ligands Inhibit Growth of Prostate, Renal, and Colon Cancers in Vitro.

We report on the synthesis, characterization, and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = -OC(O)--CH-S-) bound to gold(I)-N-heterocyclic carbene fragments through the thiolate group: [(η-CH)TiMe(μ-mba)Au(NHC)]. The cytotoxicities of the heterometallic compounds along with those of novel monometallic gold-N-heterocyclic carbene precursors [(NHC)Au(mbaH)] have been evaluated against renal, prostate, colon, and breast cancer cell lines. The highest activity and selectivity and a synergistic effect of the resulting heterometallic species was found for the prostate and colon cancer cell lines.

Pyrazole and Pyrazolate as Ligands in the Synthesis and Stabilization of New Palladium(II) and (III) Compounds.

The versatility of pyrazole/pyrazolate as ligands has allowed the synthesis and the structural characterization of four different types of new orthometalated palladium compounds, for which DFT calculations have been performed in order to investigate their relative stabilities. [Pd2{μ-(C6H4)PPh2}2{μ-(R,R'2pz)}2] (R = R' = H, 2a; R = Br, R' = H, 2b; R = CH3, R' = H, 2c; R = H, R' = CH3, 2d; R = Br, R' = CH3, 2e) compounds with exo-bidentate pyrazolatos are the first paddlewheel dinuclear palladium(II) compounds with pyrazolato bridging ligands described and characterized in the literature. In the process of the synthesis of 2a, a new tetranuclear intermediate compound, [Pd4{μ-(C6H4)PPh2}4(μ-pz)2(μ-OH)2] (3a), has been isolated and structurally characterized.

Versatile synthesis of cationic N-heterocyclic carbene-gold(i) complexes containing a second ancillary ligand. Design of heterobimetallic ruthenium-gold anticancer agents.

We describe a versatile and quick route to cationic gold(i) complexes containing N-heterocyclic carbenes and a second ancillary ligand (such as phosphanes, phosphites, arsines and amines) of interest for the synthesis of compounds with potential catalytic and medicinal applications. The general synthetic strategy has been applied in the preparation of novel cationic heterobimetallic ruthenium(ii)-gold(i) complexes that are highly cytotoxic to renal cancer Caki-1 and colon cancer HCT 116 cell lines while showing a synergistic effect and being more selective than their monometallic counterparts.

Organometallic Titanocene-Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties.

Early-late transition metal TiAu compounds [(η-CH)Ti{OC(O)CHPPhAuCl}] () and new [(η-CH)Ti{OC(O)-4-CHPPhAuCl}] () were evaluated as potential anticancer agents against renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and gold(I) [{HOC(O)RPPh}AuCl] (R = -CH- , -4-CH- ) derivatives in renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on renal cancer cell lines (for in the nanomolar range) was considerably higher than that of cisplatin and highly active titanocene Y.

In vitro and in vivo evaluation of water-soluble iminophosphorane ruthenium(II) compounds. A potential chemotherapeutic agent for triple negative breast cancer.

A series of organometallic ruthenium(II) complexes containing iminophosphorane ligands have been synthesized and characterized. Cationic compounds with chloride as counterion are soluble in water (70-100 mg/mL). Most compounds (especially highly water-soluble 2) are more cytotoxic to a number of human cancer cell lines than cisplatin.

Auranofin and related heterometallic gold(I)-thiolates as potent inhibitors of methicillin-resistant Staphylococcus aureus bacterial strains.

A series of new heterometallic gold(I) thiolates containing ferrocenyl-phoshines were synthesized. Their antimicrobial properties were studied and compared to that of FDA-approved drug, auranofin (Ridaura), prescribed for the treatment of rheumatoid arthritis. MIC in the order of one digit micromolar were found for most of the compounds against Gram-positive bacteria Staphylococcus aureus and CA MRSA strains US300 and US400.

Luminescent iminophosphorane gold, palladium and platinum complexes as potential anticancer agents.

A series of coordination gold(III), palladium(II), and platinum(II) complexes with a luminescent iminophosphorane ligand derived from 8-aminoquinoline [PhP=N-CHN] (), have been synthesized and structurally characterized. The coordination palladium(II) and platinum(II) compounds can evolve further, under appropriate conditions, to give stable cyclometalated species [M{κ-C,N,N-CH(PPh=N-8-CHN}Cl] (M = Pd, Pt) by C-H activation of the phenyl group of the PPh fragment. Iminophosphorane and the new metallic complexes are luminescent in DMSO or DMSO:HO (1:1 mixture) solutions at RT.

