Alcoholic liver disease (ALD) represents the main type of chronic liver disease in the world (Seitz et al., 2018). It has been reported that cyclooxygenase-2 (COX-2) plays a vital role in the pathogenesis of ALD (Dunn and Shah, 2016). Enhanced expression of COX-2 can be seen in ALD (Nanji et al., 1997), and downregulating COX-2 can reduce inflammation and oxidative stress (Deol et al., 2018). Hence, an inhibitor of COX-2 may be an appropriate choice for the treatment of ALD.

Previously, Lee and coworkers demonstrated that 10-fluoro-2-methoxyrutaecarpine (3) (Figure 3) retained anti-inflammatory activity both in vitro and in vivo (Lee et al., 2019). Based on the results, they further found that 3 exhibited better COX-2 suppression activity and lower cytotoxicity compared to its parent RUT as a COX-2 selective inhibitor.

Another team, Xu and coworkers, introduced a sulfonyl group to RUT to improve the anti-inflammatory effect and obtained a novel analog termed 3-B-RUT (4) (Figure 3) (Xu et al., 2021). Then, they explored its protective effect on alcoholic liver injury (ALI) in vivo and in vitro. The results showed that 4 (20 μg/kg) attenuated ALI and suppressed oxidative stress and liver inflammation, and the effect was comparable to that of RUT (20 mg/kg). Mechanistically, the results of Western blot showed that administration of 4 inhibited the phosphorylation of P65 and IκBα (silencing COX2 also achieves this effect), leading to suppressing the transfer of P65 into the nucleus. As is known, NF-κB commonly refers to the dimer protein formed by the P65/P50 subunits, and it controls DNA transcription, cytokine production, cell survival, and other important cell events; it specifically plays a key role in regulating immune development, immune responses, oxidative stress, and inflammation (Mitchell et al., 2016). Therefore, 4 might suppress oxidative stress and inflammation by regulating the COX-2/NF-κB pathway. The increased anti-inflammatory activity leading to a lower concentration may overcome the undesirable side effects, such as in gastrointestinal or heart diseases. Therefore, 4 was considered to be a promising clinical candidate for the treatment of ALI.

Acute kidney injury (AKI) is a clinical syndrome caused by multiple factors, including ischemic–reperfusion injury, sepsis, and drug toxicity (such as cisplatin). Similarly, inflammation and oxidative stress have been shown to play critical roles in the pathogenesis of AKI (Liu et al., 2020).

Liu et al. found that phosphodiesterase 4B (PDE4B), a key enzyme modulator in immune and inflammation-related diseases, was significantly upregulated in the serum of AKI patients and participated in the progression of AKI (Liu et al., 2020). Therefore, they synthesized and obtained a series of 3-aromatic sulphonamide-substituted RUT derivatives, and compound 5 (Figure 4) exhibited the best renoprotective and anti-inflammatory activity (Liu et al., 2020). Using target prediction (performed by Discovery Studio 2017 software), molecular docking (pdb code: 5O0J), and cellular thermal shift assay (CETSA), they identified PDE4B as the target of 5. Therefore, 5 might serve as a therapeutic candidate for AKI via the PDE4B pathway.

Atherosclerosis is a chronic disease featuring lipid deposition and an inflammatory response (Libby et al., 2011). It is well known that nitric oxide (NO) and tumor necrosis factor (TNF)-α play vital roles in inflammation (Kaltenmeier et al., 2022). Furthermore, the NLRP3 inflammasome, a protein complex associated with the inflammatory progression of atherosclerosis, has attracted much interest in the pathogenesis of atherosclerosis (Abderrazak et al., 2015; Guo et al., 2015; Grebe et al., 2018). Therefore, compounds with reduced effects on NO, TNF-α, or NLRP3 that alleviate vascular inflammation would be beneficial for anti-atherogenic progression.

Previously, Lee et al. (2017) reported that compound 3 could also inhibit the production of NO and TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. In addition, no cytotoxicity was observed toward RAW264.7 macrophages at a concentration of 20 µM. Although Luo et al. first demonstrated that 5-deoxy-rutaecarpine (R3, 6) (Figure 5), a novel derivative of RUT, could alleviate atherosclerotic burden in Apoe^−/− mice fed a high-fat diet, pharmacokinetics studies showed that 6 had better oral bioavailability (F% = 27.89) than RUT (F% = 0.07) in male rats via gastric gavage at a dosage of 20 mg/kg. Subsequently, they explored its anti-atherosclerotic mechanisms (Luo et al., 2020). The results showed that 6 inhibited NLRP3 inflammasome activation through NF-κB, and the MAPK signaling pathway blocked atherosclerotic progression via debilitating NLRP3 inflammasome-related inflammation.

