Keywords

1 Introduction

Sirtuins are existing in both prokaryotes and eukaryotes, which are NAD+-dependent mono-ADP ribosylases and protein lysine deacylases. The sirtuin family in living things consists of seven isoforms, each with a unique subcellular location and biological functions (Alvarez et al. 2011; Fiorentino et al. 2022b). Sirtuins have established cumulative consideration in the past couple of decades specified their vital roles in a range of biological processes, including cytodifferentiation, transcriptional control, cell cycle progression, apoptosis, swelling, breakdown, brain-related and heart physiology, and cancer. Thus, it has been noted that sirtuin activity regulation represents a prospective therapeutic approach for several illness (Fiorentino et al. 2022a).

Since 2000, sirtuins (SIRT1–7) have drawn increasing interest for their associations with an extensive variety of biological functions, including the control of cellular metabolism, neuroprotection, apoptosis, inflammation, and the growth of cancer (Mellini et al. 2015). In particular, SIRT1 has received the greatest research attention, both for its involvement in calorie restriction and as an eventual path for the therapy of illnesses associated with aging (Yeong et al. 2020). SIRT suppression can have advantageous effects on aging-related conditions including metabolic, cardiovascular, and neurodegenerative illnesses, whereas SIRT inhibitors may be beneficial for the treatment of muscular disorders, HIV infection, or cancer (Mellini et al. 2015; Valente et al. 2016).

The sirtuin route has drawn superior interest since it is linked to the advantages of calorie restriction for anti-aging (Mohamad Nasir et al. 2018). In aging-related laboratory models, pharmacological or genetically overexpression of the sirtuin system has also revealed encouraging outcomes. Mammalian sirtuins, which are related of the yeast Sir2 family, consist of seven members (SIRT1–SIRT7). ADP-ribosyltransferase and a deacetylase activity are two distinct actions that sirtuins have been discovered to exhibit (Liszt et al. 2005; Landry et al. 2000). Histones, transcription factors, and apoptosis modulators are just a few of the targets that sirtuins use to convey out their deacetylase activity (Youcef et al. 2007; Dai et al. 2018).

Similar to this, the revelation which are catalytic action requires NAD+, as opposed to Zn2+ in the situations of other groups of deacetylases, suggests their potential significance in balancing management in the cell’s breakdown and its functional state. Seven sirtuin iso-forms regulate numerous metabolic, anxiety, and aging processes in living things. For illnesses associated with metabolism and aging, such as metabolic syndrome and neurodegenerative disorders, sirtuins are supposed to be promising therapeutic targets. Sirtuins are thought to be prospective therapeutic targets for disorders of metabolism and aging, such as neurodegenerative illnesses and metabolic disorders.

Few powerful and selective compounds have been produced despite intensive attempts to generate minor-molecule sirtuin inhibitors and activators, in part because of the limitations of currently available assays and a lack of mechanistic characterisation of discovered compounds (Schutkowski et al. 2014).

2 Types of Sirtuin

See Table 15.1.

Table 15.1 Aspects of sirtuin’s biochemistry and functionality (Anekonda and Reddy 2006; Baur et al. 2012; Bonda et al. 2011; Outeiro et al. 2008; Wątroba and Szukiewicz 2016)
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3 Pharmacological Sirtuin Modulation

Sirtuins have fascinated attention as possible therapeutic targets, therefore much work has been put into developing specialised sirtuin agonist and inhibitors, both are utilised in research for understanding sirtuin function and as potential anti-ageing medications. Recent growths in sirtuin biochemistry, analytical test, and crystal structures of sirtuin/modulator composite, which disclose a challenging relationship between numerous chemicals and the structure and function of the enzyme, are currently assisting in the discovery of pharmacological sirtuin modulators (Dai et al. 2018).

3.1 Sirtuin Activators

Since more than 75 years ago, it has been recognised that calorie restriction (CR) increases mammalian longevity and promotes better health. When sirtuins were eliminated, it had been assumed that food restriction did not increase lifespan (Rogina and Helfand 2004; Lin et al. 2000) and that calorie restriction might lengthen mammalian lifetime by bringing SIRT1 expression (Cohen et al. 2004) led researchers to study sirtuins and to discover and develop molecules that could stimulate them.

