The interaction of transition metal complexes with deoxyribonucleic acid

La presente tesi `e suddivisa in quattro capitoli. Il Capitolo 1 `e di carattere introduttivo. Nel Capitolo 2 viene trattata la sintesi e la caratterizzazione strutturale dei complessi di CuII, NiII e ZnII con il legante N,N’-Bis-5-(trietil ammonio metil salicilidene)-1,2- fenilendiammina. Inoltre, vengono riportati e confrontati i risultati dello studio della loro interazione con DNA nativo. Viene in particolare mostrato come l’interazione con DNA aumenti la stabilit`a fotochimica del complesso di ZnII. Infine, vengono evidenziati gli effetti del confinamento in cristalli liquidi sull’interazione del complesso di CuII e DNA.Nel Capitolo 3 `e riportata la sintesi e la caratterizzazione strutturale dei complessi di CuII, ZnII e NiII con due leganti 1,2,4-ossadiazolici sostituiti. Viene inoltre riportato il primo studio sull’attivit`a biologica di un complesso di rame(II) con un legante di questo tipo. I saggi biologici mostrano che, sebbene uno dei due leganti non sia efficace, il suo complesso di rame riduce la vitalit`a di linee cellulari umane di epatoblastoma e di carcinoma colorettale. I risultati dei saggi biologici trovano riscontro negli studi di interazione con DNA dello stesso complesso. Infine, nel Capitolo 4 `e riportata la sintesi e la caratterizzazione strutturale di un legante derivato dal 2,7-diazapirenio e di un suo metallociclo binucleare di PtII oltre che lo studio, spettroscopico ed elettroforetico, della loro interazione con DNA nativo. Sono infine riportati risultati di saggi in vitro che dimostrano la citotossicit`a di tali composti nei confronti di diverse linee cellulari tumorali.This thesis is divided in four chapters. The aim of the work and a general introduction on the main DNA-drugs binding modes are reported in Chapter 1. In Chapter 2, the synthesis and structural characterization of CuII, NiII e ZnII complexes of N,N’-Bis-5- (triethyl ammonium methyl salicylidene)-1,2-phenylenediamine will be described. Furthermore, the results of the investigation of their interaction with native DNA will be reported and compared. In particular, it will be shown that the interaction with DNA increases the photochemical stability of the ZnII complex. Finally, the confinement effects of tetraethylene glycol monododecyl ether liquid crystals on the interaction of the CuII complex with DNA will be highlighted. The synthesis and structural characterization of CuII, ZnII and NiII complexes of two 1,2,4-oxadiazole ligands is presented in Chapter 3. Moreover, the first study of the biological activity of a copper(II) complex of 1,2,4-oxadiazole ligands is reported. In this respect, biological assays show that, despite the free ligand is not being effective, its CuII complex reduces the vitality of human hepatoblastoma and colorectal carcinoma cells in a dose- and time-dependentmanner. The results of the biological assays receive a positive feedback in the DNA binding studies performed for the same complex. Finally, in Chapter 4, the synthesis and structural characterization of a 2,7-diazapyrenium derivate and of his binuclear PtII metallacycle is reported, as well as the spectroscopic and electrophoretic study of their interaction with native DNA. Finally, in vitro essays are reported that show the cytotoxic effect of such compounds toward tumor cell lines

(Dipyrido[3,2-a:2',3'-c]phenazine)(glycinato)copper(II) perchlorate: A novel DNA-intercalator with anti-proliferative activity against thyroid cancer cell lines

A novel copper(II) heteroleptic complex of dipyrido[3,2-a:2′,3′-c]phenazine (dppz) and glycinato (gly) as chelating ancillary ligand, [Cu(dppz)(gly)]ClO4 (1), was synthesized and characterized. X-ray crystallography revealed that the coordination geometry of the cationic [Cu(dppz)(gly)]+ unit is hexacoordinated and shows a distorted octahedral coordination geometry in the solid state, with the N,N and N,O chelating atoms of dppz and glycinato, respectively, in the square plane and in which the planar units are connected in a monodimensional polymeric array by the apical copper coordination of the second carboxylic oxygen atom. Biological assays showed that 1 exhibits a remarkable anti-proliferative activity against the two human anaplastic thyroid cancer cell lines 8505c (BrafV600E/V600E) and SW1736 (BrafWT/V600E), in a dose- and time-dependent manner. In details, the IC50 after 48 h of drug exposure was 2.86±0.54 μM for SW1736 and 1.05±0.48 μM for 8505c. On the other hand, the IC50 shown by cis-diamminedichloroplatinum(II) (cisplatin) against the same cell lines was 2.50±0.40 μM and 6.03±0.78 μM, respectively. Optical microscopy observations, after 48 h of treatment, showed morphological cell changes typical of apoptosis, confirmed by DNA ladder assays. DNA interaction studies, performed by UV absorption spectrophotometry, circular dichroism and viscosimetry, clearly showed that [Cu(dppz)(gly)]ClO4 is a DNA-intercalator, with a DNA-binding constant, Kb, of 2.1×106 M−1, suggesting that the mechanism of the cytotoxic activity can be related to its DNA-binding

Understanding the Interactions of Guanine Quadruplexes with Peptides as Novel Strategies for Diagnosis or Tuning Biological Functions

Guanine quadruplexes (G4s) are nucleic acid structures exhibiting a complex structural behavior and exerting crucial biological functions in both cells and viruses. The specific interactions of peptides with G4s, as well as an understanding of the factors driving the specific recognition are important for the rational design of both therapeutic and diagnostic agents. In this review, we examine the most important studies dealing with the interactions between G4s and peptides, highlighting the strengths and limitations of current analytic approaches. We also show how the combined use of high-level molecular simulation techniques and experimental spectroscopy is the best avenue to design specifically tuned and selective peptides, thus leading to the control of important biological functions

ANALISI DI LUNGO PERIODO DELLA TRASFORMAZIONE DEL PAESAGGIO FORESTALE NELL’AREA METROPOLITANA DI ROMA CAPITALE A SUPPORTO DELLA GOVERNANCE DEL TERRITORIO PER LA TRANSIZIONE ECOLOGICA

Restoring the forest ecosystem’s functionality is as an urgent action for biodiversity conservation and carbon mitigation as well as for achieving the 2030 Agenda of United Nations sustainability goals. By developing a landscape dynamics framework to guide future management and planning policies we characterised the historical trend of forest area changes from 1936 to 2010 in the Metropolitan City of Rome Capital (Italy). Remote sensing-based products and historical forest maps, coupled with landscape pattern metrics and fragmentation analysis have been implemented. Two main forest landscape dynamics were reconstructed: I) the increase of forest cover fragmentation in the lowland areas; (II) the rise in forest area by recently established forest in the interior sectors of the mountain landscape, mainly within protected areas. Results revealed the urgent need to establish new protected areas and rewilding spaces. The proposed framework can be used for testing the effectiveness of environmental planning and management in other forest landscapes to achieve the Agenda 2030 goals and EU 2030 Biodiversity Strategy