Based on the aforementioned information, we found that i) modification of the D-ring of RUT, especially the introduction of a sulfonyl group to the D-ring of RUT, seemed beneficial to enhance its anti-inflammatory activity; and ii) removal of the carbonyl group from the C-ring of RUT may improve its oral bioavailability (Figure 6).

Although 6 was demonstrated to exhibit anti-atherogenic activity, it is worth noting that it was first synthesized by Decker in early 2005, and its cholinesterase inhibitory activity was evaluated (Decker, 2005). The results showed that 6 exhibited moderate inhibitory activity toward both AChE and BChE with IC₅₀ values of 3.4 μM and 0.5 μM, respectively.

In 2010, the research group of Huang synthesized a series of novel RUT derivatives and evaluated their AChE inhibitory activity (Wang et al., 2010). Most of the derivatives were found to be selective for AChE over BChE. In particular, compound 7 showed the highest inhibitory activity toward AChE and also demonstrated the highest selectivity index (SI) over BChE. However, it showed a cytotoxic effect on SH-SY5Y cells. Considering that the dehydrorutaecarpine moiety had better potency than derivatives with the RUT moiety, they reported another series of dehydrorutaecarpine derivatives (He et al., 2013). All these synthetic compounds, particularly 8, showed higher inhibitory activity against AChE, Aβ aggregation, and oxidative stress compared to RUT. Notably, 8 showed a lower cytotoxic effect on SH-SY5Y cells (Figure 7).

Another research group, Li et al. (2013), reported a series of novel 2-(2-indolyl-)-4 (3H)-quinazoline (2IQ, 9) derivatives, which were regarded as the ring-opened analogs of RUT. Subsequently, they evaluated their pharmacological activity against AChE. Among them, 10 possessed the strongest inhibitory activity toward AChE with high selectivity over BChE (Figure 8).

Phosphodiesterases (PDEs), being responsible for hydrolyzing two second messengers, cyclic GMP (cGMP) and cyclic AMP (cAMP), can affect neuronal cell survival (Tsunada et al., 2021). Thus, PDEs play important roles in neurodegenerative diseases, including AD (Zuccarello et al., 2020). Among the different PDEs, PDE5 specifically hydrolyzes cGMP. Recently, an upregulated PDE5 expression has been found in the brains of mild AD patients, and studies have confirmed that PDE5 inhibitors exhibit therapeutic effects on AD patients by improving learning and memory, and reversing cognitive impairment (Boccia et al., 2011; Hosseini-Sharifabad et al., 2012; Al-Amin et al., 2014). Therefore, several researchers are developing anti-AD drugs by reducing PDE5 levels.

Considering RUT containing a quinoline structure, which has been demonstrated to be a privileged structure for the PDE5 inhibitor (Bi et al., 2004), Huang et al. decided to use RUT as the lead compound to develop PDE5 inhibitors for the treatment of AD (Huang et al., 2020). Thus, a series of RUT derivatives were synthesized, and their PDE5 inhibitory activities were tested. As a result, 11 showed the most potent PDE5 inhibitory activity with an IC₅₀ value of 0.086 μM. Moreover, it also exhibited good effects against scopolamine-induced cognitive impairment in vivo. These results might provide significant instruction for further developing PDE5 inhibitors derived from RUT (Figure 9).

It is well known that topoisomerases are important targets in tumor therapy, and their inhibitors, including camptothecin, irinotecan, topotecan, etc., are widely used in clinic applications. In 2006, Xu et al. revealed that RUT itself did not show any significant activity against topoisomerases I and II (Topo I and Topo II) despite its significant cytotoxicity on several cancer cell lines (Xu et al., 2006). However, Kim et al. found that two derivatives of RUT (12 and 13) not only exhibited cytotoxicity against selected human cancer cell lines (GI₅₀ values of 5 μM, 3 μM, and 3 μM for 15b against U251, SKOV3, and DU145 cell lines, respectively; GI₅₀ values of 2.5 μM, 2 μM, and 2 μM for 15c against U251, SKOV3, and DU145 cell lines, respectively) (Baruah et al., 2004) but also showed inhibitory activities against Topo I and Topo II (Kim et al., 2012) (Figure 10).

Huang et al. synthesized two sets of RUT derivatives with amine groups to improve their solubility (Huang et al., 2017). The results showed that the solubility of the compounds with the amine moieties connected to the indole-N atom (14) was improved significantly. Moreover, cell viability on HeLa cells and reduction of metabolic activity were in the same range or better for these derivatives compared to the chemically unaltered parent compounds (Figure 11).