SIRT2, the cytoplasmic member of the sirtuin family, is generally acknowledged to promote cancer and contribute to the progression of various pathologies, including neurodegeneration, inflammation, obesity, and bacterial infection through the deacetylation of target substrates. In our previous efforts we identified potent and highly selective SIRT2 inhibitors with IC50 values in the micromolar range. To further optimize their activity, we performed molecular docking-guided design and subsequent synthesis of a series of novel 1,3,4-thiadiazole derivatives. SIRT inhibitory screening identified that ST131 and ST132 achieved moderate inhibitory effects against SIRT2 with IC50 values of 8.95 and 6.62 µM, respectively. Moreover, cellular assays in MCF-7 breast cancer cells revealed that ST132 has shown an antiproliferative effect, as well as increased acetylated α-tubulin expression levels, which is typically consistent with SIRT2 inhibition. In addition, docking studies were performed to analyze and rationalize the structural differences responsible for SIRT2 activity, shedding light on the importance of the interactions occurring at the entrance of the binding site. Finally, molecular mechanics-generalized born surface area (MM-GBSA) and molecular dynamics (MD) simulation approaches were conducted to verify the stability of ST132 in the complex with SIRT2.
© 2026 The Author(s). Drug Development Research published by Wiley Periodicals LLC.

Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase implicated in various physiological and pathological processes, including cardiovascular diseases. The lead compound for SIRT1, resveratrol (1), as well as natural-derived and synthetic SIRT1-activating compounds demonstrated to exert cardioprotective effects. In the present work, we evaluated a small series of diarylimidazoles, of which 4 emerged, in in vitro enzymatic assays, as an activator of SIRT1 endowed with a similar potency compared with that of 1. Therefore, 4 was subjected to pharmacological investigation, where it was proven to reduce myocardial damage induced by ischemia/reperfusion injury in isolated rat hearts, thus demonstrating its cardioprotective properties. An in silico study suggested the binding mode of this derivative within SIRT1 in the presence of the p53-AMC-peptide. These promising results could pave the way to further expand and optimize this chemical class of new SIRT1 activators as potential cardioprotective agents.

Tubby-like protein-3 (TULP3), a member of the tubby family, is recognized for its role in ciliary trafficking, linking membrane-associated proteins to the intraflagellar transport complex A (IFT-A). Mammalian tubby family proteins (TULP1-4), featuring a C-terminal tubby domain, play crucial roles in intracellular transport, signaling, cell differentiation, and motility. TULP3 is also associated with renal and hepatic fibrocystic disease and liver, kidney, and heart degeneration. However, the modulation of TULP3 function and its interacting partners in the cell still need to be understood. Recent studies have indicated interactions between TULP3 and various proteins, including acetylating and deacetylating enzymes. In this study, we investigate the interaction of TULP3 with Sirtuins, SIRT1, and SIRT2 using biochemical and biophysical techniques. Our findings revealed that both the N- and C-terminal domains of TULP3 are necessary for the interaction with SIRT1 and SIRT2. Furthermore, we have identified that TULP3 is not a deacetylation substrate for SIRT1.

Sirtuin 2 (SIRT2) belongs to the family of silent information regulators (sirtuins), which comprises nicotinamide adenine dinucleotide (NAD+)-dependent protein lysine deacetylases. With a distribution across numerous tissues and organs of the human body, SIRT2 is involved in a wide range of physiological and pathological processes, such as regulating the cell cycle, energy metabolism, DNA repair, and tumorigenesis. Aberrant expression of SIRT2 has been closely associated with particular etiologies of human diseases, positioning SIRT2 as a promising therapeutic target. Herein, we detail the design overview and findings of novel symmetrical 2,7-disubstituted 9H-fluoren-9-one derivatives targeting SIRT2. SG3 displayed the most potent SIRT2-selective inhibitory profile, with an IC50 value of 1.95  μ M $\mu {\rm{M}}$ , and reduced the cell viability of human breast cancer MCF-7 cells accompanied by hyperacetylation of α-tubulin. Finally, molecular docking, molecular dynamics simulations, and binding free energy calculations using molecular mechanics/generalized born surface area method were performed to verify the binding ability of SG3 to SIRT2. Taken together, these results could enhance our understanding of the structural elements necessary for inhibiting SIRT2 and shed light on the mechanism of inhibition.
© 2024 The Author(s). Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.

Metformin is an anti-diabetic drug that exerts protective effects against neurodegenerative diseases. In this study, we investigated the protective effects of metformin against manganese (Mn)-induced cytotoxicity associated with Parkinson's disease-like symptoms in N27-A dopaminergic (DA) cells. Metformin (0.1-1 mM) suppressed Mn (0.4 mM)-induced cell death in a concentration-dependent manner. Metformin pretreatment effectively suppressed the Mn-mediated increase in the levels of oxidative stress markers, such as reactive oxygen species (ROS) and thiobarbituric acid reactive substances. Moreover, metformin restored the levels of the antioxidants, superoxide dismutase, intracellular glutathione, and glutathione peroxidase, which were reduced by Mn. Metformin (0.5 mM) significantly attenuated the decrease in sirtuin-1 (SIRT1) and peroxisome proliferator activated receptor gamma coactivator-1 alpha levels, which were increased by Mn (0.4 mM). In addition, metformin inhibited the expression of microRNA-34a, which directly targeted SIRT1. Metformin also inhibited the loss of Mn-induced mitochondrial membrane potential (ΔΨm) and activation of the apoptosis marker, caspase-3. Furthermore, metformin-mediated inhibition of ROS generation and caspase-3 activation, recovery of ΔΨm, and restoration of cell viability were partially reversed by the SIRT1 inhibitor, Ex527. These results suggest that metformin may protects against Mn-induced DA neuronal cell death mediated by oxidative stress and mitochondrial dysfunction possibly via the regulation of SIRT1 pathway.