Adding Diversity to a Diruthenium Biscyclopentadienyl Scaffold via Alkyne Incorporation: Synthesis and Biological Studies

We report the synthesis and the assessment of the anticancer potential of two series of diruthenium biscyclopentadienyl carbonyl complexes. Novel dimetallacyclopentenone compounds (2-4) were obtained (45-92% yields) from the thermal reaction(PhCCPh exchange) of [Ru2Cp2(CO)(& mu;-CO){& mu;-& eta;(1):& eta;(3)-C(Ph)C(Ph)C(O)}], 1, with alkynes HCCR [R = C5H4FeCp (Fc),3-C6H4(Asp), 2-naphthyl; Cp = & eta;(5)-C5H5, Asp = OC(O)-2-C6H4C(O)Me]. Protonation of 1-3 by HBF4 afforded the corresponding & mu;-alkenyl derivatives 5-7, in 40-86% yields. All productswere characterized by IR and NMR spectroscopy; moreover, cyclic voltammetry(1, 2, 5, 7) andsingle-crystal X-ray diffraction (5, 7)analyses were performed on representative compounds. Complexes 5-7 revealed a cytotoxic activity comparableto that of cisplatin in A549 (lung adenocarcinoma), SW480 (colon adenocarcinoma),and ovarian (A2780) cancer cell lines, and 2, 5, 6, and 7 overcame cisplatin resistancein A2780cis cells. Complexes 2, 5, and 7 (but not the aspirin derivative 6) inducedan increase in intracellular ROS levels. Otherwise, 6 strongly stabilizes and elongates natural DNA (from calf thymus,CT-DNA), suggesting a possible intercalation binding mode, whereas 5 is less effective in binding CT-DNA, and 7 isineffective. This trend is reversed concerning RNA, and in particular, 7 is able to bind poly(rA)poly(rU) showing selectivity forthis nucleic acid. Complexes 5-7 caninteract with the albumin protein with a thermodynamic signature dominatedby hydrophobic interactions. Overall, we show that organometallicspecies based on the Ru2Cp2(CO)( x ) scaffold (x = 2, 3) are activeagainst cancer cells, with different incorporated fragments influencingthe interactions with nucleic acids and the production of ROS

Atomically Precise Ni-Pd Alloy Carbonyl Nanoclusters: Synthesis, Total Structure, Electrochemistry, Spectroelectrochemistry, and Electrochemical Impedance Spectroscopy

The molecular nanocluster [Ni36-xPd5+x(CO)46]6- (x = 0.41) (16-) was obtained from the reaction of [NMe3(CH2Ph)]2[Ni6(CO)12] with 0.8 molar equivalent of [Pd(CH3CN)4][BF4]2 in tetrahydrofuran (thf). In contrast, [Ni37-xPd7+x(CO)48]6- (x = 0.69) (26-) and [HNi37-xPd7+x(CO)48]5- (x = 0.53) (35-) were obtained from the reactions of [NBu4]2[Ni6(CO)12] with 0.9-1.0 molar equivalent of [Pd(CH3CN)4][BF4]2 in thf. After workup, 35- was extracted in acetone, whereas 26- was soluble in CH3CN. The total structures of 16-, 26-, and 35- were determined with atomic precision by single-crystal X-ray diffraction. Their metal cores adopted cubic close packed structures and displayed both substitutional and compositional disorder, in light of the fact that some positions could be occupied by either Ni or Pd. The redox behavior of these new Ni-Pd molecular alloy nanoclusters was investigated by cyclic voltammetry and in situ infrared spectroelectrochemistry. All three compounds 16-, 26-, and 35- displayed several reversible redox processes and behaved as electron sinks and molecular nanocapacitors. Moreover, to gain insight into the factors that affect the current-potential profiles, cyclic voltammograms were recorded at both Pt and glassy carbon working electrodes and electrochemical impedance spectroscopy experiments performed for the first time on molecular carbonyl nanoclusters

