1,721,003 research outputs found
Ruolo dei leganti ancillari nella coordinazione delle nucleobasi modello del DNA a complessi fosfinici di Platino(II)
Full text linkCisplatin, cis-diamminedichloroplatinum(II), plays an important role as a drug against different tumours (testicle, ovary, bladder and neck). The biological properties of this drug, casually discovered by Rosemberg in 1965, have incited studies on the interactions between Platinum (and other metals) complexes and DNA components (nucleobases, nucleotides and nucleosides).
In this thesis is reported a deep study of the coordination of the model nucleobases with Platinum(II) complexes, stabilized by phosphine ligands, analogues to cisplatin.
The use of phosphine ligands (L) PMe3, PMe2Ph, PMePh2 and PPh3, characterized by a progressive basicity reduction and steric hindrance increase, led to peculiar and original aspects of the coordination chemistry of the nucleobases concerning the metallation sites and the nuclearity of the isolated compounds. The study is based on the reactivity of neutral complexes cis-L2Pt(ONO2)2 and cationic ones cis-[L2Pt(m-OH)]22+ versus 1-MeCy, 1-MeTy, 9-MeAd and 9-MeGu.
Hydroxo complexes cis-[L2Pt(m-OH)]22+ can depronate the NH2 exocyclic group of the 1-MeCy and 9-MeAd to form polynuclear adducts such as cis-[L2Pt{Nucleobase(-H)}]nn+, whose nuclearity depends on the nature of L. Low steric hindrance phosphines form very stable trinuclear species (with dinuclear intermediates species with L = PMe3). In these compounds, the 1-MeCy nucleobase is coordinated through the exocyclic deprotonated nitrogen N4 and the endocyclic nitrogen N3, forming species such as cis-[L2Pt{1-MeCy(-H),N3N4}]nn+ (n = 2, 3). With the PMe2Ph ligand we have been able to characterize a trinuclear asymmetric intermediate, a coordination isomer of the analogue trinuclear symmetric one more termodinamically stable. With PPh3, characterized by a high steric hindrance, a mononuclear species, cis-[L2Pt{1-MeCy(-H)}(1-MeCy)]+ has been obtained where the two nucleobases are coordinated to the same metallic centre with different sites, N3 the neutral cytosine and N4 the deprotonated one.
With the 9-MeAd, the phosphine complexes showed a similar reactivity. PMe3 stabilizes a dinuclear specie cis-[L2Pt{9-MeAd(-H),N1N6}]22+ with the nucleobase, bridging two metal centres through the deprotonated exocyclic nitrogen N6 and the exocyclic nitrogen N1. PMe2Ph and PMePh2 stabilize the analogues trinuclear species, where the nucleobases maintain the same coordination mode. PPh3 leads to a change in the coordination mode of the nucleobase and forms a mononuclear specie, where 9-MeAd chelates a Platinum(II) centre through N6 and N7.
In the condensation reactions conducted in acetonitrile, less basic phosphines with a high steric hindrance stabilize a new class of acetamidine compounds, where a solvent molecule of CH3CN is inserted into a Pt-Nucleobase bond.
The neutral specie cis-L2Pt{1-MeTy(-H)}(ONO2) (L = PPh3) with the deprotonated nucleobase 1-MeTy allows to characterize the mixed complex cis-[L2Pt{1-MeTy(-H)}(1-MeCy,N4)]+ , where the neutral nucleobase 1-MeCy is coordinated through the exocyclic nitrogen N4 with a shift of a proton from N4 to N3. This complex stabilizes the rare imino-oxo tautomer of the 1-MeCy.
Complexes cis-L2Pt(ONO2)2 react with the nucleobases 1-MeCty and 9-MeGu in their neutral form, leading to the isolation of mono and bis-adducts X-Ray structurally characterized. Also in this case, the biggest PPh3 phosphine plays an important role in the stabilization of monoadducts. In fact, the X-Ray analysis of these complexes shows a strong p-p interaction between the phenyl rings of the PPh3 and the aromatic rings of the two nucleobases. The substitution of both the nitrato groups leads to the bisadducts analogues cis-[L2Pt(Nucleobase)2]2+, where the nucleobases are coordinated in a head-to-tail fashion.
