Indirect daylight oxidative degradation of polyethylene microplastics by a bio-waste modified TiO2-based material

Microplastics are recognized as an emerging critical issue for the environment. Here an innovative chemical approach for the treatment of microplastics is proposed, based on an oxidative process that does not require any direct energy source (irradiation or heat). Linear low-density polyethylene (LLDPE) was selected as target commodity polymer, due to its widespread use, chemical inertness and inefficient recycling. This route is based on a hybrid material coupling titanium oxide with a bio-waste, rosin, mainly constituted by abietic acid, through a simple sol-gel synthesis procedure. The ligand-to-metal charge transfer complexes formed between rosin and Ti4+ allow the generation of reactive oxygen species without UV irradiation for its activation. In agreement with theorical calculations, superoxide radical ions are stabilized at ambient conditions on the surface of the hybrid TiO2. Consequently, an impressive degradation of LLDPE is observed after 1 month exposure in a batch configuration under indirect daylight, as evidenced by the products revealed by gas chromatography-mass spectrometry analysis and by chemical and structural modifications of the polymer surface. In a context of waste exploitation, this innovative and sustainable approach represents a promising cost-effective strategy for the oxidative degradation of microplastics, without producing any toxic by-products

The pivotal role of MBD4-ATP7B in the human Cu(i) excretion path as revealed by EPR experiments and all-atom simulations

Copper's essentiality and toxicity require a meticulous mechanism for its acquisition, cellular distribution and excretion, which remains hitherto elusive. Herein, we jointly employed electron paramagnetic resonance spectroscopy and all-atom simulations to resolve the copper trafficking mechanism in humans considering the route travelled by Cu(i) from the metallochaperone Atox1 to the metal binding domains 3 and 4 of ATP7B. Our study shows that Cu(i) in the final part of its extraction pathway is most likely mediated by binding of Atox1 monomer to MBD4 of ATP7B. This interaction takes place through weak metal-stabilized protein-protein interactions

Transition metal-based complexes as chemitherapeutic agents. Theoretical investigation of MoA, interaction with biological molecules and environmental conditions

Dottorato di Ricerca in Medicina Traslazionale. Ciclo XXIXMolti metalli e, conseguentemente, molti complessi metallici svolgono ruoli importanti all’interno di sistemi biologici e biochimici. Oggigiorno, è risaputo che essi rappresentano ingredienti molto importanti per la vita altrettanto quanto i composti organici. Per esempio, i complessi di ferro svolgono un ruolo fondamentale nel trasporto di O2 nel sangue, i complessi di calcio sono alla base delle ossa, lo zinco è presente nell’ insulina che regola la quantità di zucchero nel nostro corpo. Questo è possibile perché i metalli possiedono particolari proprietà chimiche. Infatti, tendono facilmente a perdere elettroni, diventando specie elettron-deficienti più reattive nei confronti di diverse molecole biologiche e più solubili in soluzioni acquose. I metalli non solo sono elementi vitali in molti fenomeni biologici, ma possono anche essere sfruttati per il trattamento di diverse malattie. L'esempio più importante di questa categoria di composti è il complesso organometallico cisplatino [Pt(Cl)2(NH3)2], il chemioterapico più potente disponibile sul mercato. Scoperto nel 1969 da Rosenberg, esso svolge un ruolo chiave nell’ inibizione della divisione cellulare, causando la morte delle cellule tumorali. Dopo la scoperta della sua attività citotossica, l'applicazione di farmaci metallici nelle varie terapie ha registrato una crescita enorme e la continua ricerca dell'uso di metalli in medicina, in particolare per la cura del cancro, è diventata una disciplina, indicata come Medicinal Inorganic Chemistry. Dopo la scoperta del cisplatino, altri due farmaci antitumorali a base di platino, derivati del cisplatino, sono stati scoperti: carboplatino e ossaliplatino. Questi complessi esercitano la loro azione citotossica coordinando il DNA e bloccando la divisione cellulare. Tuttavia, anche se questi complessi, di formula generale [Pt(X)2(L)2], sono ancora tra i farmaci più frequentemente utilizzati, risultano essere tossici a causa della loro reattività e instabilità. In questi anni, per superare i problemi relativi all’uso di complessi di Pt(II), l’ attenzione è stata concentrata sullo sviluppo di nuovi complessi, generando due diverse categorie di farmaci antitumorali: i complessi di Pt(IV), considerati "profarmaci" e ottenuti per ossidazione dai complessi di Pt(II), e i "farmaci che non contengono platino", come i complessi di iridio, rodio, osmio o rutenio. Le caratteristiche di questi farmaci dovrebbero renderli più inerti, quindi più efficaci dei complessi di Pt(II), e provocare una differenziazione nel meccanismo di azione. Lo studio teorico dei sistemi biologici ha ormai raggiunto la maturità necessaria per fornire informazioni complementari rispetto a quelle ottenibili sperimentalmente nello studio di molte proprietà e fenomeni. Infatti, l’impressionante sviluppo sia delle metodologie teoriche, sia della tecnologia informatica ha consentito di fornire un importante supporto di studi teorici alle bioscienze. Inoltre, l’uso della teoria del funzionale della densità (DFT), che rappresenta un ottimo compromesso tra accuratezza e costi computazionali, è particolarmente adatto allo studio dei sistemi biologici come dimostrato dal fatto che negli ultimi anni sono stati completati con successo molti studi DFT e sono state affrontate questioni fondamentali nelle simulazioni biologiche. Scopo di questa tesi è lo studio teorico di farmaci antitumorali contenenti metalli, in particolare complessi di Pt(IV) e Ir(III), delle principali reazioni del farmaco che avvengono dal momento della sua iniezione o somministrazione orale al raggiungimento del suo bersaglio biologico e investigazione del meccanismo di azione che può essere sia quello classico, già proposto per il cisplatino e, quindi, associato all’accumulo cellulare e al legame con il DNA, sia un meccanismo di diversa natura. In alcuni casi, la teoria del funzionale della densità è stata utilizzata come approccio computazionale supportato da calcoli eseguiti a livello Coupled Cluster post Hartree-Fock nella sua versione CCSD(T).Università della Calabri

