2,622 research outputs found
Synthesis, characterization, reactivity and biological evaluation of octahedral Pt(IV) prodrugs with active axial ligands
No full textPlatinum(II) complexes are very important drugs in anticancer chemotherapy. Although few Pt(II) complexes have been approved for the clinical use, in recent years attention has been paid to Pt(IV) complexes as prodrugs, which generally exhibit higher chemical inertness than their Pt(II) counterparts and undergo fewer side reactions with biomolecules. These complexes can be in vivo reduced in the hypoxic and reducing environment of the tumor so that the octahedral Pt(IV) complexes are transformed into their active square-planar Pt(II) metabolites by loss of the axial ligands (activation by reduction). The choice of the ligands is essential to modulate lipophilicity and redox properties of the Pt(IV) prodrugs: they can be biologically active molecules themselves (synthesizing, in this way, bifunctional prodrugs) or linker between the Pt core and a vector for drug targeting and delivery (DTD) methods.
The works of this thesis is composed by three projects about three different topics of the modern research on platinum anticancer drug development.
The first project involves the development of a new way for the oxidation of Pt(II) complexes with N-chlorosuccinimide as oxidant in ethylene glycol and the study of the stability and reactivity toward different reactions (esterification, synthesis of carbamates and CuAAC click chemistry reaction) of the resulting axially unsymmetric Pt(IV) complexes.
The second project, inspired by the philosophy of the active drug targeting and delivery strategy, is aimed to evaluate the effect of the anchoring site of glutamine and glutamine-like to the platinum complex on the cellular recognition by means of antiproliferative activity and cellular uptake tests.
The third project is focused on the bifunctional drug concept and is structured in the synthesis, characterization and evaluation of the antiproliferative activity of cisplatin- and [PtCl2(1R,2R-cyclohexanediamine)]- based Pt(IV) complexes bearing clofibric and perillic acid as bioactive axial ligands
Synthesis of PtIV-Biomolecule Conjugates through Click Chemistry
No full textThe azide-functionalized PtIV complex (OC-6–34)-chlorido(cyclobutane-1,1′-dicarboxylato)(cyclohexane-1R,2R-diamine)[2-hydroxyethyl(2-2-[2-(2-azidoethoxy)ethoxy]ethoxyethyl)carbamate]platinum(IV) was synthesized and characterized to obtain a starting complex that was suitable for coupling with appropriate biological carriers in a drug targeting and delivery strategy. The following click reaction (CuI-catalyzed Huisgen cycloaddition, CuAAC) was successfully applied for coupling with three different model biomolecules that can be exploited for selective targeting of the platinum conjugate toward tumor cells; i.e., the amino acid alanine and the dipeptide lysine-alanine, both previously alkyne-functionalized with pent-4-ynoic acid, and the hormone 17α-ethynylestradiol. The title complex demonstrated very good compatibility with both CuAAC reaction and solid-phase peptide synthesis conditions, making it a suitable antiproliferative fragment for the design of nanovectors
May glutamine addiction drive the delivery of antitumor cisplatin-based Pt(IV) prodrugs?
No full textA small series of Pt(IV) prodrugs containing Gln-like (Gln=glutamine) axial ligands has been designed with the aim to take advantage of the increased demand of Gln showed by some cancer cells (glutamine addiction). In complex 4 the Gln, linked through the α-carboxylic group is recognized by the Gln transporters, in particular by the solute carrier transporter SLC1A5. All compounds showed cellular accumulation, as well as antiproliferative activity, related to their lipophilicity, as already demonstrated for the majority of Pt(IV) prodrugs, that enter cells mainly by passive diffusion. On the contrary, when the Gln concentration in cell medium is near or lower to the physiological value, complex 4 acts as a Trojan horse: it enters SLC1A5-overexpressing cells, where, upon reduction, it releases the active metabolite cisplatin and the Gln-containing ligand, thus preventing any possible extrusion by the L-type amino acid transporter LAT1. This selective mechanism could decrease off-target accumulation of 4 and, consequently, Pt-associated side-effects
Who is the author of the 1876 Stefano manuscript?
No full textFor over one hundred years the Stefano manuscript was a private document in the possession of the Baccich family and descendants. It told a story of the 1875 Stefano shipwreck as narrated by the shipwreck survivor and the founding family patriarch Miho Baccich. In these circumstances the question of authorship of the manuscript was immaterial and did not arise as an issue. However, with the publication of the manuscript the author‟s name, or names, need to be formally attributed to it. It turns out that this is not such a clear-cut matter.
