Recent Advances on Natural Aryl-C-glycoside Scaffolds: Structure, Bioactivities, and Synthesis—A Comprehensive Review

Aryl-C-glycosides, of both synthetic and natural origin, are of great significance in medicinal chemistry owing to their unique structures and stability towards enzymatic and chemical hydrolysis as compared to O-glycosides. They are well-known antibiotics and potent enzyme inhibitors and possess a wide range of biological activities such as anticancer, antioxidant, antiviral, hypoglycemic effects, and so on. Currently, a number of aryl-C-glycoside drugs are on sale for the treatment of diabetes and related complications. This review summarizes the findings on aryl-C-glycoside scaffolds over the past 20 years, concerning new structures (over 200 molecules), their bioactivities—including anticancer, anti-inflammatory, antioxidant, antivirus, glycation inhibitory activities and other pharmacological effects—as well as their synthesis.


Introduction
Aryl-C-glycosides (ACGs), natural secondary metabolites, are glycosides in which the anomeric center is covalently linked to the carbon atom of arenes or heterocycles (C sp3 -C sp2 ) [1]. They tend to have high oral bioavailability and reach high plasma levels without needing to be converted to a prodrug. The stable linkage between the sugar and the arene or heterocycle moieties is resistant to enzymatic hydrolysis, allowing these compounds to interfere with DNA and RNA synthases more efficiently [2]. Both natural and synthetic aryl-C-glycosides are of marked pharmaceutical interest, and many of them have proven to be efficient antibiotics, antitumor agents, and antidiabetics. Therefore, aryl-C-glycosides have received considerable attention [3].

Flavonoid C-Glucosides
To the best of my knowledge, Flavonoid C-α-D-glucopyranosides, Flavonoid C-α-L-glucopyranosides, and Flavonoid C-β-L-glucopyranosides have not been isolated and identified from natural source. Flavonoid C-β-D-glucopyranosides are the largest group of isolated aryl-C-glycosides. Since 2002, more than 80 new compounds have been isolated and identified. It was found that the D-glucose unit is directly attached to the flavonoid or flavonoid derivatives in β configuration. Compared with the known aryl-C-glycosides previously reported, some of the new ones differ in their core structure, while others differ in the number and/or position of their substituents. The sites of glycosylation in the flavonoids are usually C6 and/or C8. Very few examples are known of C-glycosylation occurring at position C4 . Figure 1 illustrates the new aryl-C-glycosides with varied core structures or special substituents. These structures differ in the aglycon and or glucoside portions. The core structures are often abundantly decorated with substituents such as aromatic acids (e.g., benzoic acid, 2-methyl butyric acid, gallic acid, veratric acid, sinapic acid, ferulic acid, and acetic acid) and various saccharides (e.g., L-rhamnose, D-xylose, D-glucose, D-galactose, and L-arabinose) through ester or glycosidic linkages, respectively. These isolated structures are often associated with other known compounds, such as flavonoids, lignan, sesquiterpene, steroid, alkaloids, O-glycosides, etc.

Pharmacological Activity
Numerous researchers have investigated the pharmacological activities of various aryl-C-glycosides. Table 1 summarizes the pharmacological features of recently discovered aryl-C-glycoside molecules. They include, but are not limited to, anticancer, anti-inflammatory, antioxidant, antiviral activities, glycation inhibitory activity, other pharmacological activities such as neuroprotective effects, hepatoprotective activity, and antipyretic activity. These pharmacological activities are summarized below.

Pharmacological Activity
Numerous researchers have investigated the pharmacological activities of various aryl-C-glycosides. Table 1 summarizes the pharmacological features of recently discovered aryl-C-glycoside molecules. They include, but are not limited to, anticancer, anti-inflammatory, antioxidant, antiviral activities, glycation inhibitory activity, other pharmacological activities such as neuroprotective effects, hepatoprotective activity, and antipyretic activity. These pharmacological activities are summarized below.

Anticancer Activity
The indole C-glucopyranoside 178 exhibited significant cytotoxic activity against human myeloid leukemia cells HL-60 and human liver cancer cells HepG2, with IC50 of 1.3 ± 0.1 and 2.1 ± 0.3 µM, respectively. The indole C-glucopyranoside 179 showed potential cytotoxic activity against HL-60 and human myeloid leukemia Mata cells, with IC 50 of 5.1 ± 0.4 and 12.1 ± 0.8 µM, respectively [85]. Monacycliones I (195) and J (192), isolated from the marine-derived Streptomyces sp. HDN15129, showed cytotoxic activity against multiple human cancer cell lines, with IC 50 values ranging from 3.5 to 10 µM [31]. Marmycin A (198), isolated from the culture broth of a marine sediment-derived actinomycete related to the genus Streptomyces, displayed significant cytotoxicity against several cancer cell lines, some at nanomolar concentrations, while marmycin B (199) was less potent. For marmycin A (198), tumor cell cytotoxicity appeared to coincide with a modest induction of apoptosis and the arrest in the G1 phase of the cell cycle [32]. Li

