174 research outputs found
Palladium organometallic compounds bearing N-Heterocyclic Carbene ligands as promising anticancer agents
No full textDespite the appearance in the market of platinum compounds with minor side effects than cisplatin (i.e. carboplatin and oxaliplatin), they did not solve the ineffectiveness on some types of tumors, having the same mechanism of action proposed for cisplatin (DNA platination).
For this reason, many research groups have focused their attention on the synthesis and determination of the anticancer properties of compounds with metals different from platinum.
Among the most investigated metals there are certainly ruthenium and gold and, only recently, palladium.
The latter, despite belonging to the same group of platinum, has some rather different features:
•Better water solubility of its complexes.
•Structure-activity relationships and mechanisms of action generally different from platinum compounds.
However, the fast dissociation pattern of palladium complexes compared to platinum represents a problem since the speciation, which heavily affects the biological activity and the pharmacokinetic properties, could be increased. To remedy this contraindication the most direct option is the introduction of ligands firmly anchored to the metal such as N-Heterocylic Carbenes (NHCs), which are known to give strong s-bonds with most of the transition metals.
Moreover, several NHC-palladium complexes have already exhibited an interesting cytotoxic activity in vitro and tumour growth suppression even in vivo.
In this PhD thesis, the synthesis and characterization of new palladium compounds stabilized by different types of N-Heterocyclic Carbenes and important organometallic fragments such as h3-allyl-Pd(II), palladacyclopentadienyl and h2-olefin-Pd(0) will be exposed.
The reactivity and the importance in many catalytic processes of the fragments reported in Fig. A1 are well known, on the contrary, their biological activity is almost unexplored.
Starting from these premises, it was decided to test the synthesized compounds toward different tumor lines, particularly on ovarian carcinoma, and human fibroblasts (healthy cells).
From the antiproliferative activity data collected for about one hundred compounds, emerges that, regardless of the nature of the selected carbene ligand, the most active compounds bear the allyl fragment.
For these species the evaluation of their activity in vivo and experiments aimed at identify the primary biological target, in order to propose the possible mechanism of action, are planned.
A class of compounds generally slightly less active than that containing the allyl residue is represented by the palladacyclopentadienyl complexes and their derivatives. Nevertheless, for some of the synthesized compounds, an excellent antiproliferative and proapoptotic activity has been shown on ovarian cancer cell lines (CisPt sensitive and CisPt resistance), accompanied by a poor activity against normal cells.
For the compound 40a a thorough investigation on the main biological target, which was found to be DNA, and on the degree of uptake in tumor cells was also carried out.
Due to the high stability imparted by the palladaciclopentadienyl fragment and the chelatig biscarbene ligand, this compound does not undergo substitution reactions when reacted with reduced glutathione (GSH), which is a potential coordinating species present in abundance in the biological environment.
It is therefore reasonable to suppose that the interaction with the DNA occurs through non-covalent interactions with the polynucleotide chain.