Despite the fact that the function of sirtuins in enhancing lifespan is currently being called into doubt, based on the beneficial effects of calorie restriction on mammalian health and the consequent rises in SIRT1 (Cohen et al. 2004), sirtuins are gaining a lot of attention and compounds that can activate them due to the identification and formation of medicines that activate SIRT1.

3.1.1 Resveratrol

Two phenyl rings of the polyphenol resveratrol (RSV), which are connected by a methylene bridge (Fig. 15.1a), was the primary substance to be found that can imitate calorie restriction via activating sirtuins (Howitz et al. 2003; Wood et al. 2004). The primary substance identified that may imitate calorie restriction through activating sirtuins is resveratrol, a polyphenol comprising two phenyl rings split apart by a methylene bridge (Fig. 15.1a) (Howitz et al. 2003; Wood et al. 2004).

Fig. 15.1
The chemical structure of resveratrol, S R T 1720, Oxazolo pyridines derivative, Imidazol thiazole derivatives, 1,4 Dihydropyridine, all with ring structures. They have 2 or more benzene structures with zigzag structures.

Sirtuin activators. (a) Resveratrol (3,5,4′-Trihydroxy-trans-stilbene) (b) SRT1720; (c) Oxazolo[4,5-b]pyridines derivative; (d) Imidazo[1,2-b]thiazole derivatives; (e) 1,4-Dihydropyridine (DHP) derivatives are a few examples

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RSV significantly reduced ageing symptoms without altering the pattern of expression of any sirtuin genetic factor and mimicked CR-induced gene expression patterns in several organs (Barger et al. 2008; Pearson et al. 2008). RSV’s bioavailability and pharmacokinetics have been updated and reported in the past (Alcain and Villalba 2009; Vang et al. 2011). It has been shown that RSV, in in vivo testing to significantly slow down the ageing process in mice fed a diet loaded with calories (Baur et al. 2006). The occurrences of cataracts and albuminuria are reduced, vascular endothelium inflammation and apoptosis are decreased, aortic flexibility is increased, motor coordination is enhanced, and bone mineral density is maintained (Pearson et al. 2008). RSV’s limited bioavailability has led to modifications to boost bioavailability. A nutraceutical product called resVida, which contains 150 mg of resveratrol daily, has demonstrated success in lowering intrahepatic lipid levels, moving glucose, fatty acids, alanine-aminotransferase, or signs of inflammation in healthy obese males. These outcomes are identical to CRs (Timmers et al. 2011).

Severe dose-sensitive improvements in vasodilation mediated by the endothelium were also seen by oral RSV supplementation, and these improvements were associated with higher plasma RSV concentrations (Wong et al. 2011). After 3 months of treatment, RSV administered when nutritional preparation Longevinex® increased dilatation mediated by flow, but 3 months later Longevinex® was stopped. This option went back to its default value. The medication had no effect on inflammatory markers, lipid profiles, blood pressure, insulin resistance, or any of these parameters (Fujitaka et al. 2011).

3.1.2 Sirtuin Activators Structurally Unrelated to Resveratrol

The hunt for new compounds that may activate sirtuins more efficiently than RSV has gained attention because sirtuins are important for maintaining metabolic activities and disorders linked to ageing. Milne et al., in 2007 found small molecule SIRT1 activators that are structurally different from RSV but 100 times more powerful.

The most efficient substance was SRT1720, which at 10 M increased SIRT1 activity by 750%. Due to additive SIRT1 activation caused by medication combination, it was shown that SRT1720 (Fig. 15.1b) binds to and activates the enzyme at the same molecular site as RSV. The key domain’s nitrogen-terminal protein sequences 183–225 were significant in identifying the chemical attaching region.

In vivo and in vitro, SRT1720 boosted the deacetylation of SIRT1 substrates such p53, the transcriptional co-activator PGC-1α, and Foxo1a. Innately overweight mice (Lep ob/ob), DIO mice, and the Zucker fa/fa rat were used as in vivo disease models to examine the healing potential of SIRT1720 to cure insulin resistance and type-2 diabetes (Smith et al. 2009).