Anti-Inflammatory Activity
Compound 68, isolated from the rhizomes of Cyperus rotundus, showed moderate inhibitory activity against MRB, with an IC 50 value of approximately 56.03 µM [15]. Nervilifordin J (94), isolated from a 60% EtOH extract of the aerial parts of Nervilia fordii, showed interesting inhibitory effects on nitric oxide production in lipopolysaccharide-activated RAW264.7 macrophages, with EC 50 values of 14.80 µM [17]. Vicenin-2 was isolated and identified from an ethanol extract of the aerial parts of Urtica circularis. This crude extract was found to possess significant anti-inflammatory activity in a carrageenan-induced rat hind paw edema model (41.5% inhibition at a dose of 300 mg/kg). In cultured murine macrophages, this compound modified LPS-induced total nitrite and TNF-α production, in addition to promoting the LPS-induced translocation of nuclear factor NF-κB [87].

Antiviral Activity
Speciflavoside A (32), isolated from a 70% methanolic extract of Lilium speciosum var. gloriosoides Baker, showed potent antiviral activity against RSV, with an IC 50 value of 2.9 µg/mL, comparable to that of ribavirin, an approved drug for the treatment of RSV infections in humans [10].

Glycation Inhibitory Activity
In 2003, Okuyama T. et al. reported that chrysoeriol 6-C-β-fucopyranoside 109, isolated from the style of Zea mays L. showed an inhibitory effect on glycation, with a percent inhibition value greater than that of aminoguanidine, a known glycation inhibitor [19]. Compounds 130-131, which contains the rare sugar boivinose, exhibited a glycation inhibitory activity similar to that of aminoguanidine [20].

Other Pharmacological Effects
Other pharmacological effects include neuroprotective effects, hepatoprotective activity, HIV inhibitory activity, antipyretic activity, transcriptional inhibitory activity of RXRα, cytotoxicity activity, and other activities.

Synthesis
In nature, most C-glycosides are derived from plants. Aryl C-glycosides are biosynthetically prepared by the catalysis of C-glycosyltransferases (CGTs). However, while a large family of O-glycosyltransferases (OGTs) is known, a limited number of CGTs have been discovered in plants [88]. Many detailed reviews on the chemical synthesis of aryl-C-glycoside have been published [8,[89][90][91][92][93]. Herein, a brief historical review of the total synthesis of natural aryl-C-glycosides is presented. From a retrosynthetic viewpoint, the strategy of synthesis of aryl-C-glycoside usually includes two protocols, as described below.
Toshiyuki Kan et al. reported the regioselective synthesis of chafurosides A (107) and B (108) using a novel protecting-group strategy. The construction of the dihydrofuran ring was achieved via an intramolecular Mitsunobu reaction. The key step in the C-glycosylation is the O→C rearrangement of the phenolic glycoside formed by TMSOTf-catalyzed glycosylation (Scheme 1) [94].

Scheme 1. Concise synthesis of chafurosides A and B.
Martin et al. reported the total synthesis of isokidamycin, which features the use of a silicon tether as a disposable regiocontrol element in an intramolecular Diels-Alder reaction between a substituted naphthyne and a glycosyl furan and a subsequent O→C-glycoside rearrangement (Scheme 2) [95].  Suzuki K. et al. reported the total synthesis of the proposed structure of ardimerin, whose key step includes the β-selective formation of the crucial C-glycoside linkage by the reaction between aryl iodide, through a halogen-metal exchange reaction, and lactone (Scheme 4) [97].   Besides the nucleophilic attack reaction of the aryl portions to provide aryl-C-glycoside molecules, the transition metal-catalyzed cross-coupling reactions to form the Csp3-Csp2 bond of aryl-C-glycosides are becoming more and more powerful. The Negeshi [114], Kumada [115], Stille [116][117][118], Heck [119,120], Sonogashira [121], Hiyama [122], and radical [123][124][125] cross-coupling reactions with different metals such as Pd [126,127], Ni [128,129], Fe [124,125], Co [115], Ir [130] as catalysts, as well as C-H activation [131,132] were successfully applied to the construction of aryl-C-glycoside scaffolds.