Finally, the class of compounds decidedly less active than those described so far is represented by the Pd (0) derivatives stabilized by olefinic ligands. For these complexes the antiproliferative and proapoptotic activity was evaluated only in ovarian carcinoma lines, observing only in very few cases IC50 values comparable to those of cisplatin
La nascita di un corpus di scolii a Sofocle: il caso del Parmensis 3176 (De Rossi 8) e del Marc. Gr. IX 27
No full textThis paper deals with the Renaissance tradition of the scholia on Sophocles, both ancient and Byzantine. The focus will be on the manuscript Parma, Biblioteca Palatina, Parm. 3176 which hands down a peculiar set of scholia on Sophocles whereby ancient and Byzantine scholia written by Manuel Moschopoulos, Thomas Magister and Demetrius Triclinius are combined. The aim is threefold: (1) to clarify the principles according to which the Parma set of scholia was put together; (2) to present the manuscript Venezia, Biblioteca Nazionale Marciana, Marc. gr. ix 27 which I will show to be the only surviving complete apograph of the Parma recension; (3) to shed some light on the historical milieu of the manuscripts, with special regard to the vexed question of the missed opportunity of publishing the first print edition of the scholia to accompany the editio princeps of the tragedies of Sophocles (Venice 1502)
Antibody Drug Conjugates for Cancer Therapy: From Metallodrugs to Nature-Inspired Payloads
No full textThis review highlights significant advancements in antibody–drug conjugates (ADCs)
equipped with metal-based and nature-inspired payloads, focusing on synthetic strategies for antibody conjugation. Traditional methods such us maleimide and succinimide conjugation and classical condensation reactions are prevalent for metallodrugs and natural compounds. However, emerging non-conventional strategies such as photoconjugation are gaining traction due to their milder conditions and, in an aspect which minimizes side reactions, selective formation of ADC. The review also summarizes the therapeutic and diagnostic properties of these ADCs, highlighting their enhanced selectivity and reduced side effects in cancer treatment compared to non-conjugated payloads. ADCs combine the specificity of monoclonal antibodies with the cytotoxicity of chemotherapy drugs, offering
a targeted approach to the elimination of cancer cells while sparing healthy tissues. This targeted mechanism has demonstrated impressive clinical efficacy in various malignancies. Key future advancements include improved linker technology for enhanced stability and controlled release of cytotoxic agents, incorporation of novel, more potent, cytotoxic agents, and the identification of new cancer-specific antigens through genomic and proteomic technologies. ADCs are also expected to play a crucial role in combination therapies with immune checkpoint inhibitors, CAR-T cells, and small molecule inhibitors, leading to more durable and potentially curative outcomes. Ongoing research and clinical trials are expanding their capabilities, paving the way for more effective, safer, and personalized treatments, positioning ADCs as a cornerstone of modern medicine and offering new hope to patients
Liposomal Formulations of Metallodrugs for Cancer Therapy
No full textThe search for new antineoplastic agents is imperative, as cancer remains one of the most
preeminent causes of death worldwide. Since the discovery of the therapeutic potential of cisplatin,
the study of metallodrugs in cancer chemotherapy acquired increasing interest. Starting from cisplatin
derivatives, such as oxaliplatin and carboplatin, in the last years, different compounds were explored,
employing different metal centers such as iron, ruthenium, gold, and palladium. Nonetheless,
metallodrugs face several drawbacks, such as low water solubility, rapid clearance, and possible side
toxicity. Encapsulation has emerged as a promising strategy to overcome these issues, providing both
improved biocompatibility and protection of the payload from possible degradation in the biological
environment. In this respect, liposomes, which are spherical vesicles characterized by an aqueous
core surrounded by lipid bilayers, have proven to be ideal candidates due to their versatility. In
fact, they can encapsulate both hydrophilic and hydrophobic drugs, are biocompatible, and their
properties can be tuned to improve the selective delivery to tumour sites exploiting both passive
and active targeting. In this review, we report the most recent findings on liposomal formulations of
metallodrugs, with a focus on encapsulation techniques and the obtained biological results
Confronto tra i filtri di Tow-Thomas e Kerwin-Huelsman-Newcomb
No full textLa tesi realizzata ha come scopo il confronto su basi teoriche dei filtri composti da celle biquadratiche di Tow-Thomas e Kerwin-Huelsman-Newcomb, in particolare si suddivide nelle seguenti aree tematiche: introduzione ai filtri ideali e reali, analisi della struttura di celle biquadratiche con doppio integratore ad anello di retroazione, sintesi del filtro attraverso l’utilizzo di MATLAB (date le specifiche), simulazione dei filtri progettati tramite software Cadence, analisi teorica della sensibilità alle variazioni parametriche e conclusioni finaliope
Synthetic routes to late transition metal-NHC complexes
No full textTransition metal complexes bearing N-heterocyclic carbene ligands (NHCs) have gained a place of crucial importance in numerous areas of research such as medicinal chemistry, material sciences, and homogeneous/heterogeneous catalysis. In the present review, an updated overview of the main synthetic routes used for the preparation of this broad class of compounds along with their main applications are reported. Particular attention will be paid to the synthesis of late transition metal-NHC complexes using weak bases, eco-friendly solvents, and mild operating conditions. This simple synthetic approach, also known as the 'weak base route', represents a recent development with yet unrealized potential
The addition of bromine and iodine to palladacyclopentadienyl complexes bearing bidentate heteroditopic P−N spectator ligands derived from differently substituted quinolinic frames. The unexpected evolution of the reaction.