The study of biological activity of the complexes has been focused on four cell lines. So far, only the precursors have been investigated and the results are quite modest in comparison to cisplatin
Phosphate Diester Cleavage, DNA Interaction and Cytotoxic Activity of a Bimetallic Bis(1,4,7-triazacyclononane) Zinc Complex
Full text linkThe dinuclear zinc complex [Zn-2{bcmp(-H)}(mu-Cl)](ClO4)(2)center dot H2O {bcmp = 2,6-bis(1,4,7-triazacyclonon-1-ylmethyl)-4-methylphenol} has been synthesized and structurally characterized. The DNA binding affinity was assessed by ethidium bromide fluorescence quenching experiments. The complex relaxes supercoiled pUC19 DNA into the nicked form at low micromolar concentration. Mechanistic studies were carried out using the DNA and RNA models bis(2,4-dinitrophenyl) phosphate (BDNPP) and 2-hydroxypropyl p-nitrophenyl phosphate (HPNP). A detailed kinetic analysis suggested that the bridging OH group of the solution species [Zn-2{bcmp(-H)}(mu-OH)](2+) acts as the nucleophile in the hydrolysis of BDNPP, while in the case of HPNP, the bridging OH group acts as a general base and seems to shift to a terminal position upon substrate coordination. Finally, the cytotoxicity profile of the dinuclear zinc(II) complex was assessed. The complex showed promising in vitro antitumour activity against pancreatic and lung cancers cell lines
DNA damage and induction of apoptosis in pancreatic cancer cells by a new dinuclear bis(triazacyclonane) copper complex
Full text linkThe dinuclear copper(II) complex [Cu2{bcmp(-H)}(μ-OH)](NO3)2·H2O (1, bcmp=2,6-bis(1,4,7-triazacyclonon-
1-ylmethyl)-4-methylphenol) has been synthesized and characterized by electrospray ionization mass spectrometry,
potentiometric titration and cyclovoltammetry. The X-ray structure of the analogous perchlorate salt
[Cu2{bcmp(-H)}(μ-OH)](ClO4)2·2.5H2O (2) was determined. Cytotoxicity studies showed very promising activity
of 1 against various pancreatic tumor cell lines with IC50 values comparable or even lower than those of cisplatin.
The Cu complex displayed low toxicity against a human non-tumor cell line (HEK 293) demonstrating
selectivity for cancer cells. 1 converts supercoiled pUC19 plasmid DNA into the nicked form at micromolar concentrations
in the absence of added reductants. A detailed kinetic study on the hydrolysis of the DNA model
bis(2,4-dinitrophenyl) phosphate (BDNPP) has been performed. 1 hydrolyses BDNPP with a second order rate
constant of 0.047Ms−1 at pH 8 and 40 °C. Finally, single cell electrophoresis (comet assay) and fluorescence microscopy
analysis showed that 1 interacts with cellular DNA and induces apoptotic cell death of Capan-1 pancreatic
cancer cells.Western blotting analysis indicated that the Cu complex activates the p53 dependent pathway of
apoptosis
Synthesis, characterization and cytotoxic activity of palladium (II) dithiocarbamate complexes with alpha,omega-diamines
Full text linkThe polymeric [PdCl(dithiocarbamate)]n complexes, in which the ligand ion is dimethyldithiocarbamate (DMDT), pyrrolidine dithiocarbamate (PyDT, (CH2)4NCS2) and sarcosine ethyl ester dithiocarbamate (ESDT, EtO2CCH2N(CH3)CS2), have been reacted with chelating diamines, like ethylenediamine (en) or 1,3-diaminopropane (dap) and long chain diamines, like 1,4-diaminobutane (dab) or 1,7-diaminoheptane (dah). The reaction products depend on either diamine chain length or molar ratio. By operating at PdCl(dithiocarbamate)/diamine molar ratio 1:1 chelating diamines yielded the ionic [Pd(dithiocarba- mate)(diamine)]Cl species (diamine = en or dap), whereas with long chain diamines species of the type [Pd(dithiocarbamate)(diamine)]nCln (diamine = dab or dah) were obtained, in which each Pd(dithiocarba- mate)+ unit binds to the NH2 group of two different molecules, in a network of bridging diamines. At molar ratio 1:0.5, the long chain diamines yielded the binuclear [Pd2Cl2(dithiocarbamate)2(diamine)] complexes (diamine = dab or dah), whereas exchange reactions take place generally in the presence of en or dap. The reaction trend is described on the basis of IR and proton NMR spectra. The new dithiocar- bamate complexes were preliminarily tested for their cytotoxicity on human cancer cells
