Elena Cerrada

Anticancer therapeutics that target selenoenzymes: synthesis, characterization, in vitro cytotoxicity, and thioredoxin reductase inhibition of a series of gold(I) complexes containing hydrophilic phosphine ligands.

Gold(I) complexes bearing water‐soluble phosphine ligands, including 1,3,5‐triaza‐7‐phosphaadamantane (PTA), 3,7‐diacetyl‐1,3,7‐triaza‐5‐phosphabicyclo[3.3.1]nonane (DAPTA), and sodium triphenylphosphine trisulfonate (TPPTS), in combination with thionate ligands, were screened for their antiproliferative activities against human ovarian cancer cell lines A2780 either sensitive or resistant to cisplatin. In addition, the compounds were screened for their inhibition of mammalian thioredoxin reductases (TrxR), enzymes that are overexpressed in many tumor cells and contribute to drug resistance. The gold(I)–phosphine complexes efficiently inhibited cytosolic and mitochondrial TrxRs at concentrations that did not affect the related oxidoreductase glutathione reductase (GR). Additional complementary information on the enzyme metallation process and potential gold binding sites was obtained through the application of a specific biochemical assay using a thiol‐tagging reagent, BIAM (biotin‐conjugated iodoacetamide).

Synthesis, Characterization, and in Vitro Cytotoxicity of Some Gold(I) and Trans Platinum(II) Thionate Complexes Containing Water-Soluble PTA and DAPTA Ligands. X-ray Crystal Structures of [Au(SC4H3N2)(PTA)], trans-[Pt(SC4H3N2)2(PTA)2], trans-[Pt(SC5H4N)2(PTA)2], and trans-[Pt(SC5H4N)2(DAPTA)2]

A series of gold(I) and platinum(II) complexes of the type [Au(SR)(P)] and trans-[Pt(SR) 2(P) 2] [SR = 2-thiopyridine (SPy), 2-thiopyrimidine (SPyrim); P = 1,3,5-triaza-7-phosphaadamantane (PTA), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA)] were prepared and characterized, and their in vitro cytotoxicities against a panel of seven human cancer cell lines were evaluated. The highly water soluble gold(I) complexes [Au(SR)(P)] [P = PTA and SR = SPy ( 1), SPyrim ( 2); P = DAPTA and SR = SPy ( 3), SPyrim ( 4)] showed low cytotoxicity, while the platinum(II) complexes trans-[Pt(SR) 2(P) 2] [P = PTA and SR = SPyrim ( 5), SPy ( 6); P = DAPTA and SR = SPyrim ( 7), SPy ( 8)] demonstrated potent cytotoxicity for ovarian, colon, renal, and melanoma cancer cell lines on the basis of a comparison with ID 50 values for some established cytotoxic drugs. Single crystals of 2, 5, 6, and 8 suitable for X-ray structural characterization were obtained, and the study revealed the trans configuration for 5, 6, and 8 in their solid states.

Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death. Most cases of CRC are detected in Western countries, with its incidence increasing year by year. The probability of suffering from colorectal cancer is about 4%–5% and the risk for developing CRC is associated with personal features or habits such as age, chronic disease history and lifestyle. In this context, the gut microbiota has a relevant role, and dysbiosis situations can induce colonic carcinogenesis through a chronic inflammation mechanism. Some of the bacteria responsible for this multiphase process include Fusobacterium spp, Bacteroides fragilis and enteropathogenic Escherichia coli. CRC is caused by mutations that target oncogenes, tumour suppressor genes and genes related to DNA repair mechanisms. Depending on the origin of the mutation, colorectal carcinomas can be classified as sporadic (70%); inherited (5%) and familial (25%). The pathogenic mechanisms leading to this situation can be included in three types, namely chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Within these types of CRC, common mutations, chromosomal changes and translocations have been reported to affect important pathways (WNT, MAPK/PI3K, TGF-β, TP53), and mutations; in particular, genes such as c-MYC, KRAS, BRAF, PIK3CA, PTEN, SMAD2 and SMAD4 can be used as predictive markers for patient outcome. In addition to gene mutations, alterations in ncRNAs, such as lncRNA or miRNA, can also contribute to different steps of the carcinogenesis process and have a predictive value when used as biomarkers. In consequence, different panels of genes and mRNA are being developed to improve prognosis and treatment selection. The choice of first-line treatment in CRC follows a multimodal approach based on tumour-related characteristics and usually comprises surgical resection followed by chemotherapy combined with monoclonal antibodies or proteins against vascular endothelial growth factor (VEGF) and epidermal growth receptor (EGFR). Besides traditional chemotherapy, alternative therapies (such as agarose tumour macrobeads, anti-inflammatory drugs, probiotics, and gold-based drugs) are currently being studied to increase treatment effectiveness and reduce side effects.

