Introduction

Histone deacetylases (HDACs) are enzymes that can catalyze the removal of acetylated groups from the N-acetyl lysine of both histones and non-histones proteins, hence regulating the cell cycle [1, 2]. Sirtuin is a type of protein belonging to the class III HDACs, which is the only class being nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases and mono ADP-ribosyltransferases, in comparison to the other three classes (class I, II, and IV) being zinc-dependent deacetylases [3]. In the deacetylation of protein, sirtuin acts as a catalyst to break the bond between NAD+ and niacinamide ribosomes to release the nicotinamide and transfer the acetylated groups from proteins to ADP-ribose. Sirtuin was first discovered in yeast but later found in bacteria and eukaryotes, such as plants and mammals [4]. In the mammalian system, sirtuin can be classified into seven isoforms (SIRT1–7), which contain a highly conserved catalytic domain made up of 275 amino acids, with the addition of N-terminal and C-terminal that differ in length. Different isomers of sirtuin are expressed in different subcellular localization, where SIRT1 can be found in both the nucleus and the cytosol, SIRT2 is expressed in the cytosol, with SIRT3, 4, and 5 are localized in mitochondrial, and SIRT6 and 7 are mainly in the nucleus [5, 6]. There were increased studies of sirtuin due to its unique role in regulating the function of the brain, and its relationship with several age-related diseases such as cardiovascular disorders, neurodegenerative disease, metabolic disease, and cancer [1, 7, 8]. Likewise, sirtuin modulators are also gaining attention, as regulating sirtuin enzymes may be a possible treatment for age-related disease in human [9]. In recent years, the role of sirtuins in microorganisms have gained traction and they have been implicated in parasitic diseases. Thus, further research in sirtuin may also lead to therapeutic solutions to diseases such as schistosomiasis, malaria, and toxoplasmosis [10]. Despite the identification of numerous sirtuin modulators from natural sources or chemical synthesis, the number of these modulators that have advanced to clinical trials remains limited [11]. Some sirtuin modulators such as resveratrol was found to have poor bioavailability with limited potency in clinical trials. It is clear that such compounds require further modifications before it can enter the market [11]. EX-527 is another sirtuin modulator which entered the clinical trials for Huntington’s disease. Although it was found to be safe and well tolerated by patients, the study concluded that there was no specific advantage brought by compound over placebo control [12]. Nevertheless, due to the broad spectrum of downstream targets being regulated by sirtuin enzymes through their signaling pathway, they remain attractive pharmacological targets. Hence, this review aims to identify new sirtuin modulators reported from 2013 to current and discuss their potential as valuable therapeutic agents. By examining the discovery of these modulators, their modes of action and their possible weakness in being crafted as a drug candidate the presented information can contribute to the progression of research in the field of sirtuin modulation and facilitate the identification of promising candidates for further development.

Overview of seven sirtuin isoforms

Nuclear sirtuins

Seven isomers of sirtuins in mammals are in different parts of cells and possess different functions and physiology, but some may have overlapping functions and related disease (Fig. 1). SIRT1, 6, and 7 are usually found in the nucleus of the cell, SIRT1 mainly involves in the metabolism process, SIRT6 is responsible for DNA repair and maintaining the stability of mammalian cells, and SIRT7 acts as the regulator of ribosomal RNA (rRNA) transcription [13]. Among the seven sirtuins, SIRT1 is being studied the most and was found to involve in gene expression, metabolism, and oxidative stress response. SIRT1 is thought to be the key regulator of cellular metabolism and may inhibit apoptosis through interaction with proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) to modulate glycolysis and the output of hepatic glucose [4]. Moreover, SIRT1 may act as either a tumor suppressor or promoter to affect the development of cancer. It may deacetylate the tumor suppressors such as p53 and forkhead box O (FOXO) proteins that respond to oxidative stress and DNA damage, leading to its role as a tumor promoter [14, 15]. Specifically, SIRT1 was found to promote both prostate and gastric cancers in previous studies [16, 17]. Conversely, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) that promotes the proliferation of tumor cells and suppresses apoptosis can be inhibited by SIRT1 [18]. According to the study, the level of SIRT1 was lower for the breast cancer and hepatic cell carcinoma (HCC) groups than control groups [19]. Therefore, both activators and inhibitors of SIRT1 may have different therapeutic potential in clinical settings. SIRT6 locates in the heterochromatic region and was found to undergo both NAD+-dependent deacetylases and mono ADP-ribosyltransferases with its function in regulating aging, immunity, and cancer [13]. From the aging aspect, SIRT6 can positively regulate longevity and maintain cellular homeostasis by repairing DNA and retaining gene stability [20]. SIRT6 is proven to also regulate inflammation and immune response, by suppressing transcriptional factors, NF-κB-dependent protein [21]. Lastly, SIRT6 can suppress tumors in response to oxidative stress, and overexpression of it may lead to apoptosis of cancer cells [20, 22]. Hence, activators of SIRT6 may be a similar value as SIRT1 activators as a potential treatment for some disorders. Among the nucleus sirtuins, SIRT7 is being studied the least but was also identified to involve in several cellular processes. The main role of SIRT7 is regulating rRNA transcription and cell cycle by activating RNA polymerase I (RNA Pol I) and upstream binding transcription factor (UBF), hence overexpressing of SIRT7 may increase the rRNA transcription [23]. In addition, SIRT7 was also found to deacetylate p53 to defend against hypoxia-induced damage and apoptosis for cardiomyocytes [24]. Nonetheless, limited studies had identified the sirtuin modulators for SIRT7.

