New Hybrid Pyrazole and Imidazopyrazole Antinflammatory Agents Able to Reduce ROS Production in Different Biological Targets

Several anti-inflammatory agents based on pyrazole and imidazopyrazole scaffolds and a large library of substituted catechol PDE4D inhibitors were reported by us in the recent past. To obtain new molecules potentially able to act on different targets involved in inflammation onset we designed and synthesized a series of hybrid compounds by linking pyrazole and imidazo-pyrazole scaffolds to differently decorated catechol moieties through an acylhydrazone chain. Some compounds showed antioxidant activity, inhibiting reactive oxygen species (ROS) elevation in neutrophils, and a good inhibition of phosphodiesterases type 4D and, particularly, type 4B, the isoform most involved in inflammation. In addition, most compounds inhibited ROS production also in platelets, confirming their ability to exert an antiinflammatory response by two independent mechanism. Structure-activity relationship (SAR) analyses evidenced that both heterocyclic scaffolds (pyrazole and imidazopyrazole) and the substituted catechol moiety were determinant for the pharmacodynamic properties, even if hybrid molecules bearing to the pyrazole series were more active than the imidazopyrazole ones. In addition, the pivotal role of the catechol substituents has been analyzed. In conclusion the hybridization approach gave a new serie of multitarget antiinflammatory compounds, characterized by a strong antioxidant activity in different biological targets

Insight into GEBR\u201032a: Chiral Resolution, Absolute Configuration and Enantiopreference in PDE4D Inhibition

Alzheimer\u2019s disease is the most common type of dementia, affecting millions of people worldwide. One of its main consequences is memory loss, which is related to downstream effectors of cyclic adenosine monophosphate (cAMP). A well\u2010established strategy to avoid cAMP degradation is the inhibition of phosphodiesterase (PDE). In recent years, GEBR\u201032a has been shown to possess selective inhibitory properties against PDE type 4 family members, resulting in an improvement in spatial memory processes without the typical side effects that are usually correlated with this mechanism of action. In this work, we performed the HPLC chiral resolution and absolute configuration assignment of GEBR\u201032a. We developed an efficient analytical and semipreparative chromatographic method exploiting an amylose\u2010based stationary phase, we studied the chiroptical properties of both enantiomers and we assigned their absolute configuration by 1H\u2010NMR (nuclear magnetic resonance). Lastly, we measured the IC50 values of both enantiomers against both the PDE4D catalytic domain and the long PDE4D3 isoform. Results strongly support the notion that GEBR\u201032a inhibits the PDE4D enzyme by interacting with both the catalytic pocket and the regulatory domains

L’alfabeto con meno parabaleni. Una proposta per un’educazione alla letto-scrittura in italiano L2 con giovani e adulti scarsamente o non alfabetizzati nella L1 e scarsamente o non scolarizzati.

The systems for hospitality and social inclusion of migrants in Italy offer a privileged point of view for debating about language education policies. The challenge of literacy education and second language learning for young people and adults who are illiterate or scarcely literate and uneducated or scarcely educated requires thinking accurately about the impact one’s actions have in the pre-A1 level classes. The specific needs of asylum seekers and refugees may lead teachers to adopt means and attitudes of community-building, which could be useful even in a broader educational environment, and may be a chance to re-evaluate the political potential of literacy. We propose a path for literacy education where the aims are driven by the students’ needs of self-determination and involvement in our society: it is necessary to acquire oral competence in Italian as a second language, to develop the semiotic system of writing, to acquire phonological awareness, to master the use of pencil and paper, to understand what is written all around you. The proposal, rooted in acquisitional linguistics research, is intended to create a safe community environment, fruitful for interaction and learning. The development of this model is possible when the teacher and the students work and play together, and the class becomes a societal structure in which everybody takes part. Literacy classes can therefore become a training ground for democratic participation in society

New different catecholic and heterocyclic compounds able to interfere with different pathways in inflammation and cancer.

During my 3 years of PhD, I followed in parallel two projects: 1) synthesis of selective PDE4D3 inhibitors (PDE4Is), characterized by a substituted catechol scaffold, typical of Rolipram (pan-PDE4I), connected to an amino/amide tail through different linkers; 2) synthesis and biological evaluation of new compounds in which catechol moiety is connected to pyrazole and imidazo-pyrazole scaffolds through an acylhydrazonic linker to obtain potential anti-inflammatory and anticancer agents. In the 1st part of my PhD, I performed the chiral resolution of our lead GEBR-32a racemate, a PDE4D3I with no side-effects, to verify the potency of single enantiomers; I was also involved in the identification of an enzyme useful for the enantioselective synthesis of GEBR-library compounds (Industrial Organic Chemistry and Biotechnology Department at Bielefeld). Finally, to obtain more selective PDE4D3Is and expand SAR information, three new classes of compounds were designed and synthesized, in detail: a) isosteric derivatives of GEBR-32a; b) molecules with more rigid catecholic core; c) molecules with bulkier linkers. All the new compounds will be tested on PDE4D catalytic domain and PDE4D3 enzyme to evaluate their inhibitory activity. Crystallographic studies will be also performed (Latvian Institute of Organic Synthesis, Riga, Latvia). In the 2nd part of my PhD, based on previous compounds able to inhibit neutrophil chemotaxis towards inflamed tissues and having in mind the potential role of PDE4Is in inflammation, cancer and angiogenesis process, we designed new hybrid compounds to obtain molecules able to act on inflammation through different intracellular mechanisms. These new compounds, characterized by a pyrazole and imidazo-pyrazole scaffolds, were tested on platelet to evaluate their inhibition on ROS production and were also submitted to a large screening to evaluate their anticancer activity at National Cancer Institute (NCI) and Policlinico San Martino Hospital (IRCCS)