Thiolato gold(i) complexes containing water-soluble phosphane ligands

A series of thiolate gold(I) derivatives bearing water soluble phosphanes--namely sodium triphenylphosphane monosulfonate (TPPMS), sodium triphenylphosphane trisulfonate (TPPTS), 1,3,5-triaza-7-phosphaadamantane (PTA) and 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA)--is reported and the compounds studied for their luminescence properties in the solid state. Two of these derivatives, [Au(SMe(2)pyrim)(PTA)] and [Au(SBenzoxazole)(DAPTA)], are also structurally characterized by X-ray diffraction analysis. Strong antiproliferative effects are observed for most of the compounds in the human ovarian carcinoma cell lines (A2780/S) and its cisplatin-resistant variant (A2780/R), which depend on both the type of thiolate and phosphane ligands. ICP-MS studies were also performed to evaluate the influence of the gold uptake on the cytotoxic potency of the compounds.

trans-Thionate Derivatives of Pt(II) and Pd(II) with Water-Soluble Phosphane PTA and DAPTA Ligands: Antiproliferative Activity against Human Ovarian Cancer Cell Lines

A series of PTA and DAPTA platinum(II) and palladium(II) thionate complexes of the type trans-[M(SN)2P2] were prepared from the reaction of cis-[MCl2P2] [M = Pt, Pd; P = PTA (1,3,5-triaza-7-phosphaadamantane), DAPTA (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane)] with the in situ generated sodium salts of the heterocyclic thiones S-m-methylpyrimidine-2-thione, S-4,6-dimethylpyrimidine-2-thione, S-4,6-dihydroxypyrimidine-2-thione, benzothiazole-2-thione, benzoxazole-2-thione, S-1,3,4,-thiadiazole-2-thione, S-4,5-H-thiazolan-2-thione, and S-pyrimidine-4(1H)-one-2-thione. The X-ray structures of six of the compounds confirm the trans disposition and, only in the case of [Pd2Cl2(S-pyrimidine-4(1H)-one-2-thionate)2(PTA)2], a dinuclear structure with a Pd-Pd distance of 3.0265(14)Å was observed. In vitro cytotoxicities against human ovarian cancer cell lines A2780 and A2780cisR were evaluated for ten complexes showing a high inhibition of cellular growth with a comparable inhibitory potency (IC50) against A2780 cells to that of cisplatin. Notably, the compounds also show significant (up to 7-fold higher) activity in cisplatin-resistant A2780cisR cell lines.

Synthesis of dithiolate gold(III) complexes by dithiolate transfer reactions. X-ray structure of [Au(C6F5)(S2C6H4)(PPh3)]

Abstract The reaction of ethanolic solutions of Na 2 (SS) {SS &.dbnd; 1,2-S 2 C 6 H 4 or 3,4-S 2 C 6 H 3 (CH 3 )} with [Sn(CH 3 ) 2 Cl 2 ] or (PPN) 2 [ZnCl 4 ] gives [Sn(CH 3 ) 2 (SS)] and (PPN) 2 [Zn(SS) 2 ], respectively. The tin derivative with 1,3-dithiol-2-thione-4,5-dithiolate (dmit), [Sn(CH 3 ) 2 (dmit)], is obtained by reaction of [Sn(CH 3 ) 2 Cl 2 ] with (NEt 4 ) 2 [Zn(dmit) 2 ]. The tin and zinc complexes further react with the gold(III) derivatives cis -[Au(C 6 F 5 )Cl 2 L] giving rise to dithiolate gold(III) complexes [Au(C 6 F 5 )(SS)L]. The structure of [Au(C 6 F 5 )(S 2 C 6 H 4 )(PPh 3 )] has been established by an X-ray diffraction study, and shows a square-planar coordination of the gold with the dithiolate chelating.