Fig. 1
figure 1

The subcellular location of different human sirtuins and their implicated diseases

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Cytoplasmic sirtuins

Of the seven isoforms of sirtuins, SIRT2 is the only cytoplasmic protein in the cytosol, but it may shift to the nucleus during mitosis. SIRT2 is most expressed in the brain with the ability to deacetylate the α-tubulin to regulate the cell cycle and tumorigenesis [25]. Functions and related disease for SIRT2 was found to overlap with SIRT1 [26, 27]. During the G2 to mitosis phase, SIRT2 was found to increase in the nucleus with the mechanism to reduce the level of Lys16 on histone 4, which is essential in mediating chromatin compaction to regulate the cell cycle [28]. Besides, SIRT2 may also regulate the anaphase-promoting complex/cyclosome (APC/C) protein that controls chromosome segregation and mitosis exit [29]. Regarding its involvement in tumorigenesis, SIRT2 is similar to SIRT1, which can vary depending on the type of cancer. SIRT2 may exhibit overexpression in certain cancers, while downregulated in others [3]. Take breast cancer as an example, it was found that SIRT2 has dual functions as both tumor suppressors and oncogenic properties according to the type of tumors and grade of breast cancer [30]. When facing an aggressive tumor linked to Grade 3 breast cancer, SIRT2 was observed to be overexpressed, while expressed at a lower level when facing Grade 2 breast tumors [31, 32]. Consequently, both activators and inhibitors of SIRT2 should be valued, as they may hold different therapeutic values when treating different types of tumors.

Mitochondrial sirtuins

SIRT3, 4, and 5 reside in the mitochondria, which are involved in mitochondrial metabolism from several aspects. Among the three mitochondrial sirtuins, SIRT3 has been studied the most which plays a significant role in maintaining the integrity and function of mitochondria through the deacetylation of various proteins [33]. SIRT3 is involved in mitochondrial metabolism via several pathways, including ATP synthesis, oxidative phosphorylation (OXPHOS), and the tricarboxylic acid (TCA) cycle [34]. Interestingly, SIRT3 cannot be identified as either tumor suppressors or promoters similar to SIRT1 and 2, due to different characteristics found depending on the cancer type. It was determined to be a suppressor in gastric, prostate, and breast carcinomas as it may trigger cell death; while promoting head, and neck squamous carcinomas by regulating reactive oxygen species (ROS) causing cell proliferation [33, 35, 36]. SIRT4 had the weakest enzymatic activity among the seven isoforms; it was initially only found to undergo mono ADP-ribosyltransferases, but recent studies also identified its activity in deacetylation, lipoamidase, and deacylation [37]. Lastly, demalonylase, desuccinylase, and deglutarylase activities were found in SIRT5 by catalyzing the removal of negatively charged acyl lysine modifications during protein deacetylation [38]. Remarkably, SIRT5 also takes a role in the urea cycle by catalyzing the first step of the cycle [34]. Overall, SIRT3, 4, and 5 were all found to be involved in metabolic regulation and are implicated in cardiovascular diseases and cancer [26, 27].

New sirtuin modulators of the past decade

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 activators
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Natural 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
figure 2

The chemical structure of dehydroabietic acid

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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
figure 3

The chemical structure of YK-3-327

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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
figure 4

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

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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 inhibitors
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Selective 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
figure 5

The chemical structure of quinoxaline derivative 4bb

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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
figure 6

The chemical structure of SirReal2

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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
figure 7

The chemical structure of γ-mangostin

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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
figure 8

The chemical structure of LC-0296

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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
figure 9

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

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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 [65]. Consequently, toxoflavin and its derivatives have the potential to serve as valuable chemical probes as pan-sirtuin inhibitors and they were found to have anti-tumor activity. However, future research may need to focus on addressing their toxicity concerns and exploring their suitability for clinical development.

