This review provided an overview of the sirtuin modulators reported from 2013 to current. Relevant works were retrieved from JSTOR, ScienceDirect, and PubMed. During this period, extensive research has expanded the understanding of sirtuins and their physiological functions, leading to the discovery of new scaffolds of sirtuin modulators. These sirtuin modulators can be further separated into activators and inhibitors, where both categories involve natural and synthetic substances. The sirtuin activator may increase the sirtuin activity, where most of them are focused on activating SIRT1 with a few targeting SIRT6 [13]. Previous studies had revealed SIRT1 activators are linked to age-related diseases, such as cancer, diabetes, and neurodegenerative disease [39]. The discovery of activators and inhibitors for SIRT6 has gained significance due to its vital role in DNA repair, tumorigenesis, and neurodegeneration [40]. While SIRT1–3 generally acts as tumor suppressors by enhancing cell survival through DNA repair mechanisms, they can transition into tumor promoters as tumor cells reach a certain grade, stimulating cell proliferation [41]. Consequently, numerous studies have been conducted on inhibitors targeting various sirtuin isoforms, including SIRT1, 2, 3, and 5, to uncover their anti-cancer or anti-aging properties. Sirtuin modulators can be of natural or synthetic origin, and they can be further classified as selective to one type of sirtuins or nonselective, exerting effects on multiple sirtuin isoforms. Therefore, this section incorporates different types of sirtuin modulators to provide a comprehensive perspective.

Sirtuin activators

Sirtuin activators sourced from the nature, or those rationally designed and synthesized in the past decade have shown vast therapeutic potential as can be seen in Table 1. During this period, some traditional Chinese medicines (TCMs) were reported to activate SIRT1 [42, 43]. Meanwhile, synthetic SIRT1 activator, such as YK-3-237, has been shown to exhibit anti-proliferative effects toward breast cancer and possesses potential applications in renal fibrosis and spermatozoa-related processes [44, 45]. SIRT6 activators, specifically pyrrolo-[1,2-a]quinoxaline derivatives such as UBCS039, have been demonstrated to offer therapeutic advantages against inflammation, SARS-CoV-2, and cancer [46].

Table 1 The effects and targeted disorders of sirtuin activatorsNatural SIRT1 activators

Traditional Chinese medicine (TCM) is part of the natural plant that has long been studied, as it holds high therapeutic values and links to anti-aging functions through various pathways such as regulation of telomere and telomerase, sirtuins, and resistance of DNA damage [47]. An in vitro SIRT1 activity assay was conducted on the 19 activators selected through TCM database screening, where four specific compounds (ginsenoside F1, ginsenoside Rb2, ginsenoside Rc, and schisandrin A) were found to be active, requiring supplementary validation tests. From liquid chromatography–mass spectrometry (LC–MS) analysis, it revealed their actions in the enzymatic reaction, and activities against tert-butyl hydroperoxide (t-BHP) stimulated oxidative damage. In addition, the study revealed SIRT1 activators may enhance mitochondrial function, by suppressing ROS formation and increasing the activity of manganese superoxide dismutase (Mn-SOD) and ATP contents [43]. Building on this finding, numerous studies have extensively explored the potential of ginsenosides as SIRT1 activators [48]. Ginsenosides, a class of compounds found in ginseng, have been identified to target the SIRT1 signaling pathway and possess bioactive properties against oxidative stress, inflammation, cancer, and aging [48].

Dehydroabietic acid (DAA) is a diterpene resin acid found in coniferous plants, where it has been shown to possess various therapeutic activities such as anti-microbial, anxiolytic, and anti-tumor activities [42]. DAA (Fig. 2) is a non-polyphenolic-based compound, a distinct deviation from most natural sirtuin modulators. Notably, DAA exhibited an increase in SIRT1 activity twofold higher than resveratrol. Although DAA was postulated to be able to act as an anti-aging agent in a C. elegans model, it binds directly to SIRT1 and its mechanism of action is independent of NAD+ [42]. Furthermore, it was discovered that the direct binding of DAA to SIRT1 upregulates the protein and increases the collagen secretion in dermal fibroblasts from human skin, providing evidence of its anti-aging effect. Another study found DAA may improve non-alcoholic liver disease by increasing ferroptosis suppressor protein 1 (FSP1) gene while inhibiting ROS accumulation [49]. Notably, FSP1 was also found to be a possible therapeutic target to activate SIRT1 [50]. A more recent study revealed the DAA may induce apoptosis to inhibit the proliferation of gastric cancer cells [51]. However, additional studies are needed to fully understand the mechanism of action of DAA and its potential applications in various disorders.