No full textWe have synthesized two palladacyclopentadienyl derivatives bearing bidentate ligands heteroditopic
8-(diphenylphosphino)quinoline or 8-(diphenylphosphino)-2-methylquinoline. We have reacted the palladacyclopentadienyl
complexes with Br2 and I2 to gain clues on the formation mechanism of the corresponding
σ-butadienyl derivatives. We were able to obtain the pure σ-butadienyl derivative only in the case
of Br2 reacting with the palladacyclopentadienyl complex bearing the unsubstituted quinoline. However,
an equilibrium mixture of the σ-butadienyl and a novel zwitterionic species was obtained when the same
complex reacts with I2. Furthermore, we have obtained exclusively an unprecedented zwitterionic
complex when I2 reacts with the palladacyclopentadienyl complex bearing the substituted quinoline and
a different ratio of an equilibrium mixture of σ-butadienyl and the zwitterionic species when the latter
derivative reacts with Br2. The solid state structures of one σ-butadienyl complex and of the two novel
zwitterionic derivatives were determined and an interpretation of the observed reactivity based on kinetic
data and a computational study has been suggested
Reactions of palladium(0) olefin complexes stabilized by some different hetero- and homo-ditopic spectator ligands with propargyl halides
No full textSeveral new allenyl and propargyl complexes have been obtained by oxidative addition with propargyl chlorides of palladium (0) olefin complexes stabilized by N−N, P−P, N−P, N−S. and N−C homo− and hetero−ditopic spectator ligands. The oxidative addition of some of the isolated palladium(0) olefin derivatives with 3−chloro−1−propyne and 3−chloro−1− phenyl−propyne has been investigated and the ensuing tautomeric mixtures bearing propargyl and allenyl fragmenst η1− coordinated isolated. As a consequence of a detailed kinetic study, we have analyzed the influence of the electronic and steric parameters of the involved reactants and hypothesized the mechanism of reaction. The tautomeric rearrangement of one allenyl isomer into its propargyl counterpart was also investigated and in this case the complete determination of all the rate constants involved has been obtained. Beside these studies, two very rare η3−propargyl palladium derivatives have been isolated and characterized
Platinum(0)-η2-1,2-(E)ditosylethene Complexes Bearing Phosphine, Isocyanide and N-Heterocyclic Carbene Ligands: Synthesis and Cytotoxicity towards Ovarian and Breast Cancer Cells
No full textA wide range of platinum(0)-η2-(E)-1,2-ditosylethene complexes bearing isocyanide, phosphine and N-heterocyclic carbene ancillary ligands have been prepared with high yields and selectivity. All the novel products underwent thorough characterization using spectroscopic techniques,
including NMR and FT-IR analyses. Additionally, for some compounds, the solid-state structures were elucidated through X-ray diffractometry. The synthesized complexes were successively evaluated for their potential as anticancer agents against two ovarian cancer cell lines (A2780 and A2780cis) and one breast cancer cell line (MDA-MB-231). The majority of the compounds displayed promising cytotoxicity within the micromolar range against A2780 and MDA-MB-231 cells, with IC50 values comparable to or even surpassing those of cisplatin. However, only a subset of compounds was cytotoxic against cisplatin-resistant cancer cells (A2780cis). Furthermore, the assessment of antiproliferative
activity on MRC-5 normal cells revealed certain compounds to exhibit in vitro selectivity. Notably, complexes 3d, 6a and 6b showed low cytotoxicity towards normal cells (IC50 > 100 μM) while concurrently displaying potent cytotoxicity against cancer cells
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