As we shall see, all informed sources attributed the authorship, and the ownership, of the manuscript to Miho Baccich. But the manuscript itself was written by Canon Stjepan Skurla – a priest from Miho‟s hometown of Dubrovnik. The question then arises: should Skurla also be considered as an author of the manuscript, or, even as the sole author (as some would have it)
A new entry to asymmetric platinum(IV) complexes via oxidative chlorination
No full textPt(IV) complexes are usually prepared by oxidation of the
corresponding Pt(II) counterparts, typically using hydrogen peroxide or
chlorine. A different way to synthesize asymmetrical Pt(IV) compounds is the
oxidative chlorination of Pt(II) counterparts with N-chlorosuccinimide. The
reaction between cisplatin cis-[PtCl2(NH3)2], carboplatin, cis-[PtCl2(dach)]
and cis-[Pt(cbdc)(dach)] (cbdc = cyclobutane-1,1′-dicarboxylato; dach =
cyclohexane-1R,2R-diamine) with N-chlorosuccinimide in ethane-1,2-diol was
optimized to produce the asymmetric Pt(IV) octahedral complexes [PtA2Cl-
(glyc)X2] (A2 = 2 NH3 or dach; glyc = 2-hydroxyethanolato; X2 = 2 Cl or
cbdc) in high yield and purity. The X-ray crystal structure of the
[Pt(cbdc)Cl(dach)(glyc)] complex is also reported. Moreover, the oxidation method proved to be versatile enough to produce
other mixed Pt(IV) derivatives varying the reaction medium. The two trichlorido complexes easily undergo a pH-dependent
hydrolysis reaction, whereas the dicarboxylato compounds are stable enough to allow further coupling reactions for drug
targeting and delivery via the glyc reactive pendant. Therefore, the coupling reaction between the [Pt(cbdc)Cl(dach)(glyc)] and
a model carboxylic acid, a model amine, and selectively protected amino acids is reported
Keratinocyte wound healing activity of galactoglycerolipids from the fern Ophioglossum vulgatum L.
No full textThe genus Ophioglossum consists of ferns with different therapeutic properties, including vulnerary virtues. The species Ophioglossum vulgatum L. is traditionally used on wounds and burns as an ointment, suggesting the occurrence of lipophilic compounds with tissue repair properties. We isolated and characterized a galactosyldiacylglycerol mixture (1), composed mainly of 1,2-di-O-linolenoyl-3-O-β-D-galactopyranosyl-glycerol, from the frond dichloromethane extract. The wound healing properties of 1 were assessed in vitro on keratinocytes. Scratch wound assays showed increased wound closure rates in keratinocyte monolayers exposed to subtoxic doses, previously determined in cytotoxicity assays. The strongest effect, obtained at a dose of 5 μg/mL, approached that of a platelet lysate used in clinical settings. The use of inhibitors of the main cellular pathways involved in wound repair, revealed important roles for intracellular calcium and the ERK1/2 MAP kinase. Conversely, a PCR array of genes involved in wound healing showed an almost total absence of gene modulation. Taken together, the data suggest that 1 acts through a Ca2+-dependent, nongenomic mechanism involving the activation of ERK1/2 MAP kinase. Hence, 1 is a main candidate to explain the wound healing virtues of O. vulgatum ointment, and is proposed as a possible new drug in tissue repair and regenerative medicine
Fashion Culture: Power In Fashion with Stefano Tonchi and Grazia d'Annunzio
No full textStefano Tonchi, global chief creative officer for L’Officiel Group, and Grazia d’Annunzio, former deputy director of Vogue Italia, discuss the power of military uniforms and their influence on high fashion. Tonchi is co-author of the book "Uniform: Order and Disorder.
Introduzione [a I cartolari del notaio Stefano di Corrado di Lavagna]
No full textSaggio introduttivo all’edizione dei frammenti dei protocolli del notaio Stefano di Corrado di Lavagna nel quale viene fatta l’analisi codicologica dei frammenti e si ricostruisce la biografia del notaio. Vengono inoltre esaminate la tipologia dei documenti, le tecniche redazionali del notaio e l’organizzazione burocratica della Chiesa genovese nella seconda metà del secolo XIII.
Introduction essay to the edition of the fragments of the protocols of the notary Stefano di Corrado of Lavagna in which the analysis of the codex fragments and reconstructs the biography of the notary is made by the author. She also examined the types of documents, the technical drafting of the notary and the bureaucratic organization of the Church of Genoa in the second half of the thirteenth century
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