Further orthometalated dinuclear palladium(III) compounds with bridging N,S-donor ligands.

New dinuclear palladium(III) compounds of general formula Pd2[(C6H4)PPh2]2[N-S]2Cl2, N-S being 2-mercaptopyridinate, 3a; 2-mercapto-6-methylpyridinate, 3b; 2-quinolinethiolate, 3c; 2-mercaptopyrimidinate, 3d; 1-methyl-1H-imidazole-2-thiolate, 3e; 1-methyl-1H-benzimidazole-2-thiolate, 3f; 2-mercaptobenzothiazolate, 3g and 5-mercapto-1-methyltetrazolate, 3h have been obtained by oxidation with PhICl2 of the corresponding palladium(II) counterparts. The stability of the new compounds has been studied by (31)P NMR spectroscopy from 200 to 298 K. Compounds 3f-h were relatively stable until room temperature and they have been synthesized and characterized by (31)P, (1)H and (13)C NMR spectroscopy at 223 K.

Potential anticancer heterometallic Fe-Au and Fe-Pd agents: initial mechanistic insights.

A series of gold(III) and palladium(II) heterometallic complexes with new iminophosphorane ligands derived from ferrocenylphosphanes [{Cp-P(Ph2)═N-Ph}2Fe] (1), [{Cp-P(Ph2)═N-CH2-2-NC5H4}2Fe] (2), and [{Cp-P(Ph2)═N-CH2-2-NC5H4}Fe(Cp)] (3) have been synthesized and structurally characterized. Ligands 2 and 3 afford stable coordination complexes [AuCl2(3)]ClO4, [{AuCl2}2(2)](ClO4)2, [PdCl2(3)], and [{PdCl2}2(2)]. The complexes have been evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), in human breast cancer cells (MCF7) and in a nontumorigenic human embryonic kidney cell line (HEK-293T).

Organometallic Palladium Complexes with a Water-Soluble Iminophosphorane Ligand as Potential Anticancer Agents.

The synthesis and characterization of a new water-soluble iminophosphorane ligand TPA=N-C(O)-2BrC(6)H(4) (C,N-IM; TPA = 1,3,5-triaza-7-phosphaadamantane) 1 is reported. Oxidative addition of 1 to Pd(2)(dba)(3) affords the orthopalladated dimer [Pd(μ-Br){C(6)H(4)(C(O)N=TPA-kC,N)-2}](2) (2) as a mixture of cis and trans isomers (1:1 molar ratio) where the iminophosphorane moeity behaves as a C,N-pincer ligand. By addition of different neutral or monoanionic ligands to 2, the bridging bromide can be cleaved and a variety of hydrophilic or water-soluble mononuclear organometallic palladium(II) complexes of the type [Pd{C(6)H(4)(C(O)N=TPA-kC,N)-2}(L-L)] (L-L = acac (3); S(2)CNMe(2) (4); 4,7-Diphenyl-1,10-phenanthrolinedisulfonic acid disodium salt C(12)H(6)N(2)(C(6)H(4)SO(3)Na)(2) (5)); [Pd{C(6)H(4)(C(O)N=TPA-kC,N)-2}(L)Br] (L = P(mC(6)H(4)SO(3)Na)(3) (6); P(3-Pyridyl)(3) (7)) and, [Pd(C(6)H(4)(C(O)N=TPA)-2}(TPA)(2)Br] (8) are obtained as single isomers.

Cytotoxic hydrophilic iminophosphorane coordination compounds of d⁸ metals. Studies of their interactions with DNA and HSA.

The synthesis and characterization of a new water-soluble N,N-chelating iminophosphorane ligand TPAN-C(O)-2-NC(5)H(4) (N,N-IM) (1) and its d(8) (Au(III), Pd(II) and Pt(II)) coordination complexes are reported. The structures of cationic [AuCl(2)(N,N-IM)]ClO(4) (2) and neutral [MCl(2)(N,N-IM)] M=Pd (3), Pt(4) complexes were determined by X-ray diffraction studies or by means of density-functional calculations. While the Pd and Pt compounds are stable in mixtures of DMSO/H(2)O over 4 days, the gold derivative (2) decomposes quickly to TPAO and previously reported neutral gold(III) compound [AuCl(2)(N,N-H)] 5 (containing the chelating N,N-fragment HN-C(O)-2-NC(5)H(4)).

Easy preparation of Cp*-functionalized N-heterocyclic carbenes and their coordination to rhodium and iridium.