De Novo Construction of the Sugar Moiety
This approach uses the reactions of assembled aryl units based on methods for the construction of a sugar, including, but not limited to (a) the hetero-Diels−Alder reaction, (b) the 1,3-dipolar cycloaddition of nitrile oxides, (c) the ring-closing olefin metathesis [8], the de novo asymmetric approach [133][134][135], and the ring opening-ring closure strategy Toshiyuki Kan et al. reported the regioselective synthesis of chafurosides A (107) and B (108) using a novel protecting-group strategy. The construction of the dihydrofuran ring was achieved via an intramolecular Mitsunobu reaction. The key step in the Cglycosylation is the O→C rearrangement of the phenolic glycoside formed by TMSOTfcatalyzed glycosylation (Scheme 1) [94].
Martin et al. reported the total synthesis of isokidamycin, which features the use of a silicon tether as a disposable regiocontrol element in an intramolecular Diels-Alder reaction between a substituted naphthyne and a glycosyl furan and a subsequent O→C-glycoside rearrangement (Scheme 2) [95].
Suzuki K. et al. reported the total synthesis of the proposed structure of ardimerin, whose key step includes the β-selective formation of the crucial C-glycoside linkage by the reaction between aryl iodide, through a halogen-metal exchange reaction, and lactone (Scheme 4) [97].
Lee et al. reported the total synthesis of aciculatin. The key step is the glycosylation of the digitoxosyl thioglycoside with an electron-rich phenol activated by NIS/TfOH, which afforded the β-D-digitoxopyranoside (Scheme 5) [98].

De Novo Construction of the Sugar Moiety
This approach uses the reactions of assembled aryl units based on methods for the construction of a sugar, including, but not limited to (a) the hetero-Diels-Alder reaction, (b) the 1,3-dipolar cycloaddition of nitrile oxides, (c) the ring-closing olefin metathesis [8], the de novo asymmetric approach [133][134][135], and the ring opening-ring closure strategy [136]. It was successfully applied to the synthesis of O-spiro-C-aryl glycosides [137] and 2-deoxyβ-C-aryl glycosides [138].
Hauser et al. reported that de novo synthesis of C-aryl glycosides based on cycloaddition of an aryl nitrile oxide with 4-pentyn-2-ol, which was straightforwardly converted to the pyranone through sequential hydrogenolysis of the N-O bond of the isoxazole followed by acid-catalyzed intramolecular cyclization. (Scheme 6) [139]. [136]. It was successfully applied to the synthesis of O-spiro-C-aryl glycosides [137] and 2-deoxy-β-C-aryl glycosides [138].
Hauser et al. reported that de novo synthesis of C-aryl glycosides based on cycloaddition of an aryl nitrile oxide with 4-pentyn-2-ol, which was straightforwardly converted to the pyranone through sequential hydrogenolysis of the N-O bond of the isoxazole followed by acid-catalyzed intramolecular cyclization. (Scheme 6) [139].

Conclusions and Perspectives
In this review, the recently discovered aryl-C-glycoside structures were listed and their biological activities as well as their synthetical approaches were summarized. The diverse structures of natural aryl-C-glycosides and their multiple pharmacological effects suggest significant medicinal applications. This review presents a summary of studies published from 2002 to date on this promising compounds. The core structure of aryl-Cglycosides, which is glycosylated and/or acylated, exhibits a great number of molecular entities and possesses various pharmaceutical effects. It is expected that more and more aryl-C-glycoside scaffolds including natural and synthetical molecules will be disclosed, and their medicinal application will come true in the near future to benefit human health. Johann Mulzer et al. reported the development of a convergent and concise route to an advanced precursor of kendomycin by applying an S N 1 ring cyclization as a key step. The sugar moiety formed by the acid-catalyzed intramolecular etherification reaction of aryl-substituted 1, 3, 5-triol (Scheme 7) [140]. [136]. It was successfully applied to the synthesis of O-spiro-C-aryl glycosides [137] and 2-deoxy-β-C-aryl glycosides [138].
Hauser et al. reported that de novo synthesis of C-aryl glycosides based on cycloaddition of an aryl nitrile oxide with 4-pentyn-2-ol, which was straightforwardly converted to the pyranone through sequential hydrogenolysis of the N-O bond of the isoxazole followed by acid-catalyzed intramolecular cyclization. (Scheme 6) [139].

Conclusions and Perspectives
In this review, the recently discovered aryl-C-glycoside structures were listed and their biological activities as well as their synthetical approaches were summarized. The diverse structures of natural aryl-C-glycosides and their multiple pharmacological effects suggest significant medicinal applications. This review presents a summary of studies published from 2002 to date on this promising compounds. The core structure of aryl-Cglycosides, which is glycosylated and/or acylated, exhibits a great number of molecular entities and possesses various pharmaceutical effects. It is expected that more and more aryl-C-glycoside scaffolds including natural and synthetical molecules will be disclosed, and their medicinal application will come true in the near future to benefit human health. Scheme 7. Concise synthesis of kendomycin.

Conclusions and Perspectives
In this review, the recently discovered aryl-C-glycoside structures were listed and their biological activities as well as their synthetical approaches were summarized. The diverse structures of natural aryl-C-glycosides and their multiple pharmacological effects suggest significant medicinal applications. This review presents a summary of studies published from 2002 to date on this promising compounds. The core structure of aryl-Cglycosides, which is glycosylated and/or acylated, exhibits a great number of molecular entities and possesses various pharmaceutical effects. It is expected that more and more aryl-C-glycoside scaffolds including natural and synthetical molecules will be disclosed, and their medicinal application will come true in the near future to benefit human health.