SRT1720 treatment significantly decreased fasting blood glucose in mice on a high-fat diet to levels close to normal, moderately controlling raised insulin amount, and protected mice from DIO and insulin resistance by improving oxidative metabolism in skeletal muscle, the liver, and brown adipose tissue through a general metabolic change that mimicked low energy levels (Feige et al. 2008).

Mice fed a diet rich in fat received SRT1720, which significantly dropped their fasting blood glucose levels to levels that were almost normal, partially normalised their increased insulin levels, and reduced their feeding glucose levels (Messa et al. 2020). By increasing oxidative metabolism in skeletal muscle, the liver, and brown adipose tissue through a general metabolic adaptation imitating low energy levels, these results effectively protected mice from DIO and insulin resistance (Feige et al. 2008).

Novel small molecule SIRT1 stimulants that are distinct from RSV have been identified, including a series of Oxazolo[4,5-b]pyridines (Fig. 15.1c). Additionally, a series of imidazo(1,2-b)thiazole derivatives bearing an oxazolopyridine core have been synthesised, and they may represent novel healing aims for the treatment of several illnesses.

Compound 29 (Fig. 15.1d), the least effective homologue in this generation, demonstrated oral antidiabetic activity for three distinct forms of type-2 diabetes and had a significant oral bioavailability in mouse and rat models of type-2 diabetes. In the DIO model after 2 weeks of dosage, in the genetic Zucker fa/fa rat model after 3 weeks, and in the ob/ob deficient mice after just 1 week of therapy, an intake of 100 mg/kg of compound 29 administered per day resulted in a considerable drop in fasting blood glucose content. Compound 29 was capable to control a noticeably minor amount of administered insulin and glucose in the DIO mice even after 10 weeks of dosage without having any effects on body weight, overall clinical chemistry, or haematology (Vu et al. 2009) (Fig. 15.2).

Fig. 15.2
A pathway for activating Sirt1 begins with agonists fusing with a membrane, triggering a series of steps that release Nampt and NAD plus. This process ultimately leads to mitochondrial biogenesis.

Sirt1 activation pathway by resveratrol

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3.2 Sirtuin Blockers

Entirely sirtuins comprise the co-factor nicotinamide adenine dinucleotide (NAD+) (Landry et al. 2000). The acetyl-peptide remains bound by ADP-ribose, which causes the creation of a 0-alkylamidate intermediate, in the first stage of the suggested reaction process, which involves the cleavage of nicotinamide (NIC) from NAD+.

NIC is a powerful process product inhibitor due to its potential to re-bind the enzyme’s intermediate form the 0-alkylamidate and target the intermediate (Sauve and Schramm 2003). The NIC promotes megakaryocyte maturation and ploidy, in part, by inhibiting SIRT1 and by enhancing p53 binding to the NIC consensus DNA binding sequence (Giammona et al. 2009).

Due to up-regulated SIRT1 being reported in cancer cell lines, sirtuin inhibitors may also be effective as therapeutic drugs. That opens up the possibility of sirtuin inhibition can restrict the tumorigenesis. In various animal models, increased SIRT1 activity was discovered to be advantageous, which stimulated the creation of pharmacological sirtuin activators, perhaps as CR mimics. Sirtuin blockers are also suggested for the therapy for other condition like Parkinson’s disease, leishmaniosis, or HIV in along with treatment of cancer (Pagans et al. 2005). It is also crucial to take into account that SIRT3, SIRT4, and SIRT5 are found in the mitochondria, wherever many mitochondrial proteins undergo run of acetylation/deacetylation (Verdin et al. 2010) processes crucial for energy utilisation and apoptotic the beginning, as well as in the situation of certain illnesses such as cancer and the metabolic disorder (Pereira et al. 2012).