Pyrazolyl-Ureas as Interesting Scaffold in Medicinal Chemistry

The pyrazole nucleus has long been known as a privileged scaffold in the synthesis of biologically active compounds. Within the numerous pyrazole derivatives developed as potential drugs, this review is focused on molecules characterized by a urea function directly linked to the pyrazole nucleus in a different position. In the last 20 years, the interest of numerous researchers has been especially attracted by pyrazolyl-ureas showing a wide spectrum of biological activities, ranging from the antipathogenic activities (bacteria, plasmodium, toxoplasma, and others) to the anticarcinogenic activities. In particular, in the anticancer field, pyrazolyl-ureas have been shown to interact at the intracellular level on many pathways, in particular on different kinases such as Src, p38-MAPK, TrKa, and others. In addition, some of them evidenced an antiangiogenic potential that deserves to be explored. This review therefore summarizes all these biological data (from 2000 to date), including patented compounds

Pyrazolyl-Ureas as Interesting Scaffold in Medicinal Chemistry

The pyrazole nucleus has long been known as a privileged scaffold in the synthesis of biologically active compounds. Within the numerous pyrazole derivatives developed as potential drugs, this review is focused on molecules characterized by a urea function directly linked to the pyrazole nucleus in a different position. In the last 20 years, the interest of numerous researchers has been especially attracted by pyrazolyl-ureas showing a wide spectrum of biological activities, ranging from the antipathogenic activities (bacteria, plasmodium, toxoplasma, and others) to the anticarcinogenic activities. In particular, in the anticancer field, pyrazolyl-ureas have been shown to interact at the intracellular level on many pathways, in particular on different kinases such as Src, p38-MAPK, TrKa, and others. In addition, some of them evidenced an antiangiogenic potential that deserves to be explored. This review therefore summarizes all these biological data (from 2000 to date), including patented compounds

Insights into the Pharmacological Activity of the Imidazo-Pyrazole Scaffold

In previous studies, we synthesized different imidazo-pyrazoles 1 and 2 with interesting anticancer, anti-angiogenic and anti-inflammatory activities. To further extend the structure-activity relationships of imidazo-pyrazole scaffold and to identify novel antiproliferative/anti-inflammatory agents potentially active with multi-target mechanisms, a library of compounds 3-5 has been designed and synthesized. The chemical modifications characterizing the novel derivatives include: i) decoration of the catechol ring with groups with different electronic, steric and lipophilic properties (compounds 3); ii) insertion of a methyl group on C-6 of imidazo-pyrazole scaffold (compounds 4); iii) shift of the acylhydrazonic substituent from position 7 to 6 of the imidazo-pyrazole substructure (compounds 5). All synthesized compounds were tested against a panel of cancer and normal cell lines. Derivatives 3 a, 3 e, 4 c, 5 g and 5 h showed IC50 values in the low micromolar range against selected tumor cell lines and proved to have antioxidant properties, being able to inhibit ROS production in human platelet. In silico calculation predicted favourable drug-like and pharmacokinetic properties for the most promising compounds. Furthermore, molecular docking and molecular dynamic simulations suggested the ability of most active derivative 3 e to interact with colchicine binding site in the polymeric tubulin & alpha;/tubulin & beta;/stathmin4 complex

Novel insights on the molecular mechanism of action of the anti-angiogenic pyrazolyl-urea GeGe-3 by functional proteomics

In recent years, 5-pyrazolyl-ureas have mostly been known for their attractive poly-pharmacological outline and, in particular, ethyl 1-(2-hydroxypentyl)-5-(3-(3-(trifluoromethyl) phenyl) ureido)-1H-pyrazole-4-carboxylate (named GeGe-3) has emerged as a capable anti-angiogenic compound. This paper examines its interactome by functional proteomics using a label-free mass spectrometry based platform, coupling Drug Affinity Responsive Target Stability and targeted Limited Proteolysis-Multiple Reaction Monitoring. Calreticulin has been recognized as the GeGe-3 principal target and this evidence has been supported by immunoblotting and in silico molecular docking. Furthermore, cell studies have shown that GeGe-3 lowers cell calcium mobilization, cytoskeleton or- ganization and focal adhesion kinase expression, thus linking its biological potential to calreticulin binding and, ultimately, shedding light on the reasonable action mechanism of this molecule as an anti-angiogenic factor