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).