166 ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192

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Digital Chinese Medicine

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Antioxidant Nature Adds Further Therapeutic Value: An Updated Review on Natural Xanthones and Their Glycosides

ZAFAR Salmana, JIAN Yu-Qingb, LI Binb, PENG Cai-Yunb, CHOUDHARY Muhammad Iqbalc, RAHMAN Atta-urc, WANG Weib* a. Institute of Chemical Sciences, University of Peshawar, Peshawar 25120, Pakistan b. TCM and Ethnomedicine Innovation & Development International Laboratory, Sino-Pakistan TCM and Ethnomedicine Research Center, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China c. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan

A R T I C L E I N F O A B S T R A C T

Article history Plants have so much to offer as far as the discovery of new Received 28 Mar. 2019 bioactive molecules is concerned. Among the several classes of Accepted 10 Jul. 2019 phytochemicals, xanthones offer greater structural diversity and Available online 25 Sep. 2019 pharmacological value. They are variable but definitely

antioxidant in nature. Thus they are attractive targets for natural Keywords product and medicinal chemists. Xanthones and their glycosides Xanthones possess broad spectrum interesting biological activities, such as Xanthone glycosides cytotoxic, anti-inflammatory, antioxidant, anti-bacterial, Antioxidant neuroprotective, anti-HIV, enzyme inhibition, and hypoglycemic. Radical scavenging The radical scavenging ability of these molecules accounts for Xanthone dimers most of their added therapeutic values. This paper intended to Xanthone trimers

serve as a guide for future endeavors in quest for these molecules. *Corresponding author: WANG Wei, Ph.D.， Structure-Activity Relationship (SAR) and mechanism of action is Hunan Furong Distinguished Professor. given for better understanding of their role as pharmacological Research direction: natural products research agents. The most recent advances in the isolation of bioactive and ethnomedicine. xanthones and their glycosides were presented here. This paper E-mail: [email protected]. will assist in directed approaches towards the discovery of Peer review under the responsibility of Hunan analogues of xanthones. University of Chinese Medicine.

DOI: 10.1016/j.dcmed.2019.12.005 Citation: ZAFAR S, JIAN YQ, LI B, et al. Antioxidant nature adds further therapeutic value: an updated review on natural xanthones and their glycosides. Digital Chinese Medicine, 2019,2(3): 166–192.

1 Introduction γ-pyrone ring (Figure 1). Xanthone analogues and glycosides are obtained Xanthones and xanthone glycosides are an important by functionalization of the same basic skeleton at dif- class of organic molecules, found abundantly in ferent positions, offering great structural diversity. nature. Xanthone has the molecular formula These molecules have shown pronounced potential [1] [2-4] [5] C13H8O2, having two benzene rings fused to a as antioxidants , anti-viral , anti-HIV , anti-mi-