High-throughput and computational analysis screens identified sirtuin inhibitors for SIRT1, SIRT2, SIRT3, and SIRT5, in contrast to the activators sector, where only SIRT1 activators have been discovered (Villalba and Alcaín 2012). The majority of sirtuin inhibitors that have been studied till now, only SIRT1 and/or SIRT2 have been inhibited; however, a few of them have lesser affinity inhibitory effects on SIRT3 and SIRT5.

3.2.1 Splitomicin and Its Derivatives

Bedalov et al., discovered a substance called splitomicin (Fig. 15.3a) that produces a restricted phenocopy of a Sir2 deletions variant in Saccharomyces cerevisiae, provide a fresh method to study the vital function of Sir2 in vivo. IC50 for splitomicin’s inhibition of Sir2 is 60 μM (Bedalov et al. 2001). Splitomicin’s effects on human SIRT1 were, however, only moderately inhibited.

Fig. 15.3
The chemical structures of Splitomicin, H R 73, Sirtinol, A G K 2, Cambinol, Salermide, Tenovin, and Suramin. They have benzene rings connected by zigzag chains.

Sirtuin inhibitors. (a) Splitomicin, (b) HR73, (c) sirtinol, (d) AGK2, (e) cambinol, (f) salermide, (g) tenovin, (h) Suramin

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One of the two β-phenylsplitomicin stereoisomers was clearly preferred, as shown by docking and free energy computing, and a connection between enhanced enzyme inhibition and antiproliferative action in MCF-7 breast cancer cells was identified (Neugebauer et al. 2008).

By heterochromatinizing the regulator and silencing the gene, SIRT1 contributes significantly to the amplification of the CGG·CCG-repeat tract that causes Fragile X syndrome, one of maximum prevalent genetic form of psychological illness. Its interesting to note that the Fragile X intellectual disabilities syndrome gene silence is reduced by splitomicin-mediated regulation of SIRT1 activity (Biacsi et al. 2008).

The HIV Tat protein is controlled by process of acetylation and deacetylation. Through its acetyl group and the bromodomain of PCAF, acetylated Tat that is linked to the expanding polymerase attracts the transcriptional coactivator PCAF. Tat’s separation from the expanding polymerase and PCAF might result from SIRT1’s deacetylation of the protein. A splitomicin analogue known as HR73 (Fig. 15.3b) was shown by Pagans et al. to decrease SIRT1 functioning in vitro with an IC50 value less than 5 μM, confirming SIRT1 as a new therapeutic aim for HIV infection (Pagans et al. 2005).

The Tat protein of the HIV virus is controlled by processes of acetylation and deacetylation (Chen et al. 2020). Through the polymerases elongating domain and the bromodomain of PCAF, acetylated Tat attracts the transcriptional coactivator PCAF. Tat’s separation from the elongating polymerase and PCAF could occur if SIRT1 deacetylates Tat. A splitomicin analogue (Villalba and Alcaín 2012) identified as HR73 (Fig. 15.3b) was discovered by Pagans et al. (2005) and it suppressed SIRT1 action in vitro with an IC50 value of less than 5 μM, establishing SIRT1 as a new HIV infection treatment target (Pagans et al. 2005).

3.2.2 Sirtinol

An additional sirtuin antagonist, sirtinol (2-[(2-hydroxy-naphthalen-1-ylmethylene)-amino]-N-(1-phenyl-ethyl)-benzamide) (Fig. 15.3c), was also found by Grozinger et al. (2001), in a cell-based screen. This substance decreased both yeast Sir2 and human SIRT2 action in vitro. It was proven that the 2-hydroxyl-1-napthol portion was enough to block (Grozinger et al. 2001). Sirtinol’s two derivatives, m- and p-sirtinol, were two- to tenfold highly effective against human SIRT1 and SIRT-2 than sirtinol (Mai et al. 2005). The activation of SIRT1 may be crucial in fostering cell development. As a result of decrease in apoptosis in consequence of diverse genotoxic stimuli caused by deacetylation of p53, SIRT1 inhibitors like sirtinol have potential to treat cancer (Mirzayans et al. 2017). Sirtinol also led to senescence-like growth arrest in human breast cancer MCF-7 and lung cancer H1299 cells, in addition to raising chemosensitivity to camptothecin and cisplatin in PC3, DU145, and HeLa cells (Carafa et al. 2016). The result of an increase in programmed cell death, this led to a large decrease in viable cells (Kojima et al. 2008; Peck et al. 2010).

