0000000000889124
AUTHOR
María Contel
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 [Ph3P[double bond, length as m-dash]N–C9H6N] (1) have been synthesized and structurally characterized. The coordination palladium(II) and platinum(II) compounds can evolve further, under appropriate conditions, to give stable cyclometalated endo species [M{κ3-C,N,N-C6H4(PPh2[double bond, length as m-dash]N-8-C9H6N)}Cl] (M = Pd, Pt) by C–H activation of the phenyl group of the PPh3 fragment. Iminophosphorane 1 and the new metallic complexes are luminescent in DMSO or DMSO–H2O (1 : 1 mixture) solutions at RT. The compounds have been evaluated f…
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. Remarkably, auranofin inhibited S. aureus, US300 and US400 in the order of 150-300 nM. This is the first time that the potent inhibitory effect of auranofin on MRSA strains has been described. The effects of a selected heterometallic compound and auranofin were also stu…
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)). The cytotoxicities of co…
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 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-Diph…
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). The highly cytotoxic trimeta…
Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo
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-C6H4-COO-) bound to gold(I)-phosphane fragments through a thiolate group ([(η-C5H5)2TiMe(μ-mba)Au(PR3)]. 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 s…
Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo † †This paper is dedicated to Prof. Roberto Sánchez-Delgado, great mentor and excellent friend, on the occasion of his 65th birthday. ‡ ‡Electronic supplementary information (ESI) available: Stability studies of the new compounds by NMR, UV-vis spectroscopy and MS spectrometry, crystallographic data for compound 6, DFT calculations for compounds 4–7, IC50 values in human renal cells at both 24 and 72 h, details on migration studies, TrxR inhibition studies for 3, 5 and AF at different times, inhibition studies of compound 5 against a panel of 35 protein kinases, effects of AF on MAPKAPK-3 in Caki-1 cells, effects of compound 3 in Caki-1 mouse xenografts. CCDC 1400886. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5sc01753j Click here for additional data file. Click here for additional data file.
Heterometallic compounds as anticancer agents demonstrating in vivo potential for the first time. Titanocene–gold derivatives: promising candidates for renal cancer.
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)-p-C6H4-S−) bound to gold(I)−N-heterocyclic carbene fragments through the thiolate group: [(η5 -C5H5)2TiMe(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. The colocalization of both tita…
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. Initial mechanistic studies indicate that the cell death type for these compounds is mainly through canonical or caspase-dependent apoptosis, nondependent on p53, and that the compounds do not interact with DNA or inhibit protease cathepsin B. In vivo experiments of 2 on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (…
Organometallic Titanocene–Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties
Early–late transition metal TiAu2 compounds [(η-C5H5)2Ti{OC(O)CH2PPh2AuCl}2] (3) and new [(η-C5H5)2Ti{OC(O)-4-C6H4PPh2AuCl}2] (5) were evaluated as potential anticancer agents in vitro against renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and gold(I) [{HOC(O)RPPh2}AuCl] (R = −CH2– 6, −4-C6H4– 7) derivatives in renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on renal cancer cell lines (for 5 in the nanomolar range) was considerably higher than that of cisplatin and highly active titanocene Y. Initial mechanistic studies in Caki-1 cells in vitro couple…
CCDC 977988: Experimental Crystal Structure Determination
Related Article: Yozane Hokai, Boruch Jurkowicz, Jacob Fernández-Gallardo, Nuruddinkodja Zakirkhodjaev, Mercedes Sanaú, Theodore R. Muth, María Contel|2014|J.Inorg.Biochem.|138|81|doi:10.1016/j.jinorgbio.2014.05.008
CCDC 1436326: Experimental Crystal Structure Determination
Related Article: Jacob Fernández-Gallardo, Benelita T. Elie, Mercedes Sanaú, María Contel|2016|Chem.Commun.|52|3155|doi:10.1039/C5CC09718E
CCDC 930540: Experimental Crystal Structure Determination
Related Article: Nicholas Lease, Vadim Vasilevski, Monica Carreira, Andreia de Almeida, Mercedes Sanaú, Pipsa Hirva, Angela Casini, María Contel|2013|J.Med.Chem.|56|5806|doi:10.1021/jm4007615
CCDC 1008354: Experimental Crystal Structure Determination
Related Article: Malgorzata Frik, Alberto Martínez, Benelita T. Elie, Oscar Gonzalo, Daniel Ramírez de Mingo, Mercedes Sanaú, Roberto Sánchez-Delgado, Tanmoy Sadhukha, Swayam Prabha, Joe W. Ramos, Isabel Marzo, and María Contel|2014|J.Med.Chem.|57|9995|doi:10.1021/jm5012337
CCDC 977989: Experimental Crystal Structure Determination
Related Article: Yozane Hokai, Boruch Jurkowicz, Jacob Fernández-Gallardo, Nuruddinkodja Zakirkhodjaev, Mercedes Sanaú, Theodore R. Muth, María Contel|2014|J.Inorg.Biochem.|138|81|doi:10.1016/j.jinorgbio.2014.05.008
CCDC 930539: Experimental Crystal Structure Determination
Related Article: Nicholas Lease, Vadim Vasilevski, Monica Carreira, Andreia de Almeida, Mercedes Sanaú, Pipsa Hirva, Angela Casini, María Contel|2013|J.Med.Chem.|56|5806|doi:10.1021/jm4007615
CCDC 1436327: Experimental Crystal Structure Determination
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CCDC 977990: Experimental Crystal Structure Determination
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CCDC 977991: Experimental Crystal Structure Determination
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CCDC 1008332: Experimental Crystal Structure Determination
Related Article: Jacob Fernández-Gallardo, Benelita T. Elie, Florian J. Sulzmaier, Mercedes Sanaú, Joe W. Ramos, María Contel|2014|Organometallics|33|6669|doi:10.1021/om500965k
CCDC 1400886: Experimental Crystal Structure Determination
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CCDC 887963: Experimental Crystal Structure Determination
Related Article: Monica Carreira, Rubén Calvo-Sanjuán, Mercedes Sanaú, Isabel Marzo, and María Contel|2012|Organometallics|31|5772|doi:10.1021/om3006239