Fig. 2

The chemical structure of dehydroabietic acid

Synthesized SIRT1 activator (YK-3-237)

YK-3-237 (Fig. 3) is a boronic acid chalcone analog derived from combretastatin A-4 (CA-4) that was found to induce the deacetylation of both mutant and wild-type p53 proteins through its interaction with SIRT1 [52]. Moreover, Yi et al. discovered that YK-3-237 possesses anti-proliferation at submicromolar concentration against various breast cancers, including triple-negative breast cancer (TNBC), luminal, and HER2 cancer cell lines carrying mtp53 [52]. A separate study investigated the impact of YK-3-237 on renal fibrosis through the examination of cultured rat renal interstitial fibroblasts (NRK-49F) [45]. The SIRT1 activating role of YK-3-237 can be explained by the inhibition of α-SMA and fibronectin at the concentration of 10 μM leading to the blockage of acetylation of histone H3 at lysine 9 (Ac-H3K9) [45]. Notably, a recent study highlighting the influence of YK-3-237 on capacitation-related processes in human spermatozoa [44]. Despite being a potent SIRT1 activator, the study revealed a protein lysine acetylation-independent mechanism induced by YK-3-237 [44]. Altogether, these studies suggested that the effect of YK-3-237, as a SIRT1 activator, extends beyond its potential as an anti-tumor or anti-aging agent. Further research is needed to investigate additional mechanisms through which YK-3-237 may exert its beneficial effects against various disorders.

Fig. 3

The chemical structure of YK-3-327

Synthesized SIRT6 activators (pyrrolo-[1,2-a]quinoxaline derivatives)

The compounds based on pyrrolo-[1,2-a]quinoxaline were found to enhance the SIRT6-mediated deacetylation of peptides and nucleosomes; therefore, pyrrolo-[1,2-a]quinoxaline derivatives were tested to identify their SIRT6 activated abilities. UBCS039 (Fig. 4A) was the first synthetic SIRT6 activator derived from pyrrolo-[1,2-a]quinoxaline [53]. In a dose-dependent manner, a study reported UBCS039 to boost a maximum increase of SIRT6 activities up to twofold with an EC50 value of ~38 μM [53]. Although it did not show a notable impact on SIRT1–3, it may enhance the desuccinylation activity of SIRT5 by approximately twofold [54]. The SIRT6 activators can bind to the acyl channel independently from the substrate, causing a conformational change in the enzyme, and leading to an increased affinity for substrate peptides [53]. It was shown that the 3-pyridyl group of UBCS039 plays a crucial role as the primary anchor for its activating activity, as shifting the nitrogen to different positions resulted in lower activity. In addition, another study identified the potential of UBCS039 in treating acute liver failure (ALF), as it was found to have an anti-inflammatory response and can alleviate oxidative stress [54]. In a separate study on the SAR of UBCS039, it was revealed that the incorporation of heterocycles such as 1,4-dimethylpiperazine (Fig. 4B) resulted in increased potency by up to fourfolds [46]. Additional UBCS039 derivatives were synthesized and discovered to exhibit therapeutic advantages, including the suppression of proinflammatory cytokine/chemokine production induced by LPS, suppression of SARS-CoV-2 infection, and colony inhibition of cancer cells [46]. Although the pyrrolo-[1,2-a]quinoxaline derivatives have shown potential as SIRT6 activators, further studies are required to evaluate their potential as therapeutics.