Fig. 10
figure 10

The chemical structure of toxoflavin

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Among heterocyclic scaffolds, the benzimidazole moiety is commonly found in many biologically active compounds for various therapeutic functions, such as anti-microbial, antiviral, and anti-inflammatory activities [67]. In two separate studies, the investigation of benzimidazole derivatives revealed their inhibitory activity against SIRT1 and SIRT2 [68, 69]. These two studies functioned as the basis of later research, leading to the discovery of the BZD9L1 (Fig. 11A). A study utilized both competition assay and docking studies to reveal the mechanism of BZD9L1, which functions as a reversible competitive inhibitor to replace the binding site of the NAD+ receptor [70]. Moreover, BZD9L1 was found to demonstrate inhibitory activities toward three cancer cells (leukemia, breast cancer, and colorectal cancer) and exhibited a notable fluorescence property [70]. Follow-up investigation had specifically targeted the effect of BZD9L1 on colorectal cancer, particularly its effect on HCT116 and HT-29 CRC cell lines, which were found to experience a decrease in cell viability, migration, and survival after exposure to BZD9L [71]. Another research conducted evaluated the toxicity of BZD9L1 in mice on cytochrome P450 (CYP) regulation and concluded no acute toxicity with a dose under 2000 mg/kg and no adverse effect was observed with repeating dose intake for 28 days [72]. Interestingly, BZD9L1 was only found to affect the CYP level in hepatic metabolism with no change in the kidney [72]. Although both in vitro and in vivo tests were examined for BZD9L1, advanced studies are needed to uncover the sex-specific mechanisms associated with BZD9L1. It is important to investigate further, as the expression of CYP and SIRT proteins demonstrated variations between individuals upon exposure to BZD9L1 [72].

Fig. 11
figure 11

The chemical structure of BZD9L1 (A) and BZD9Q1 (B)

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Followed by the discovery of BZD9L1, another benzimidazole derivative known as BZD9Q1 (Fig. 11B) was synthesized and evaluated for its sirtuin inhibitory properties. Results from the study revealed that BZD9Q1 acts as a pan-sirtuin inhibitor, displaying inhibitory effects on SIRT1–3 with IC50 value below 10 μM for all three sirtuins. Additionally, the investigation indicated that BZD9Q1 may also inhibit the growth of multiple cancer cell lines (HCT116, CCRF-CEM, MDA-MB-468, and H103). Specifically, it was observed that BZD9Q1 induced late apoptosis, mild necrosis, and G2/M cycle arrest in H103 oral squamous cell carcinoma (OSCC) cells, indicating its potential to be further developed as anti-cancer agent for oral cancer.

MC2494 (Fig. 12), is another pan-sirtuin inhibitor discovered that was distinctive to the selective inhibitors, as it was found to have inhibitory activity against SIRT1–6 [73]. Specifically, MC2494 possesses IC50 of 38.5 and 58.6 μM for SIRT1 and SIRT2, respectively [73]. Moreover, according to the study, MC2494 demonstrated a broad tumor-selective therapeutic potential to induce apoptosis in vitro, ex vivo (in leukemic blasts), and in vivo (in xenograft and allograft cancer models) [73]. Notably, the chemically induced mammary gland hyperproliferation may be inhibited by MC2494 in vivo, which marks its tumor-preventive activity [73].

Fig. 12
figure 12

The chemical structure of MC2494

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Over the past decade, there has been a significant increase in the discovery of new sirtuin modulators, in addition to a renewed interest in investigating the old scaffold to develop novel derivatives of sirtuin modulators. While numerous sirtuin modulators have been discovered from natural sources, their inherent potency is often relatively weak. This highlights the potential for enhancing the activity of natural sirtuin modulators through chemical modification. The group of natural sirtuin modulators encompasses various compounds, with polyphenols being the most represented. Within the polyphenol group, flavonoids are particularly abundant and commonly found in natural plants as part of their defense mechanisms [74]. Flavonoid derivatives, such as resveratrol, quercetin, and chromones, have attracted significant attention due to their potential as sirtuin modulators and their diverse therapeutic properties (e.g., anti-bacterial, anti-cancer, and anti-inflammatory) to use for designing novel drugs [74, 75]. Besides, studies have revealed the close interaction of flavonoids with SIRT1, 3, and 6 [74].