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O 1 8 We will discuss different classes of xanthones sep- 9a 8a arately, focusing on their sources, antioxidant poten- 2 9 7 A B C tial, and their correspondingly role in countering oth- 3 6 er health issues. 4a O 10a 4 5 10 2 Xanthone Derivatives (Aglycons) Figure 1 Basic skeleton of xanthone One of the very first reports of isolation of xanthone crobial [6], cytotoxic [5-7], and neuroprotective agents [8]. derivatives appeared in 1955, when Canonica and In addition, they have also been proved as significant his coworkers reported xanthones from the roots of α-glucosidase [9, 10], acetylcholinesterase [11, 12], tyro- Gentiana lutea [17]. Since then enormous literature [13] [14] sine phosphatase , HIV reverse transcriptase , has been published on the same topic. A survey of the [15] and topoisomerase inhibitors. Most of the biologi- literature reveals that the genus Swertia, Hypericum, cal activities exhibited by xanthones, are due to their and Garcinia are rich in xanthone derivatives. antioxidant potential. Their immense and diverse Xanthones have also been isolated from other plants pharmacological potential has attracted several sci- and some microbial sources. Biosynthetically, entific groups to isolate and identify these interesting xanthones are produced through the shikimate [16] secondary metabolites from nature. NEGI et al. pathway with phenylalanine as the precursor [16]. published a comprehensive review on xanthones and The xanthone skeleton is usually substituted with their glycosides in 2012. They highlighted the classi- a variety of functional groups, affording immense di- fication, occurrence, biological activities, isolation, versity to the skeleton. Thus they may be alkylated, [16] and biosynthesis of this class of compounds . An hydroxylated, prenylated, with caged skeletons, fused update on the isolation of bioactive natural xantho- ring systems, alkoxylated, or acylated. The interest- nes and xanthone glycosides since 2012 is presented ing structural skeleton and structural diversity of the here. This is the first attempt to summarize the latest xanthone analogs offer diverse biological potential as literature on all the different sub-classes of well. xanthones. Inside our body, the reactive free radical species 2.1 Hydroxylated xanthones are involved in protein oxidation, DNA damage, lipid peroxidation, covalent binding of xenobiotics to bio- Xanthones with free hydroxyl groups are mostly be molecules, lowering cell ability to maintain calcium antioxidant in nature. This is because of the fact that levels, apoptosis and other effects. Scavenging these phenolic groups can effectively scavenge free radi- species, mostly known as reactive oxygen species cals [18]. But this is not the only activity reported about (ROS), which is very important for a healthy life. Anti- simple hydroxylated xanthones. In fact, the oxidants in our diets and medicines play a pivotal production of ROS in the body is one of the causes of role in helping getting rid of these species. the onset of many health disorders. Thus an Xanthones, owing to their phenolic moieties, are antioxidant agent can be well proved as a potent strong antioxidant in nature. Thus, they are useful molecule against another disease. Following is the molecules in preventing serious health disorders breakdown of xanthones with different degrees of caused by excessive oxidizing species in the body, a hydroxylations. condition known as oxidative burst. 2.1.1 Dihydroxy xanthones DUANGSRISAI et al. [19] Xanthones react with the free radicals either isolated 6 polyhydroxylated xanthones from Garcinia through a single electron transfer (SET) or hydrogen succifolia, having 2, 3 and 4 hydroxyl groups, at- atom transfer (HAT) mechanism. Figure 2 and 3 tached at different positions. All the compounds showed the most probable pathways for reaction of showed anti-bacterial activity against various strains. xanthones with radicals following the above men- But only 2 of these compounds, i.e., 1,5-dihydroxy tioned mechanisms, respectively. xanthone and 1,7-dihydroxy xanthones (Figure 4) Antioxidants are crucial in preventing the onset of were found active against the EGFR-tyrosine kinsase certain diseases because of the fact that the ROS enzyme with IC50 values of 90.34 and 223 nM, re- present in the body are the main causes of these spectively. It was suggested that the hydroxyl groups health disorders. Some of the major implications of at position 2 and 5 enhanced the activity of the com- free radicals inside the body are diabetes, athero- pound, while hydroxyl groups at 3 and 6 reduced the sclerosis, inflammation, ageing, arrhythmia, carcino- inhibitory potential [19]. A change in the substituent genesis, rheumatoid arthritis, and Alzheimer’s dis- position from 1,5 to 2,5 might decrease this activity, ease. but it makes it be an RXR α transcriptional inhibi- 168 ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192

H H O O O O R SET R O O

RH H O O O O PT H O O

1

O O Resonance stabilized radical O

H O O O O PL H O O

RH O O O O R R O O

1

O O Resonance stabilized radical O

H H O O O O R SET R O O

H RH O O O O

Hydride H Loss O O

2

O O Resonance stabilized radical O

Figure 2 Plausible SET mechanisms in xanthones tor [20]. Moreover, the 1,7-dihydroxy compound also adds value to compounds. 3,6-Dihydroxy xanthone exhibits antioxidant and cytotoxic potency [21, 22], was reported by JO et al., and it was found inactive in which suggests that hydroxylation at these positions NO production inhibitory activity [23]. The SAR stud- ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192 An Updated Review on Natural Xanthones and Their Glycosides 169

H O O O O R

SET RH O O

O O

Resonance stabilized radical O

Figure 3 Hydrogen atom transfer (HAT) mechanism

O OH O O OH OH HO

O O O OH OH 1,5-dihydroxy xanthone 2,5-dihydroxy xanthone 1,7-dihydroxy xanthone

O O O HO OH

HO O OH O O OH OH 3,6-dihydroxy xanthone 2,7-dihydroxy xanthone 3,4-dihydroxy xanthone

Figure 4 Representative dihydroxy xanthones ies suggest that the position of the hydroxyl groups ditions for scavenging free radicals. Therefore, a tet- have a key role to play in augmentation or suppres- rahydroxy xanthone might have more potent than its sion of a particular biological activity. dihydroxy and trihydroxy counterparts. The results 2.1.2 Trihydroxy xanthones Natural tri- mostly prove this hypothesis as a tetrahydroxy hydroxylated xanthones also showed significant bio- xanthone, 1,3,6,7-tetrahydroxy xanthone (Figure 6) [24] logical potential. TAN et al. reported that 1,3,7-tri- exhibited strong antioxidant potential with IC50 va- hydroxy xanthone (Figure 5) exhibits antioxidant po- lue of 8.0l mg/mL as compared to di- or trihydroxy [27] tential with an EC50 value of 16.2 μg/mL. The com- compounds . The compound also possesses strong pound is also α-glucosidase inhibitor. The SAR of the anti-bacterial activity against different strains [19]. compound studied by LUO et al. [25], suggested that Despite being a potent antioxidative agent, the anti- the hydroxyl group at position 3 plays an important bacterial activity of the same compound is very much role in inhibition, because the compound showed comparable with 1,5,6- and 1,6,7-trihydroxy better inhibitory potential as compared with other xanthones. LUO et al. [25] also reported the α-glucosi- compounds which lack this moiety. The appropriate dase inhibitory potential of 2 tetrahydroxy xanthones, positions of the hydroxyl groups most probably help 1,3,5,8- and 1,3,7,8-tetrahydroxy xanthone. Both ex- better docking at the enzyme active site. DUANGS- hibited strong inhibitory potential with IC50 values of RISAI et al. [19] reported the anti-bacterial activity of 5.3 and 7.1 μg/mL, respectively. This strong activity 1,5,6- and 1,6,7-trihydroxy xanthones with almost has been attributed to the presence of hydroxyl group equal capacity for inhibiting various bacterial strains. at C-3, which if absent or alkylated, suppresses the In another study, the 1,4,5-trihydroxy xanthone ex- activity [25]. 1,3,5,8-tetrahydroxy xanthone (demethyl- hibited potent anti-inflammatory potential with an bellidifolin) also possesses cardio protective effects [26] [28] IC50 value of 15.6 μM . due to its antioxidant and anti-apoptosis nature . 2.1.3 Tetrahydroxy xanthones The greater number Gastroprotective effects of 1,3,5,6-tetrahydroxy of phenolic hydroxyl groups provide conducive con- xanthones were reported by MARIANO et al. [29] in 170 ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192