Fig. 4

Chemical structure of UBCS039 (A) and UBCS039-1,4-dimethylpiperazine (B)

Sirtuin inhibitors

Sirtuin inhibitors can be categorized based on their selectivity toward specific sirtuin isoforms as summarized in Table 2. Although pan-inhibitors can inhibit multiple sirtuin isoforms involved in tumorigenesis, higher doses of pan-inhibitors may pose toxicity concerns compared to selective inhibitors [55]. Conversely, one study highlighted unfavorable outcomes in cancer treatment with the selective SIRT1 inhibitor EX-527 [56]. As a result, both selective inhibitors and pan-sirtuin inhibitors offer advantages depending on the specific case. This section focuses on the progress made in developing selective inhibitors for SIRT1, 2, 3, and 5, as well as pan-sirtuin inhibitors derived from both natural and synthetic sources.

Table 2 The effects and targeted disorders of sirtuin inhibitorsSelective SIRT1 inhibitors (quinoxaline derivatives)

Quinoxaline is a heterocyclic compound consisting of two aromatic rings (benzene and pyrazine) that have gained significant interest in the field of anti-cancer therapeutics, as many clinical candidates feature the quinoxaline moiety [57]. In a study by Nakhi et al., quinoxaline derivatives were shown to exert SIRT1 inhibitory activity, thus presenting quinoxalines as a new class of moderately active SIRT1 inhibitor [58]. Through a dose-response study, it was revealed the 4-(3-(2-(2,4-dihydroxy-3-methylphenyl)-2-phenylethyl)-6-methylquinoxalin-2-yl)-2-methylbenzene-1,3-diol (4bb, Fig. 5), the most potent compound in the series, inhibited SIRT1 with IC50 value of ~33 μM. Compound 4bb was further observed to inhibit the growth of hepatocellular liver carcinoma only at a concentration of 50 μM [58]. The molecular docking study on 4bb revealed its ability to bind to the active site of SIRT1 and the IC50 value on its deacetylation activity was consistent with previously reported experimental result [59]. Subsequent viability assays on various cancer cell lines demonstrated that 4bb is able to inhibit the proliferation of cancer cells, in particular the colon cancer cells [59]. It was hypothesized that 4bb induced the apoptotic effect on colon cancer cells through the p53-dependent pathway. Based on the finding, it is suggested that the apoptosis of colon cancer cells mediated by 4bb was induced through the acetylation of p53 by the inhibition of SIRT1 [59].

Fig. 5

The chemical structure of quinoxaline derivative 4bb

Selective SIRT2 inhibitor (SirReal2 & γ-mangostin)

Sirtuin-rearranging ligands 2 (SirReal2, Fig. 6) is a family of aminothiazoles, which was found to selectively inhibit the activity of SIRT2 (IC50 of 0.14–0.4 μM) with no inhibitory activity of SIRT1 and SIRT3 at 50 μM [60]. Moreover, the consistent result of SIRT2 inhibitory activity was observed in a cellular setting, as SirReal2 may induce hyperacetylation of α-tubulin and destabilize the checkpoint protein BubR1 in HeLa cells [60]. The study also discovered that SirReal2 can induce a rearrangement of the active site of SIRT2 and interact with previously unexplored residues [60]. A subsequent study emphasized the effectiveness of SirReal2 in decreasing the proliferation of cancer cells such as lung, gastric, and lymphoma [61]. Specifically, the reduction of migration and invasion activity induced by SirReal2 was discovered in human gastric cells HGC-27 and MGC-803 [61]. In addition, a more recent study revealed the combination of SirReal2 and VS-5584 may improve the inhibition of acute myeloid leukemia (AML) cell growth [58].

Fig. 6

The chemical structure of SirReal2

Garcinia mangostana (G. mangostana) is commonly recongized for the use as traditional medicine that can be found in Southeast Asia. Various bioactive compounds were discovered in G. mangostana such as xanthones, terpenes, and α-mangostin. Specifically, α-mangostin has been shown to regulate sirtuin in mice [62]. While in a recent study had extracted and isolated another natural compound known as γ-mangostin (Fig. 7) and was identified to have selectively potency toward SIRT2 (IC50 = 3.8 μM) [8]. The study also highlighted its inhibitory activities toward breast cancer cells by increasing the acetylation of α-tubulin [8]. Moreover, γ-mangostin was found to be a potential treatment for neural diseases such as Alzheimer’s and Parkinson’s, as it may increase neuroblastoma neuro-2a (N2a) cells to combat the neuronal cell deaths [8].