It has also been discovered that sirtinol, nicotinamide, and SIRT3 down-regulation reduced cell proliferation and expansion in oral squamous cell carcinoma (OSCC) cell lines in vitro and in vivo, whereas SIRT3 is abundantly expressed comparison to other sirtuins, and triggered apoptosis. Additionally, SIRT3 downregulation increased OSCC cells susceptible to radiotherapy and cis-platin’s cytotoxic effects (Alhazzazi et al. 2011).

Oculopharyngeal muscular dystrophy is modeled using nematodes, a condition brought on via polyalanine increase in the nuclear protein PABPN1, sirtinol therapy proved protective, by boosting the dose of Sir2/SIRT1, increased muscle prognosis (Pasco et al. 2010). Furthermore, sirtinol treatment decreased pain and swelling in human superficial microvascular endothelial cells, modulated the appearance of binding molecules and monocyte sticking in main human cutaneous microvascular endothelial cells and induced cell death in Leishmania infantum, greatly reducing this axenic amastigote’s in vitro proliferation (Orecchia et al. 2011).

3.2.3 AGK2

According to reports, neuroprotection is provided by inhibiting SIRT2 activity. The protein α-synuclein (α-syn) is found in Lewy bodies which are the most prevalent histological characteristic of Parkinson disease (PD). The inhibition of SIRT2 with short interfering RNA or including AGK2 (Fig. 15.3d) prevented the impairment of dopaminergic nerve cells caused on by α-syn toxicity in a Drosophila PD model and lessened the neurotoxicity generated by mutant α-syn in rat primary dopamine-positive neurons (Outeiro et al. 2007).

Treatment with AGK2 increased the amounts of acetylated tubulin, but it also made PC12 cells more susceptible to necrosis without changing autophagy and caused C-6 glioma cells to undergo caspase-3-dependent apoptosis (He et al. 2012; Nie et al. 2011). Additionally, through down-regulated the RNAs necessary for sterol production. In both animal and cell-based models of Huntington’s disease (HD), sirt2 inhibition produced neuroprotection (Luthi-Carter et al. 2010). In contrast to the neuroprotective effects of SIRT2 suppression in PD and HD models, pharmacological inhibition of SIRT1/2 by nicotinamide, AGK2, or cambinol increased multiplication in cultivated megakaryocytic cells, boosting acetylation of nucleosomes and p53 (Giammona et al. 2009).

3.2.4 Cambinol

The chemically stable molecule cambinol (Fig. 15.3e), which suppresses both SIRT1 and SIRT2 in vitro with IC50 values of 56 and 59 μM, consequently, is known as β-naphtol. It shares a pharmacophore with sirtinol and splitomicin. Cambinol has individual marginal suppression effect (42% suppression at 300 μM) against SIRT5 (Heltweg et al. 2006). Mice showed good tolerance to cambinol and prevented the spread of Burkitt lymphoma xenografts by triggering apoptosis through hyperacetylation of the BCL6 oncoprotein and p53 (Heltweg et al. 2006).

Although the efficacy against SIRT2 improved in vitro when the substituent at the N1-position was utilised or this was not the case for SIRT1, changes to the phenyl ring of cambinol improved activity and increased selectivity for SIRT1, leading to the identification of a variety of SIRT2 selective analogues (Medda et al. 2009).

3.2.5 Suramin

Suramin, which has an IC50 value of 22 M, is a more powerful blocker of SIRT5 NAD+-dependent deacetylase activity than cambinol (Fig. 15.3h). Suramin has a strong inhibitory effect on SIRT1 and SIRT2 (IC50 = 0.297 μM and 1.15 μM, respectively) (Trapp et al. 2007). In addition to its antiproliferative and antiviral properties, the polyanionic naphthylurea known as suramin was first used to treat trypanosomiasis (Perabo and Müller 2005). A stronger inhibition of SIRT5 NAD+-dependent deacetylase activity than cambinol is suramin (Fig. 15.3h), with an IC50 value of 22 μM. SIRT1 and SIRT2 are both significantly inhibited by suramin (IC50 values of 0.297 μM and 1.15 μM, respectively) (Trapp et al. 2007). Originally used to treat trypanosomiasis, suramin is a polyanionic naphthylurea that also has antiproliferative and antiviral properties (Perabo and Müller 2005).

