ETD

• design
• HDAC6 inhibitors
• inibitori HDAC6
• istone deacetilasi zinco-dipendenti- synthesis
• progettazione
• sintesi
• zinc - dependent histone deacetylases

Le istone deacetilasi (HDAC) rimuovono gruppi acetile dalle lisine degli istoni, modulando l’accessibilità del DNA e regolando processi cellulari fondamentali come trascrizione, ciclo cellulare, differenziazione e apoptosi. Agiscono anche su proteine non istoniche coinvolte nella riparazione del DNA e nella regolazione di complessi nucleari. Nelle neoplasie, l’iperattività delle HDAC causa repressione dei geni oncosoppressori e favorisce invasione e migrazione cellulare. Le HDAC dipendenti dallo zinco sono suddivise in quattro classi e condividono un dominio catalitico con uno ione Zn²⁺ essenziale al meccanismo enzimatico. Gli inibitori HDAC comunemente contengono un gruppo idrossammico come zinc-binding group, ma la scarsa selettività dei pan-inibitori approvati provoca importanti effetti avversi, spingendo la ricerca verso molecole più selettive. In particolare, HDAC6, localizzata nel citoplasma e attiva su proteine come α-tubulina e HSP90, è implicata in tumori e patologie neurodegenerative e legate alla proteostasi. Il dominio CD2 presenta tasche strutturali peculiari (L1 e L2) sfruttabili per ottenere selettività. Gli HDAC6i includono uno ZBG, un linker variabile e un gruppo capping. La combinazione o la progettazione di molecole multitarget può ampliare l’efficacia terapeutica. Il lavoro di tesi si concentra sulla sintesi di nuovi HDAC6i basati su scaffold 2-oxo-piridin-3-carbossiammidico e 1,8-naftiridin-2(1H)-one-3-carbossiammidico, modificati con linker alifatici. I risultati preliminari mostrano composti promettenti, guidando l’ottimizzazione di selettività e potenza. Histone deacetylases (HDACs) are a large family of enzymes responsible for removing acetyl groups from lysine residues on the N-terminal tails of histones. By deacetylating histone proteins, they modulate DNA accessibility and regulate key cellular processes such as gene transcription, cell cycle progression, proliferation, differentiation, and apoptosis. Beyond their canonical role, HDACs also act on non-histone proteins involved in various biological pathways, including DNA repair, transcription factors, and other nuclear complexes. HDAC hyperactivity is a recurrent epigenetic alteration in cancer: increased deacetylation leads to repression of tumor-suppressor genes in early carcinogenesis and later to silencing of genes involved in adhesion, migration, and invasion.
Zinc-dependent HDACs are divided into four classes and share a highly conserved catalytic domain containing a narrow cylindrical pocket where Zn²⁺, coordinated by histidine and aspartate residues, plays an essential role. Most HDAC inhibitors (HDACi), both selective and broad-spectrum, include a hydroxamic group capable of chelating Zn²⁺ and mimicking the catalytic intermediate. FDA-approved pan-inhibitors show strong antitumor activity, but their low isoform selectivity causes major adverse effects, such as cardiotoxicity and thrombocytopenia, increasing interest in selective inhibitors, particularly those targeting HDAC6.
HDAC6 is mainly cytoplasmic and regulates acetylation of non-histone proteins such as α-tubulin, HSP90, ERK-1, and peroxiredoxins. It also has a non-catalytic ubiquitin-binding function and is implicated in neurodegenerative disorders. Selective HDAC6 inhibitors are promising therapeutic candidates for cancer and rare diseases involving proteostasis alterations. The CD2 catalytic domain features unique structural elements, including L1 and L2 pockets, enabling selective inhibitor design. HDAC6 inhibitors typically consist of a zinc-binding group (ZBG), a variable linker, and a capping group.
This thesis work focuses on the design and synthesis of new selective HDAC6 inhibitors based on 2-oxo-pyridine-3-carboxamide and 1,8-naphthyridin-2(1H)-one-3-carboxamide scaffolds, modified with aliphatic linkers. Preliminary results show promising profiles and support the use of these scaffolds as starting points for optimizing HDAC6 selectivity and potency.