1,721,181 research outputs found
Metal complexes as potential anticancer agents
Full text linkMetal-based antitumor drugs play a relevant role in antiblastic chemotherapy. Cisplatin is regarded as one of the most effective drugs, even if severe toxicities and drug resistance phenomena limit its clinical use. Therefore, in recent years there has been a rapid expansion in research and development of novel metal-based anticancer drugs to improve clinical effectiveness, to reduce general toxicity and to broaden the spectrum of activity.
The variety of metal ion functions in biology has stimulated the development of new metallodrugs other than Pt drugs with the aim to obtain compounds acting via alternative mechanisms of action. This work has been dedicated to the investigation of the behaviour, at cellular, subcellular and molecular level of copper(I) and gold(I) phosphine complexes.
Concerning gold(I) complexes, we highlighted their ability of interacting with one of the most important system involved in redox cellular homeostasis, thus creating the pathophysiological conditions stimulating mitochondria to undergo the way of apoptosis. Acting as potent inhibitors of the selenoenzyme thioredoxin reductase, gold complexes determine an alteration of the redox state of the cell leading to an increased production of hydrogen peroxide and oxidation of the components of the thioredoxin system, therefore creating the conditions for augmented apoptosis.
Differently, phosphine copper complexes were found to activate an atypical programmed cell death pathway. Indeed, they inhibit tumor cell growth through paraptosis, an alternative non-apoptotic cell death mechanism characterized by a massive cytoplasmatic vacuolization and a consequent ER stress. This different way to induce a programmed cell death appeared particular interesting as these copper complexes may be utilized in inducing cell death even in tumors resistant to apoptosis-inducting therapies.I complessi metallici ricoprono un ruolo rilevante nella terapia anticancro. Il cisplatino è riconosciuto come uno dei farmaci più attivi, anche se sia la sua tossicità che lo sviluppo di resistenza limitano fortemente il suo impiego clinico. Negli ultimi anni, quindi, la ricerca si è indirizzata verso lo sviluppo di nuovi complessi metallici come potenziali agenti antitumorali, al fine di ottenere composti che presentino maggior efficacia e posseggano una minore tossicità ed un più ampio spettro d’azione.
La varietà di funzioni biologiche svolte dagli ioni metallici ha notevolmente stimolato in particolare lo sviluppo di complessi metallici contenenti metalli diversi dal platino, allo scopo di ottenere composti che agiscano attraverso un meccanismo d’azione diverso. In tale ambito, questo lavoro è stato dedicato allo studio gli effetti a livello cellulare, subcellulare e molecolare indotti da complessi fosfinici di oro(I) e rame(I).
Per quanto concerne i complessi fosfinici di oro(I), è stato messo in luce la loro capacità di interagire a livello il selenoenzima tioredossina reduttasi, creando condizioni fisiopatologiche in grado di stimolare la via mitocondriale dell’apoptosi in cellule tumorali.
I complessi di oro(I), agendo come potenti e selettivi inibitori della tioredossina reduttasi determinano una alterazione dello stato redox cellulare che a sua volta porta all’aumento della produzione cellulare di perossido di idrogeno oltre che all’ossidazione dei componenti del sistema tioredossinico. Questo sbilancio dell’omeostasi cellulare determina induzione della morte cellulare per apoptosi.
Diversamente, l’attività antitumorale indotta dai complessi di rame(I) è stata correlata alla loro capacità di indurre una morte cellulare programmata atipica. Infatti, essi inibiscono la crescita cellulare tumorale mediante induzione di paraptosi, un meccanismo di morte cellulare caratterizzato dalla massiccia formazione di vacuoli e da un conseguente stress del reticolo endoplasmatico.