When ferrocene and diiron organometallics meet: triiron vinyliminium complexes exhibit strong cytotoxicity and cancer cell selectivity

Cationic triiron complexes resulting from the conjugation of the ferrocenyl skeleton (Fc) with a diiron bis-cyclopentadienyl core through a variable vinyliminium linker, [Fe2Cp2(CO)(mu-CO){mu-eta(1):eta(3)-C(Fc)CHCN(R)(R')}]CF3SO3 ([2a-i]CF3SO3, Cp = eta(5)-C5H5, R, R'= alkyl, aryl), were synthesised in 70-94% yield, and the homologous nitrate salt was also prepared in one case ([2h]NO3). The neutral derivatives [Fe2Cp2(CO)(mu-CO){mu-eta(1):eta(3)-C(Fc)CHC(CN)NMe2}], 3, and [FeCp(CO){CN(Me)(Xyl)CHC(Fc)C(=O)}], 4 (Xyl = 2,6-C6H3Me2), were obtained in ca. 70% yield by reactions of the respective precursors [2h]CF3SO3 and [2i]CF3SO3 with NBu4CN and pyrrolidine, respectively. All products were purified by alumina chromatography and fully characterised by analytical and spectroscopic methods, and by single crystal X-ray diffraction in the cases of [2a]CF3SO3 and 3. The cytotoxicity of the complexes was assessed on A2780, A2780cisR and BxPC-3 cancer cell lines, and the nontumoral Balb/3T3 clone A31. Most of the cationic complexes display IC50 values in the low micromolar/nanomolar range concerning the cancer cell lines, and up to 35 times higher values on the nontumoral cells. In order to shed light on the mode of action, selected complexes were further characterised by cyclic voltammetry and spectroelectrochemical experiments, and assessed for their potential to trigger ROS production and to interact with a range of biomolecules, i.e. a synthetic dodecapeptide as a simplified model for thioredoxin reductase (TrxR-pept), some model proteins (cytochrome c, hen egg-white lysozyme, ubiquitin, bovine serum albumin, superoxide dismutase and human carbonic anhydrase) and one single-stranded oligonucleotide (ODN2)

Pooled Analysis of Clinical Outcome of Patients with Chemorefractory Metastatic Colorectal Cancer Treated within Phase I/II Clinical Studies Based on Individual Biomarkers of Susceptibility : a Single-Institution Experience

BACKGROUND: Patients with metastatic colorectal cancer (mCRC) refractory to standard therapies have a poor prognosis. In this setting, recruitment into clinical trials is warranted, and studies driven by selection according to individual tumor molecular characteristics are expected to provide added value. OBJECTIVE: We retrospectively analyzed data from patients with mCRC refractory to or following failure of standard therapies who were enrolled into phase I/II clinical studies at the Niguarda Cancer Center based on the presence of a specific molecular profile expected to represent the target of susceptibility to the experimental drug(s). PATIENTS AND METHODS: From June 2011 to May 2016, 2044 patients with mCRC underwent molecular screening. Eighty patients (3.9%) were enrolled in ad hoc studies; the median age was 60 years (range 36-86) and the median number of previous treatment lines was five (range 2-8). Molecular characteristics exploited within these studies were MGMT promoter hypermethylation (48.7%), HER2 amplification (28.8%), BRAF V600E mutation (20%), and novel gene fusions involving ALK or NTRK (2.5%). RESULTS: One patient (1%) had RECIST (Response Evaluation Criteria In Solid Tumors) complete response (CR), 13 patients (16.5%) experienced a partial response (PR), and 28 (35%) stable disease (SD). Median progression-free survival (PFS) was 2.8 months (range 2.63-3.83), with 24% of patients displaying PFS >5 months. Median growth modulation index (GMI) was 0.85 (range 0-15.61) and 32.5% of patients had GMI >1.33. KRAS exon 2 mutations were found in 38.5% of patients, and among the 78 patients with known KRAS status, those with wild-type tumors had longer PFS than those with mutated tumors (3.80 [95% CI 2.80-5.03] vs. 2.13 months [95% CI 1.77-2.87], respectively, p = 0.001). Median overall survival (OS) was 7.83 months (range 7.17-9.33) for all patients, and patients with KRAS wild-type tumors had longer OS than those with mutated tumors (7.83 [95% CI 7.33-10.80] vs. 7.18 months [95% CI 5.63-9.33], respectively, p = 0.06). CONCLUSIONS: This single-institution retrospective study indicates that in a heavily pretreated population approximately 4% of mCRC tumors display a potential actionable molecular context suitable for therapeutic intervention. Application of molecular selection is challenging but improves clinical outcome even in later lines of treatment