A simple high-yielding method for the preparation of a tetramethylcyclopentadienyl-NHC ligand is described. This ligand has been successfully coordinated to Rh and Ir. A related Cp*-NHC ligand with a -CH(2)CMePh- linker between the Cp* and the NHC is also described, together with its coordination to Rh and Ir.

Tandem beta-boration/arylation of alpha,beta-unsaturated carbonyl compounds by using a single palladium complex to catalyse both steps.

Diphenyl(3-methyl-2-indolyl)phosphine (C(9)H(8)NPPh(2), 1) gives stable dimeric palladium(II) complexes that contain the phosphine in P,N-bridging coordination mode. On treating 1 with [Pd(O(2)CCH(3))(2)], the new complexes [Pd(mu-C(9)H(7)NPPh(2))(NCCH(3))](2) (2) or [Pd(mu-C(9)H(7)NPPh(2))(mu-O(2)CCH(3))](2) (3) were isolated, depending on the solvent used, acetonitrile or toluene, respectively. Further reaction of 3 with the ammonium salt of 1 led to the substitution of one carboxylate ligand to afford [Pd(mu-C(9)H(7)NPPh(2))(3)(mu-O(2)CCH(3))] (4), in which the bimetallic unit is bonded by three C(9)H(7)NPPh(2)(-) moieties and one carboxylate group.

Dirhodium(II) compounds with bridging thienylphosphines: studies on reversible P,C/P,S coordination.

Monocyclometalated compound [Rh(2){(C(8)H(4)S)P(C(8)H(5)S)(2)}(CH(3)CO(2)H)(2)(O(2)CCH(3))(3)] (1 a) and bis-cyclometalated compound [Rh(2){(C(8)H(4)S)P(C(8)H(5)S)(2)}(2)(CH(3)CO(2)H)(2)(O(2)CCH(3))(2)] (2 a) have been isolated from the reaction of dirhodium tetraacetate and tris(2-benzo[b]thienyl)phosphine (2 BTP) using low acidic solutions. By contrast, in pure acetic acid the reaction of Rh(2)(O(2)CCH(3))(4) with 2 BTP and tris(2-thienyl)phosphine (2 TP), followed by replacement of the axial acetate ligands by chlorides, led to [Rh(2){(2-C(8)H(5)S)P(2-C(8)H(5)S)(2)}(2)Cl(2)(O(2)CCH(3))(2)] (3 b) and [Rh(2){(2-C(4)H(3)S)P(C(4)H(3)S)(2)}(2)Cl(2)(O(2)CCH(3))(2)] (5 b), respectively. These new dirhodium(II) compounds possess equatorial bridging ligands in a phosphorous-sulfur (P,S) coordination mode.

Intramolecular apical metal-H-Csp3 interaction in molybdenum and silver complexes.

The reaction of HTIMP3 (HTIMP3=tris[1-diphenylphosphino)-3-methyl-1H-indol-2-yl]methane) with AgBF4 and Mo(CO)3(NCCH3)3 leads to Ag(HTIMP3)BF4 and Mo(CO)3(HTIMP3), respectively. The metal centre is coordinated to the three phosphorus atoms of the HTIMP3 ligand, which adopts a facial coordination mode, placing a H-Csp3 hydrogen atom at the apical position close to the metal centre. The solid-state structure of Mo(CO)3(HTIMP3) has been determined by X-ray crystallography, and the data have been used as input parameters for obtaining the optimised geometry of the complex using the B3PW91 functional.

Isolation of enantiomerically pure organometallic palladium compounds: synthesis of the triangles prepared from enantiopure [cis-Pd2(C6H4PPh2)2(NCCH3)4]2+.

Reaction of the racemic [Pd(C(6)H(4)PPh(2))Br](4) () with the silver salt of 1R-(1alpha,2beta,3alpha)]-3-methyl-2-(nitromethyl)-5-oxocyclopentaneacetate, (R)-AgO(2)CR*, results in the formation of a mixture of diastereoisomers (RRR)- and (SRR)- of the formula Pd(2)(C(6)H(4)PPh(2))(2)(O(2)CR*)(2) that were separated by standard chromatographic methods. Each diastereoisomer was readily converted into the tetrametallic stereoisomers (SS)- and (RR)-, of the formula [Pd(C(6)H(4)PPh(2))Br](4) that were isolated and characterized by X-ray crystallography. The R enantiomer of the solvated cationic species [cis-Pd(2)(C(6)H(4)PPh(2))(2)(NCCH(3))(4)](2+), obtained from (RR)-, was reacted with ammonium terephthalate yielding RRR-[Pd(2)(C(6)H(4)PPh(2))(2)](3)(O(2)CC(6)H(4)CO(2))(3), (RRR)-.