L’induzione di morte cellulare mediante un meccanismo diverso da quello dell’apoptosi appare particolarmente interessante poiché questi complessi di rame(I) potrebbero essere impiegati nel trattamento di cellule tumorali che hanno sviluppato numerosi meccanismi al fine di eludere l’induzione di apoptosi
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
Psoralenquinone proteasome inhibitors: design, synthesis and biological evaluation
No full textProteasome is an emerging target for novel drugs development. Proteasome in fact is a complex machinery involved in the intracellular protein homeostasis, and its overexpression or deregulation could been involved in cancer onset and progression or in inflammatory diseases. Human 26S proteasome is a cylinder-shaped multimeric protein complex composed by a 20S proteasome core particle (which present the catalytic activities) and a 19S component (which is involved in activity regulation). Three proteolytic activities have been to date recognized in the 20S proteasome as function of cleavage preferences: chymotripsin-like (CT), trypsin-like (T) and peptidyl-glutamyl-peptide-hydrolising (PGPH). All these activities are located in well-defined cavities and are mediated by N-terminal Threonine residues. Several peptidomimics inhibitors have been to date developed and cocrystallized with the 20S subunit. One of them, Bortezomib, have received FDA approval in 2004 for anticancer therapy. More recently several non-peptidomimics inhibitors have been individuated through virtual screening approach.
Herein we present the discovery, synthesis and biological evaluation of novel proteasome inhibitors bearing psoralenquinone structure.
Depending on the scaffold decoration it has been possible to obtain PGPH selective inhibitors and CT/T selective inhibitors. This chance was not previously observed for any other classes of derivatives until developed.
All compounds have been designed through a multi-docking approach and have been evaluated for their ability to inhibit the degradation of specific peptides. All biological data have been compared with those relative to Bortezomib and Lactacystin. Finally, a preliminary Structure Activity Relationship have been proposed
Metal- and semimetal-containing inhibitors of thioredoxin reductase as anticancer agents
Full text linkThe mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide disulfide oxidoreductases playing a central role in cellular redox homeostasis and signaling pathways. Recently, these selenoproteins have emerged as promising therapeutic targets for anticancer drug development, often being overexpressed in tumor cells and contributing to drug resistance. Herein, we summarize the current knowledge on metal- and semimetal-containing molecules capable of hampering mammalian TrxRs, with an emphasis on compounds reported in the last decade
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
Targeting kinases with anilinopyrimidines: discovery of N-phenyl-N’-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of Type III receptor tyrosine kinase subfamily
No full textKinase inhibitors are attractive drugs/drug candidates for the treatment of cancer. The most recent literature has highlighted the importance of multi-target kinase inhibitors, although a correct balance between specificity and non-specificity is required. In this view, the discovery of multi tyrosine kinase inhibitors with subfamily selectivity is a challenging goal. Herein we present the synthesis the kinase profiling and the biological evaluation of a set of novel 4-anilinopyrimidines as promising anticancer compounds. Molecular modeling simulations were used in order to rationalize the behavior of the title compounds.
Among synthesized compounds, N-phenyl-N’-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives targeted some members of type III receptor tyrosine kinase family. In particular, compound 24 was identified as a selective dual KIT/PDGFRbeta inhibitor. The compound was more cytotoxic than sunitinib against A549 and PxPC3 human cancer cell lines, and showed a preferential antiproliferative activity toward neoplastic rather than HEK293 non-tumor cells.
Overall, our data suggested that the 4-anilino-6-phenylpyrimidines constitute a promising class of subfamily selective inhibitors of Type III RTKs subfamily. These results are of remarkably importance since, despite the huge interest in identifying subfamily selective kinase inhibitors, poorly toxic and highly active as antitumor agents, nowadays there is still a paucity of reports investigating their antitumor activity
Special Issue “Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0”
No full textThe year 2023 marks the 45th year since FDA approval of cisplatin as an anticancer drug, and, at present, it is widely used against a spectrum of human tumors, including early-stage ovarian cancer, non-small cell lung cancer (typically developed by smokers), head and neck, and advanced bladder cancer [...
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
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