Gold(I) complexes with alkylated PTA (1,3,5-triaza-7-phosphaadamantane) phosphanes as anticancer metallodrugs

New stable thiolate gold(I) derivatives containing the alkylated phosphanes [PTA-CH2Ph]Br and [PTA-CH2COOMe]Br derived from 1,3,5-triaza-7-phosphaadamantane (PTA) have been prepared by different routes of synthesis. By the use of basic media to deprotonate the corresponding thiol in the former and by transmetallation reactions from tin (IV) complexes, in the later, thus avoiding side reactions on the phosphane. Strong antiproliferative effects are observed for most of the compounds, including the chloro- and bromo precursors with the series of phosphanes derived from PTA, in human colon cancer cell lines (Caco-2, PD7 and TC7 clones). Apoptosis-induced cell death is found for all compounds, being the thiolate derivatives with [PTA-CH2Ph]Br the most effective, as shown by an annexin-V/propidium iodide double-staining assay.

An investigation of the Lewis acid mediated 1,3-dipolar cycloaddition between N-benzyl-C-(2-pyridyl)nitrone and allylic alcohol. Direct entry to isoxazolidinyl C-nucleosidesElectronic supplementary information (ESI) available: optimized geometries (PDB format). See http://www.rsc.org/suppdata/ob/b3/b304112c/

The cycloaddition reaction of N-benzyl C-(2-pyridyl) nitrone with allylic alcohol has been carried out to obtain the corresponding 2-benzyl-3-(2-pyridyl)-5-hydroxymethylisoxazolidine. The influence of Lewis acids in the reaction has been studied and a complete 3,5-regioselectivity and cis diastereoselectivity was observed when the reaction was carried out with 1.0 equiv of AgOTf, [Ag(OClO3)(PPh2Me)] or Zn(OTf)2. Insight into the mechanism of the reaction has been obtained by isolating and characterizing (X-ray) the intermediate complexes. Also, a model based on both experimental and theoretical results is proposed.

Pyridine-2-thionate as a versatile ligand in Pd(II) and Pt(II) chemistry: the presence of three different co-ordination modes in [Pd2(μ2-S,N-C5H4SN)(μ2-κ2S-C5H4SN)(μ2-dppm)(S-C5H4SN)2]

Reactions of [MCl2(L-L)], M = Pt, Pd; L-L = bis(diphenylphosphino)methane (dppm) or bis(diphenylphosphino)ethane (dppe), with NaC5H4SN in a 1 : 2 molar ratio lead to mononuclear species [M(S-C5H4SN)2(P-P)], M = Pt; L-L = dppm (1) or dppe (2) and M = Pd; L-L = dppe (3), as well as to the dinuclear [Pd2(micro2-S,N-C5H4SN)(micro2-kappa2S-C5H4SN)(micro2-dppm)(S-C5H4SN)2] (4). In contrast, reaction of [MCl2(dppm)] with NaC5H4SN in a 1 : 1 molar ratio leads to [Pd2(micro2-S,N-C5H4SN)3(micro2-dppm)]Cl (5) and trans-[Pt(S-C5H4SN)2(PPh2Me)2] (6) respectively. The latter is formed in low yield by cleavage of the dppm ligand. The dinuclear derivatives 4 and 5 present an A-frame and lantern structure, respectively. The former showing three different co-ordination modes in the same molecule with a short Pd-Pd distance of 2.9583 (9) A and the latter with three bridging S,N thionate ligands showing a shorter Pd-Pd distance of 2.7291 (13) A. Both distances could be imposed by the bridging ligands or point to some sort of metal-metal interaction.

Dalton communications. New co-ordination mode of 4,5-dimercapto-1,3-dithiole-2-thionate(2–) in polynuclear gold(I) complexes. Crystal structures of [Au3(µ3-C3S5)(PPh3)3] ClO4 and [Au4(µ-C3S5)2(µ-Ph2PCH2PPh2)2]

The ligand 4,5-dimercapto-1,3-dithiole-2-thionate(2–)(C3S52–) has been transferred from [Net4]2-[Zn(C3S5)2] to gold(I) centres, affording di-, tri- or tetra-nuclear complexes containing the C3S52– ligand in unprecedented µ- or µ3-bridging forms.