Design and Synthesis of New Chemical Entities to Exploring the Multifactorial Nature of Alzheimer's Disease

Alzheimer’s disease (AD) is a multifactorial syndrome, with a complex interplay of genetic and biochemical factors contributing to the cognitive decline. Besides diffuse neuronal loss, AD brain shows protein folding defects, and there is growing evidence that amyloid-β peptide (Aβ) might trigger the disease process. In parallel, an increasing number of molecular targets, that may play an important role in the expression of its neurotoxicity, is emerging. In particular, the etiopathogenic loop generated by Aβ and oxidative stress indicates reactive oxygen species (ROS) overproduction as a crucial partner of Aβ toxicity. Moreover, a correlation between Aβ, oxidative stress and conformational changes of the transcription factor p53 has been suggested. In this context, (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway plays an important role as the major mechanism of defense in the cell against oxidative or electrophilic stress. Additionally, several evidences showed an attenuation of Aβ-induced oxidative cell death by means of activation of Nrf2 signaling, calling for a deeper investigation of Nrf2/Aβ cellular network. Besides that, an excessive glutamatergic activity together with the hyperactivation of extrasynaptic N-methyl-D-aspartate receptors (NMDARs) has been widely documented in AD. In particular, a relationship between NMDARs hyperactivation, ROS production and Aβ toxicity has been well established in AD. On the basis of these considerations, in order to obtain pharmacological tools to deepen insight into the cross-talk between Aβ functions and radical species in AD, in this project thesis new chemical entities have been synthesized combining natural privileged molecular fragments, which turned out to be versatile instruments to investigate Aβ causative role in AD. Furthermore, based on the MTDL (multi-target-directed ligand) approach, aimed to obtain single molecules able to simultaneously hit multiple targets, in this work thesis, multifunctional ligands have been developed by combining the NMDAR antagonist memantine with natural pharmacophores exerting antioxidant and anti-aggregating activities

Interfering Effects of Growing Chain Epimerization on Metallocene-Catalyzed Isotactic Propene Polymerization

The stereoregularity of polypropylene produced with C2-symmetric group 4 ansa-metallocene catalysts results from the interplay of two competing reactions, namely isotactic monomer polyinsertion and a side process of epimerization of the polymer chain at its active end; therefore, for this class of homogeneous catalysts, at variance with the “classical” heterogeneous Ziegler−Natta ones, enantioselectivity and stereoselectivity are not (necessarily) coincident. In this paper, possible methods for the separate determination of these two parameters are introduced and applied to propene polymerization in the presence of the prototypical catalyst rac-ethylene−bis(4,5,6,7-tetrahydro-1-indenyl)ZrCl2. The results prove that the relatively poor stereoselectivity of this catalyst above room temperature is consequent primarily to chain epimerization; monomer insertion indeed is highly enantioselective up to at least 80 °C. Preliminary evidence for the existence of more than one epimerization mechanism is also presented; this complicates the measurements of enantioselectivity based on 13C NMR characterizations of d-labeled poly(propene)

High-Field 13C NMR Characterization of Ethene-1-13C/Propene Copolymers Prepared with Cs-Symmetric ansa-Metallocene Catalysts: A Deeper Insight into the Regio- and Stereoselectivity of Syndiotactic Propene Polymerization

In this paper, we report the results of a 150 MHz 13C NMR characterization of ethene-1- 13C/propene copolymers at low (<5 mol %) ethene content prepared in the presence of the syndiotacticselective ansa-metallocene catalyst (Me)(Ph)C(cyclopentadienyl)(9-fluorenyl)ZrCl2 (cocatalyst, MAO). In particular, from the fine structure of the resonances of the ethene-1-13C units we conclude that the enantioselectivity of 1,2-propene insertion is substantially lower and the probability of chain back-skip substantially higher after an ethene insertion than after a propene one. Moreover, we find that the regioirregular 2,1-propene units (whose concentration is higher than claimed in the literature) are also substantially stereoirregular

Multitarget drug design strategy in Alzheimer’s disease: focus on cholinergic transmission and amyloid-β aggregation

Background: Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network. Results: By exploiting the multitarget approach, the present study provides new molecules able to target the cholinergic pathway, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit Aβ aggregation. Conclusions: These new compounds emerged as a suitable starting point for a further optimization process

Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: A few lights and many shadows

With the introduction of direct-acting antiviral agents (DAA), the rate of sustained virological response (SVR) in the treatment of hepatitis C virus (HCV) has radically improved to over 95%. Robust scientific evidence supports a beneficial role of SVR after interferon therapy in the progression of cirrhosis, resulting in a decreased incidence of hepatocellular carcinoma (HCC). However, a debate on the impact of DAAs on the development of HCC is ongoing. This review aimed to analyse the scientific literature regarding the risk of HCC in terms of its recurrence and occurrence after the use of DAAs to eradicate HCV infection. Among 11 studies examining HCC occurrence, the de novo incidence rate ranged from 0 to 7.4% (maximum follow-up: 18 mo). Among 18 studies regarding HCC recurrence, the rate ranged from 0 to 54.4% (maximum "not well-defined" followup: 32 mo). This review highlights the major difficulties in interpreting data and reconciling the results of the included studies. These difficulties include heterogeneous cohorts, potential misclassifications of HCC prior to DAA therapy, the absence of an adequate control group, short follow-up times and different kinds of follow-up. Moreover, no clinical feature-based scoring system accounts for the molecular characteristics and pathobiology of the tumours. Nonetheless, this review does not suggest that there is a higher rate of de novo HCC occurrence or recurrence after DAA therapy in patients with previous HCV infection. \ua9 2018 The Author(s). Published by Baishideng Publishing Group Inc. All rights reserved

Detectable clonal mosaicism and its relationship to aging and cancer

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases

Highly Regioselective Transition-Metal-Catalyzed 1-Alkene Polymerizations: A Simple Method for the Detection and Precise Determination of Regioirregular Monomer Enchainments

The potentialities of this approach are illustrated for propene polymn. promoted by two well-known ansa-metallocene catalysts (cocatalyst: methylaluminoxane, MAO): the isotactic-specific rac-Me2Si(1-indenyl)2ZrCl2 (I), and the syndiotactic-specific (Me)(Ph)C(cyclopentadienyl)(9-fluorenyl)ZrCl2 (II). A series of copolymn. expts. at variable ethene-1-13C-propene feeding ratios in the presence of I/MAO or II/MAO was carried out to locate the value of ethene incorporation above which "all" 2,1-propene units are followed by an ethene one. The higher regioselectivity and regioirregular sequences of the copolymers were clearly detected by 13C NMR. The 13C NMR spectra of an isotactic polypropylene prepd. with I/MAO at 10°, a copolymer of propene contg. 2.9 mol% of ethene-1-13C prepd. with I/MAO, and an ethene-1-13C-propene copolymer (ethene content 2.5 mol%) prepd. with II/MAO, were presented