Disrupting Cu trafficking as a potential therapy for cancer

Copper ions play a crucial role in various cellular biological processes. However, these copper ions can also lead to toxicity when their concentration is not controlled by a sophisticated copper-trafficking system. Copper dys-homeostasis has been linked to a variety of diseases, including neurodegeneration and cancer. Therefore, manipulating Cu-trafficking to trigger selective cancer cell death may be a viable strategy with therapeutic benefit. By exploiting combined in silico and experimental strategies, we identified small peptides able to bind Atox1 and metal-binding domains 3-4 of ATP7B proteins. We found that these peptides reduced the proliferation of cancer cells owing to increased cellular copper ions concentration. These outcomes support the idea of harming copper trafficking as an opportunity for devising novel anti-cancer therapies

Unraveling the Impact of Cysteine-to-Serine Mutations on the Structural and Functional Properties of Cu(I)-Binding Proteins

Appropriate maintenance of Cu(I) homeostasis is an essential requirement for proper cell function because its misregulation induces the onset of major human diseases and mortality. For this reason, several research efforts have been devoted to dissecting the inner working mechanism of Cu(I)-binding proteins and transporters. A commonly adopted strategy relies on mutations of cysteine residues, for which Cu(I) has an exquisite complementarity, to serines. Nevertheless, in spite of the similarity between these two amino acids, the structural and functional impact of serine mutations on Cu(I)-binding biomolecules remains unclear. Here, we applied various biochemical and biophysical methods, together with all-atom simulations, to investigate the effect of these mutations on the stability, structure, and aggregation propensity of Cu(I)-binding proteins, as well as their interaction with specific partner proteins. Among Cu(I)-binding biomolecules, we focused on the eukaryotic Atox1-ATP7B system, and the prokaryotic CueR metalloregulator. Our results reveal that proteins containing cysteine-to-serine mutations can still bind Cu(I) ions; however, this alters their stability and aggregation propensity. These results contribute to deciphering the critical biological principles underlying the regulatory mechanism of the in-cell Cu(I) concentration, and provide a basis for interpreting future studies that will take advantage of cysteine-to-serine mutations in Cu(I)-binding systems

Straightforward synthesis of [Cu(NHC)(alkynyl)] and [Cu(NHC)(thiolato)] complexes (NHC = N-heterocyclic carbene)

Synthetic access to monomeric copper-alkynyl and copper-thiolato complexes of the type [(NHC)Cu(R)] (R = alkynyl or thiolato) using a weak base approach is reported. All reported reactions proceed under mild conditions in air and in environmentally acceptable solvents. The novel complexes are fully characterized and single crystal X-ray analyses unambiguously establish the atom connectivity in these mononuclear complexes. The importance of the supporting NHC ligand's steric properties in stabilizing mononuclear complexes is discussed

Recent advances in computational design of potent aromatase inhibitors: open-eye on endocrine-resistant breast cancers

Introduction: The vast majority of breast cancers (BC) are estrogen receptor positive (ER+). The most effective treatments to fight this BC type rely on estrogen deprivation therapy, by inhibiting the aromatase enzyme, which performs estrogen biosynthesis, or on blocking the estrogens signaling path via modulating/degrading the estrogen\u2019s specific nuclear receptor (estrogen receptor-\u3b1, ER\u3b1). While being effective at early disease stage, patients treated with aromatase inhibitors (AIs) may acquire resistance and often relapse after prolonged therapies. Areas covered: In this compendium, after an overview of the historical development of the AIs currently in clinical use, and of the computational tools which were used to identify them, the authors focus on current advances in obtaining innovative inhibitors via molecular simulations. These inhibitors may help prevent or delay relapse to AIs. Expert opinion: BC remains the most diagnosed and the leading cause of death in women. In spite of the success of the adjuvant endocrine therapy, which has enormously prolonged woman\u2019s survival rate, the increasing emergence of the resistance phenomena calls for the development of novel approaches and drugs to fight it. The discovery of the last generation of AIs dates back to two decades ago, underlying a paucity of research efforts

A green route to platinum N-heterocyclic carbene complexes : mechanism and expanded scope

A sustainable and facile weak-base synthetic route to platinum N-heterocyclic carbene (NHC) complexes is disclosed. The mechanism of this reaction is also elucidated via experimental and computational investigations. This straightforward protocol is then used for the synthesis of novel Pt(ii)-NHC complexes and its utility is further explored to access key Pt(0)-NHC precatalysts