Sirtuins (SIRT1–7) are NAD⁺-dependent deacetylases that play crucial roles in multiple cellular processes, and their dysregulation has been strongly associated with neurodegenerative disorders and cancer. Among them, SIRT2 has attracted particular attention due to its involvement in cell cycle regulation, cytoskeletal dynamics via α-tubulin deacetylation, and tumor progression. The pharmaceutical potential of SIRT2 is further supported by its implication in neurodegenerative diseases. In this context, a series of pyrazolyl–thiourea derivatives (PTUs) 1 has emerged as a promising class of SIRT2 inhibitors, exhibiting selective antiproliferative activity against HepG2 cells while maintaining low toxicity toward normal fibroblasts. To further extend structure–activity relationships (SARs) on PTUs 1, a novel series of derivatives was designed and synthesized. PTUs 2 and 3 shared with the lead derivatives 1 the thiourea moiety at position 4 of the pyrazole core and were differently decorated on the heterocyclic core. In detail: i) at the C3 position, the original N-phenyl group was replaced with small alkyl substituents (e.g., methyl or tert-butyl) to modulate steric hindrance, conformational flexibility, and lipophilicity; ii) at the N1 position a (±)2-hydroxyphenylethyl side chain was introduced to enhance hydrogen-bonding interactions and fine-tuning the electronic properties of the system. The SIRT2 inhibition and the cytotoxic properties of novel PTUs 2 and 3 were assessed on isolated enzyme and cell-based models, respectively. Selected member of the series proved to inhibit SIRT2 at micromolar concentrations and evidenced a selective/promising antiproliferative activity. Furthermore, computational studies were carried out to identify the molecular determinant for the interaction between the novel PTUs and SIRT2. Synthetic approaches, biological data, and molecular docking studies will be presented and discussed in the poster.
PYRAZOLYL–THIOUREA DERIVATIVES AS SIRT2 INHIBITORS: STRUCTURAL DIVERSIFICATION AND SAR STUDIES
Chiocca Andrea;Lusardi Matteo;Cecilia Astigiano;Elena Cichero;Andrea Spallarossa;Santina Bruzzone;Chiara Brullo
2026-01-01
Abstract
Sirtuins (SIRT1–7) are NAD⁺-dependent deacetylases that play crucial roles in multiple cellular processes, and their dysregulation has been strongly associated with neurodegenerative disorders and cancer. Among them, SIRT2 has attracted particular attention due to its involvement in cell cycle regulation, cytoskeletal dynamics via α-tubulin deacetylation, and tumor progression. The pharmaceutical potential of SIRT2 is further supported by its implication in neurodegenerative diseases. In this context, a series of pyrazolyl–thiourea derivatives (PTUs) 1 has emerged as a promising class of SIRT2 inhibitors, exhibiting selective antiproliferative activity against HepG2 cells while maintaining low toxicity toward normal fibroblasts. To further extend structure–activity relationships (SARs) on PTUs 1, a novel series of derivatives was designed and synthesized. PTUs 2 and 3 shared with the lead derivatives 1 the thiourea moiety at position 4 of the pyrazole core and were differently decorated on the heterocyclic core. In detail: i) at the C3 position, the original N-phenyl group was replaced with small alkyl substituents (e.g., methyl or tert-butyl) to modulate steric hindrance, conformational flexibility, and lipophilicity; ii) at the N1 position a (±)2-hydroxyphenylethyl side chain was introduced to enhance hydrogen-bonding interactions and fine-tuning the electronic properties of the system. The SIRT2 inhibition and the cytotoxic properties of novel PTUs 2 and 3 were assessed on isolated enzyme and cell-based models, respectively. Selected member of the series proved to inhibit SIRT2 at micromolar concentrations and evidenced a selective/promising antiproliferative activity. Furthermore, computational studies were carried out to identify the molecular determinant for the interaction between the novel PTUs and SIRT2. Synthetic approaches, biological data, and molecular docking studies will be presented and discussed in the poster.
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