Fig. 7

The chemical structure of γ-mangostin

Selective SIRT3 inhibitor (LC-0296)

In comparison to other sirtuin isoforms, SIRT3 is observed to be overexpressed in OSCC [35]. The downregulation of SIRT3 was shown to inhibit the growth and proliferation of OSCC cells in vitro; likewise, the in vivo study demonstrated that reduced SIRT3 expression led to a decrease in tumor burden [35]. Thus, inhibition of SIRT3 may hold a therapeutic role in the treatment of HNSCC. Then, a later study synthesized a new novel SIRT3 inhibitor known as LC-0296 (Fig. 8) starting from the commercially available compound 4-nitro-1H-indole through a four-step process involving alkylation, nitro groups reduction, ester to primary amide conversion, and Z-Glu-OMe coupling [63]. The in vivo study suggested that LC-0296 had up to 20-fold higher inhibitory activity toward SIRT3 (IC50 of 3.6 μM) than SIRT1 and SIRT2, indicating its selectivity [63]. Moreover, the action of LC-0296 in HNSCC cells included inhibition of cell proliferation and formation of the colony, DNA fragmentation improvement in a dose-dependent manner, and apoptosis promotion [63]. Despite its promising SIRT3 inhibitory effects, the precise mechanism of action for LC-0296 remains unclear. Therefore, more studies are required to investigate its mechanism of action and potential side effects before it can progress to clinical trials.

Fig. 8

The chemical structure of LC-0296

Selective SIRT5 inhibitor (JH-I5-2 and DK1-04)

In the study, several SIRT5 inhibitors were modified from the previously identified thiosuccinyllysine peptide (H3K9TSu) that possesses weak SIRT5 inhibition [64]. Two of the H3K9TSu derivatives, JH-I5-2 (Fig. 9A) and DK1-04 (Fig. 9B) were identified to have the strongest inhibitory activities with IC50 values of 2.1 and 0.34 μM, respectively [64]. This finding indicated that a dipeptide-based compound (DK1-04) showed higher potency compared to a single lysine-based compound (JH-I5-2), suggesting the importance of compound structure in modulating SIRT5 activity [64]. Further analysis using LC–MS revealed that DK1-04 acts as a mechanism-based inhibitor of SIRT5 through a covalent intermediate formation with NAD+ [64]. Nonetheless, the presence of the free carboxylic acid structure of JH-I5-2 and DK1-04 results in a structure that hinders poor cell permeability [64]. To overcome this limitation, pro-drugs were utilized to assess their effects on cancer cells [64]. In line with the SIRT5 inhibition IC50 result, the pro-drug of DK1-04 exhibited enhanced cytotoxicity and stronger effects on cell proliferation, highlighting its promising prospects for further development as a therapeutic agent [64]. Moreover, as overexpression of SIRT5 was identified in the breast cancer model, it suggested that SIRT5 inhibitors as the potential target in combating breast cancers [64].

Fig. 9

The chemical structure of SIRT5 inhibitors, JH-I5-2 (A) and DK1-04 (B)

Pan-sirtuin inhibitors (toxoflavin, benzimidazole derivatives, and MC2494)

Toxoflavin (Fig. 10), also known as xanthothricin, is a bright yellow phytotoxin compound synthesized by bacteria that displays antibiotic function, while possessing high toxicity to plants, fungi, and animals [65, 66]. In a study, the effect of toxoflavin and its derivatives were evaluated with an in vitro assay, which found all the derivatives were inactive toward SIRT2 [65]. While toxoflavin inhibited the deacetylation activity of both SIRT1 and SIRT2, it had higher selectivity toward SIRT1 compared to SIRT2 in terms of the deacetylase activity and the inhibition activity on SIRT1 was similar to EX-527, which is known as the strongest SIRT1 inhibitor in vitro [65]. Moreover, the structure-activity relationship (SAR) for toxoflavin highlighted the significance of the triazine ring in maintaining its inhibitory activity, as substituting it with a diazine ring may eliminate its inhibitory effects [