3.2.6 Tenovin

Two SIRT1 inhibitors were discovered by Lain et al. (2008) looking for tiny molecules that might stimulate p53 and stop cancer development utilising a cell-based screening method: tenovin-1 and its more water-soluble counterpart, tenovin-6 (Fig. 15.3g). Both substances inhibited tumour development in vivo at one-digit micromolar doses in vitro, all without producing appreciable over-all toxicity. In chronic myelogenous leukaemia (CML), SIRT1 activation enhances cell survival, and proliferation was linked to the deacetylation of many SIRT1 substrates, including FOXO1, p53, and KU70. Tenovin-6, an inhibitor of SIRT1, was administered to mice to stop the course of the illness (Yuan et al. 2012).

Tenovin-1 and tenovin-6 have recently undergone a series of more water-soluble counterparts that, generally, kept the required biological activity. In the presence of a solution, tenovin-1 analogues take on a preferred shape that includes an intramolecular hydrogen bond necessary for SIRT1 binding. Additionally, When the 4-tert-butyl substituent in tenovin-6 was replaced with shorter alkyl chains (4-propyl or 4-iso-propyl substituent), analogues with longer n-alkyl chains (4-n-butyl or 4-n-pentyl substituent) showed hazardous or ineffective in cells (Mccarthy et al. 2012).

3.2.7 Salermide

A reverse amide with a strong in vitro inhibitory effect on SIRT1 and SIRT2 is salermide is (N-{3-[(2-hydroxy-1-naphthalenylmethylene)-amino]-phenyl2}-phenyl-propionamide) (Fig. 15.3f). At dosages up to 100 μM, salermide was tolerated effectively by mice and induced p53-independent apoptosis in cancer cells but not in healthy cells. This was accomplished by regenerating proapoptotic genes that SIRT1 had been epigenetically suppressed in cancer cells (Lara et al. 2009). A further SIRT1 and SIRT2 inhibitor called sirtinol requires p53, as well as salermide-induced apoptosis, according to a different research utilising breast cancer cell lines and p53-insufficient mice fibroblasts (Peck et al. 2010). The salermide impact in human non-small cell lung cancer cells could be mediated by an increase in death receptor 5 expression (Liu et al. 2012).

3.2.8 Other Inhibitors of Human Sirtuins

There are many of other SIRT1 and SIRT2 inhibitors that have been found and thoroughly explored. Tripeptide analogues based on lysine, N-thioacetyl lysine found in non-peptides, thiobarbiturates, indole derivatives (EX-527), and other inhibitors with various structural cores are among them.

4 Natural Sirtuin Inhibitors and Modulators Beneficial Effects on Health

See Table 15.2.

Table 15.2 Sirtuin inhibitors and modulators
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5 Conclusions

Sirtuins are a significant group of histone deacetylases that take part in NAD+-dependent deacetylation processes. Activation, inhibition, and regulation of sirtuins are engaged in a variety of key metabolic processes that are connected to conditions including type 2 diabetes, ageing, and inflammation. As a result, they have anti-cancer, anti-oxidant, anti-microbial, and anti-viral effects and are a significant drug target class. Natural products are renowned for being significant sources of lead compounds. In this study, we’ve made an effort to give a quick rundown of the most current findings about natural products that have been found to interact with sirtuins.

Natural sirtuin modulators and inhibitors may have positive effect on health in addition to well-recognised mechanisms of action and individuals being researched in clinical studies. Alkaloids, bichalcones, resveratrol, xanthone, tanikolide, and flavonoids are a few examples of natural substances and chemical types that have been demonstrated to have actions against sirtuins. The next generation sirtuins modulators are anticipated to be natural product derivates beginning from the discovered lead compounds.