Synthesis and reactivity of the novel hydride derivative RhHCl(TIMP(3)) (HTIMP(3) = tris[1-(diphenylphosphino)-3-methyl-1H-indol-2-yl]methane).

The reaction of HTIMP(3) (HTIMP(3) = tris[1-(diphenylphosphino)-3-methyl-1H-indol-2-yl]methane) with [RhCl(COD)](2) and Rh(acac)(CO)(2) produces RhHCl(TIMP(3)) (1H) and Rh(TIMP(3))(CO) (2), respectively, both exhibiting tetradentate kappaC,kappa(3)P-coordination of the TIMP(3) moiety. The reaction of RhHCl(TIMP(3)) with nucleophiles (L) in the presence of AgBF(4) or AgPF(6) produces different compounds depending on the nature of L. Indeed, cationic Lewis adducts of formula [RhH(L)(TIMP(3))](+) ((2H+)-(5H+)) are obtained when L is CO, CNCH(2)Ph, pyridine or CH(2)CHCN.

Synthesis of apoptosis-inducing iminophosphorane organogold(III) complexes and study of their interactions with biomolecular targets.

New stable cationic organogold(III) complexes containing the "pincer" iminophosphorane ligand (2-C(6)H(4)-PPh(2)=NPh) have been prepared by reaction of the previously described [Au{kappa(2)-C,N-C(6)H(4)(PPh(2)=N(C(6)H(5))-2}Cl(2)] 1 and a combination of sodium or silver salts and appropriate ligands. The presence of the P atom in the PR(3) fragment has been used as a "spectroscopic marker" to study the in vitro stability (and oxidation state) of the new organogold complexes in solvents like dimethyl sulfoxide and water. Compounds with dithiocarbamato ligands and water-soluble phosphines of the general type [Au{kappa(2)-C,N-C(6)H(4)(PPh(2)=N(C(6)H(5))-2}(S(2)CN-R(2))]PF(6) (R = Me 2; Bz 3) and [Au{kappa(2)-C,N-C(6)H(4)(PPh(2)=N(C(6)H(5))-2}(PR(3))(n)Cl]PF(6) (PR(3) = P{Cp(m-C(6)H(4)-SO(3)Na)(2)} n = 1 4, n = 2 TPA {1,3,5-triaza-7-phosphaadamantane} 5) have been synthesized and characterized in solution and in the solid state (the crystal structure of 2 has been determined by X-ray diffraction studies).

Multifaceted palladium catalysts towards the tandem diboration-arylation reactions of alkenes.

Novel Pd(2) (6+) compounds have been synthesized in high yield. These compounds and their Pd(2) (4+) counterparts as synthetic precursors mediate the diboration of vinylarenes and aliphatic 1-alkenes, and under mild and basic reaction conditions they produce a variety of 1,2-diboronate esters with excellent conversions and chemoselectivities. The presence of bis(catecholato)diboron (B(2)cat(2)) favours the reduction of Pd(III) to Pd(II), while the catalytic precursor of Pd(II) is transformed into Pd(0)-nanoparticles.

Dinuclear palladium(II) compounds with bridging cyclometalated phosphines. Synthesis, crystal structure and electrochemical study.

The structural characterization of bis-cyclometalated palladium(II) compounds of formula Pd2[(micro-(C6X4)PPh2]2(micro-O2CR)2 [X = H, R = CH3 (3), CF3 (4), C(CH3)3 (5) and C6F5 (6); X = F, R = CH3 (7) and CF3 (8)], has confirmed its paddle wheel structure with two palladium atoms bridged by two acetates and two metalated phosphines in a head-to-tail arrangement. The Pd..

High yield syntheses of stable, singly bonded Pd2(6+) compounds.

A general method for the syntheses of dipalladium compounds having a singly bonded Pd26+ core and the formula R,S-cis-Pd2(C6H4PPh2)2(O2CR)2Cl2 is described. When the alkyl group in the carboxylate ligands is an electron donating group, the compounds are stable and the yields high. The Pd-Pd distances for the diamagnetic compounds with R = CF3 and CMe3 are 2.

Highly stable Cp*-Ir(III) complexes with N-heterocyclic carbene ligands as C-H activation catalysts for the deuteration of organic molecules.

The preparation of a series of complexes of the type CpIrX2(NHC) provides effective catalysts for the H/D exchange of a wide range of organic molecules in methanol-d4. The reaction proceeds with higher yields under milder reaction conditions than previous CpIr systems reported thus far. For comparative purposes, we also studied the catalytic activity of CpIrCl2(PMe3) under the same reaction conditions.