Homocoupling of Halotropones Promoted by Bis(1,5-Cyclooctadiene)Nickel in the Presence of Tris(1-Pyrazolyl)Methane. An Easy Route to [Bi-1,3,5-Cycloheptatrien-1-yl]-7,7’-Diones

An efficient homocoupling of 2-halotropones, to afford 2,2'-bitropones, occurs in toluene at rt in the presence of stoichiometric amounts of [Ni(cod)2] and tris(1-pyrazolyl)methane ligand, in a 1:1 molar ratio. This methodology was extended to aryl halides

Procedimento di riduzione del complesso Pd(NH3)2Cl2 a spugna di palladio

La presente invenzione rigurda un procedimento di riduzione del complesso Pd(NH3)2Cl2 a spugna di palladio che prevede i seguenti passaggi : a) dissoluzione del complesso Pd(NH3)2Cl2 in soluzione acquosa in eccesso di ammoniaca; b) aggiunta di acido cloridrico in quantità tale da ottenere un valore di pH compreso nell'intervallo da 6 a 9; c) riduzione con acido formico ad una temperatura compresa tra 60 e 100°C; e e) eliminazione di cloruro di amminio e/o di carbonato di ammonio eventualmente presenti nella spugna proveniente dal passaggio c). La spugna di palladio così ottenuta, è estremamente pura e ha un'eccellente granulometria

Mutual Catalysis of Neutral and Anionic Cobalt Carbonyls in Their CO Scrambling Reactions

Redox-condensation equilibria, probably with the participation of [Co3(CO)10]- as intermediate, and not ion pairing as previously postulated, explain the acceleration of the CO scrambling in [Co(CO)4]- by alkali metal counterions. The studies described here show that neutral carbonyl complexes catalyze the CO scrambling for anionic metal carbonyls and vice versa, and that the catalysis is less effective in the presence of free CO. The latter is in agreement with [Co3(CO)10]- as the intermediate. These results are important mainly because neutral and anionic metal carbonyls frequently exist together as a result of side reactions

Reduction of Methanol by Tetracarbonylcobalt Anion Assisted by Carbon Dioxide and Cobalt Cation

Fundamental electron-transfer reactions involving CH3OH and Co2(CO)8 are investigated. In a fully disproportionated CH3OH solution of Co2(CO)8, in the presence of CO2, a CH3OH reduction by Co(CO)4- occurs, under the intervention of the highly polarizing Co2+ cations. In tetrahydrofuran as solvent under carbon monoxide atmosphere, the CH3O- nucleophile formed gives rise to the Co(I) species tetracarbonyl(methoxycarbonyl)cobalt. Under low carbon monoxide pressure, this Co(I) species disproportionates to Co(OCH3)2 and Co2(CO)8. Catalytic amounts of Co2(CO)8 activate the carbonylation reaction of Co(OCH3)2 to dimethyl carbonate and tetracarbonyl(methoxycarbonyl)cobalt

Preparation of Dimethyl Carbonate by Dehydrogenative Carbonylation

A new dimethylcarbonate synthesis method by means of a dehydrogenatingcarbonylation method which only uses methanol, CO, CO2 and CO2(CO)8. Newintermediate products used to carry out said method