Synthesis, characterization and cytotoxic properties of platinum(II) complexes containing the nucleosides adenosine and cytidine
Full text linkCytidine (cyt) and adenosine (ado) react with cis-[L(2)Pt(μ-OH)](2)(NO(3))(2) (L=PMe(3), PPh(3)) in various solvents to give the nucleoside complexes cis-[L(2)Pt{cyt(-H),N(3)N(4)}](3)(NO(3))(3) (L=PMe(3), 1),cis-[L(2)Pt{cyt(-H),N(4)}(cyt,N(3))]NO(3) (L=PPh(3), 2), cis-[L(2)Pt{ado(-H),N(1)N(6)}](2)(NO(3))(2) (L=PMe(3), 3) and cis-[L(2)Pt{ado(-H),N(6)N(7)}]NO(3) (L=PPh(3), 4). When the condensation reaction is carried out in solution of nitriles (RCN, R=Me, Ph) the amidine derivatives cis-[(PPh(3))(2)PtNH=C(R){cyt(-2H)}]NO(3) (R=Me, 5a; R=Ph, 5b) and cis-[(PPh(3))(2)PtNH=C(R){ado(-2H)}]NO(3) (R=Me, 6a: R=Ph, 6b) are quantitatively formed. The coordination mode of these nucleosides, characterized in solution by multinuclear NMR spectroscopy and mass spectrometry, is similar to that previously observed for the nucleobases 1-methylcytosine (1-MeCy) and 9-methyladenine (9-MeAd). The cytotoxic properties of the new complexes, and those of the nucleobase analogs, cis-[(PPh(3))(2)PtNH=C(R){1-MeCy(-2H)}]NO(3) (R=Me, 7a: R=Ph, 7b), cis-[(PPh(3))(2)PtNH=C(R){9-MeAd(-2H)}]NO(3) (R=Me, 8a: R=Ph, 8b) have been investigated in a wide panel of human cancer cells. Interestingly, whereas the Pt(II) nucleoside complexes (1-4) did not show appreciable cytotoxicity, the corresponding amidine derivatives (7a, 7b, 8a, 8b, 5b, and 6b) exhibited a significant in vitro antitumor activity
A Pt(IV) Prodrug Combining Chlorambucil and Cisplatin: A Dual-Acting Weapon for Targeting DNA in Cancer Cells
Full text linkIn this study, two DNA-targeting agents, cisplatin and chlorambucil, were combined in a Pt(IV) prodrug, 1, which was thoroughly characterized by means of spectroscopic and spectrometric techniques. Tested towards a panel of various human tumor cell lines, this compound showed superior in vitro antitumor potential than the reference drug cisplatin. In addition, an antitumor potential of 1 was found, which is comparable to that of oxaliplatin in 3D spheroid models of colon cancer cells. Mechanistic studies performed in colon cancer cells confirmed that the conjugation of chlorambucil to Pt(IV) cisplatin-based scaffold tunes the lipophilicity of the prodrug, consequently improving the ability of the compound to accumulate into cancer cells and to target DNA, ultimately leading to apoptotic cancer cell death
Stability of antibacterial Te(IV) compounds: A combined experimental and computational study
Full text linkInorganic Te(IV) compounds are important cysteine protease inhibitors and antimicrobial agents; AS-101 [ammonium trichloro (dioxoethylene-O,O′)tellurate] is the
first compound of a family with formula NH4[C2H4Cl3O2Te], where a Te(IV) centre is bound to a chelate ethylene glycol, and showed several protective therapeutic
applications. This compound is lacking in stability performance and is subjected to hydrolysis reaction with displacement of the diol ligand. In this paper, we report
the stability trend of a series of analogues complexes of AS-101 with generic formula NH4[(RC2H3O2)Cl3Te], where R is an alkyl group with different chain length and
different electronic properties, in order to find a correlation between structure and stability in aqueous-physiological conditions. The stability was studied in solution
via multinuclear NMR spectroscopy (1
H, 13C, 125Te) and computationally at the Density Functional Theory level with an explicit micro solvation model. The
combined experimental and theoretical work highlights the essential role of the solvating environment and provides mechanistic insights into the complex decomposition reaction. Antimicrobial activity of the compounds was assessed against different bacterial strains
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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