Resveratrol (RSV) is the most notable and effective SIRT1 activator that can be found in natural products, such as grapes, blueberries, and red wines, where it may increase the activity of SIRT1 by tenfold [76]. Polydatin (Fig. 13A) was the analog of resveratrol deriving from glycoside that can be found in natural products and was reported as a potential SIRT1 activator that can increase SIRT1 activity by decreasing p53 levels resulting in a reduction of oxidative stress, apoptosis, and inflammatory response [77, 78]. Besides, polydatin was also found to exhibit anti-cancer, anti-diabetic, anti-microbial, and various other therapeutic effects that provided new insights for researchers to further investigate [79]. In addition, a study utilized SIRT3 knockout mice to demonstrate the essential role of SIRT3 in mediating the protective effects of polydatin administration [80]. The presence of SIRT3 enables polydatin to inhibit apoptosis, promote autophagy, and enhance mitochondrial biogenesis in myocardial infarction, suggesting the SIRT3-activating properties of polydatin [80]. 4′-Bromo-resveratrol (Fig. 13B) is a derivative of resveratrol, which was found to have better solubility than resveratrol [81]. Remarkably, unlike resveratrol, 4′-bromo-resveratrol inhibits SIRT1 at a concentration of 0.2 mM instead of activating it. Likewise, when comparing with other resveratrol analogs (piceatannol and polydatin), 4′-bromo-resveratrol exhibited a relatively potent inhibitory effect on SIRT3 with the concentration of 0.2 mM [81]. As a consequence, 4′-bromo-resveratrol was identified to be a pan-sirtuin inhibitor on both SIRT1 and SIRT3, with an anti-proliferation effect in human melanoma cells [82]. This effect was achieved through the mechanism of 4′-bromo-resveratrol reprogramming the metabolic pathway, disrupting the cell cycle and apoptosis signaling, leading to reduced proliferation, induced apoptosis, and inhibition of melanoma cell migration [82].

Fig. 13
figure 13

The chemical structure of polydatin (A) and 4′-bromo-resveratrol (B)

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Quercetin was found to modulate SIRT1, 3, and 6 possessing antioxidant and anti-inflammatory effects [83]. However, it was not an ideal therapeutics candidate, as the study reported quercetin with poor solubility, short half-life, and low bioavailability [84]. To address these limitations, quercetin derivatives were synthesized and tested, resulting in the successful identification of diquercetin (IC50 of 130 μM; Fig. 14A) and 2-chloro-1,4-naphthoquinone-quercetin (IC50 of 55 μM; Fig. 14B) as SIRT6 inhibitors with potential anti-cancer activities in treating cancers or age-related diseases [83]. While SIRT2 can be inhibited by 2-chloro-1,4-naphthoquinone-quercetin with an IC50 value of 14 μM [83]. Molecular docking studies revealed that diquercetin and 2-chloro-1,4-naphthoquinone-quercetin bind to different sites of SIRT6, which are the NAM+ site and substrate site, respectively [83].

Fig. 14
figure 14

The chemical structure of diquercetin (A) and 2-chloro-1,4-naphthoquinone-quercetin (B)

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Conclusion

This review focuses on sirtuin modulators reported from 2013 to current, which encompass compounds derived from both synthetic and natural sources. These modulators exhibit varying levels of selectivity for specific sirtuin isoforms, and some demonstrate equal or improved effectiveness in vitro activities compared to previously reported compounds. However, many of these modulators are still in the discovery/pre-clinical phase due to various constraints, requiring further studies to fully clarify their mechanisms of action and ensure their safety profiles.

As discussed earlier, some of these sirtuin modulators do seem to be promiscuous in which they lack a specific target. Some are pan-sirtuin inhibitors while there are others that could even target non-sirtuins. This is likely to result in off-target effects which not only reduce the potency, but also increase the toxicity of the compound at a higher dosage. In recent years, research on proteolysis targeting chimeras (PROTACs) in drug discovery has progressed tremendously. PROTACs operate catalytically to degrade the target protein without consume it. This unique mechanism enables the drug to function effectively at lower dosages, reducing the risk of toxicity from high dose. Additionally, by preventing the accumulation of the target protein, PROTACs can avoid the development of drug resistance [85, 86]. Similarly, sirtuin modulators based on the PROTACs strategy may offer advantages such as enhancing cytotoxicity, and selectively [87]. Moreover, although sirtuin modulators derived from natural compounds offer benefits such as potentially lower cytotoxicity as well as biocompatibility, they may encounter challenges such as limited solubility or poor metabolic stability. To overcome these issues, future research may focus on redesigning the drug structure or controlling delivery system to optimize the efficacy of the compound. Lack of the knowledge for in vivo studies and mechanism pathways may also prevent further development of these compounds, as many compounds mentioned only at the stage of completing in vitro studies. Moreover, a more detailed understanding of the SIRT role in specific diseases may further validate the pre-clinical data and explore the potential for treating various human diseases.

In conclusion, earlier discovered sirtuin modulators continue to serve as a foundation for the development of derivative compounds, aiming to address the limitations of the original modulators. The ongoing research and development in this field hold the potential for the future discovery of effective therapeutic interventions that target sirtuins, providing new possibilities for disease management and improving human health.