O OH O OH O OH HO HO

O OH HO O HO O OH 1,3,7-trihydroxy xanthone 1,5,6-trihydroxy xanthone 1,6,7-trihydroxy xanthone

O OH O OH O OH OH

O O OH O OH OH OH OH 1,4,5-trihydroxy xanthone 1,3,5-trihydroxy xanthone 1,2,5-trihydroxy xanthone

Figure 5 Representative trihydroxy xanthones

O OH OH O OH O OH HO HO

HO O OH O OH HO O OH OH 1,3,6,7-tetrahydroxy xanthone 1,3,7,8-tetrahydroxy xanthone 1,3,5,6-tetrahydroxy xanthone

O OH O OH OH O OH OH

HO O OH O OH O OH OH OH OH 3,4,5,6-tetrahydroxy xanthone 1,3,5,8-tetrahydroxy xanthone 1,2,3,8-tetrahydroxy xanthone

Figure 6 Representative tetrahydroxy xanthones

2016. They suggested that the effect is owing to the evaluated their α-glucosidase inhibitory potential. It strong antioxidant, neutrophil migration inhibition, was concluded that 1,7,8-trihydroxy-3,4-dimethoxy and anti-secretory effect, because of the H + ,K + -AT- xanthone was the most active among the group, with [29] Pase activity . Thus it can be concluded that the an IC50 value of 5.42 μM. 1,7,8-Trihydroxy-3- strong antioxidant potential of the tetrahydroxy methoxy-, 1,3-dihydroxy-7,8-dimethoxy-, and 1- xanthones make them more effective against dis- hydroxy-3,4,5,8-tetramethoxy xanthone (IC50 = eases of which the oxidative burst is one of the cause. 75.8 μM) was accredited to the methylation at position 3, 5 and 8, because its demethylated 2.2 Alkoxylated xanthones tetrahydroxy counterpart shows significant activity

(IC50 = 5.3 μM), as mentioned in section 2.1.3. They In most cases the hydroxyl group may be also concluded that the presence of a hydroxyl group accompanied with an alkoxy group, substituted on at C-3 and C-8 is very important for inhibiting the the xanthone skeleton. Such molecules also have enzyme [25]. Three methoxylated xanthones were demonstrated interesting biological activities. isolated from Cudrania tricuspidata by JO et al., Majority of these molecules have methoxy group(s) characterized as isogentisin (1,3-dihydroxy-7- [28] attached at different positions. WANG et al. methoxy xanthone), alloathyriol (1,3,6-trihydroxy-7- isolated 1,7-dihydroxy-3,4-dimethoxy- and 1,5,8- methoxy xanthone), and laxanthone-I (1,3- trihydroxy-3-methoxy xanthone (Figure 7) from dihydroxy-6,7-dimethoxy xanthone). Only alloathy- Garcinia acuta and evaluated their cardio protective riol showed moderate inhibition of NO production. properties. The dimethoxy compound was inactive, Other compounds were found inactive [23]. while the other exhibited significant cardio protective effect against myocardial injury. This activity may be 2.3 Alkoxylated xanthones attributed to its strong antioxidant and anti-apoptosis potential [28]. LUO et al. [25] isolated a number of JO et al. [23] isolated 29 prenylated xanthones from alkoxylated xanthones from Swertia mussotii and Cudrania tricuspidata. They subjected the ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192 An Updated Review on Natural Xanthones and Their Glycosides 171 compounds to lipopolysaccharide-stimulated NO REUTRAKUL et al. [5] isolated 12 caged xanthones production activity. Among them, 9 compounds, with prenyl groups from Garcinia hanburyi. They which were identified as isocudraniaxanthone A, evaluated the cytotoxicity of all compounds and isocudraniaxanthone B, cudracuspixanthone A, found that all the isolated compounds exhibited cudraxanthone L, 2-deprenylrheediaxanthone B, 8- cytotoxicity to some extent. An interesting pattern prenylxanthone, cudracuspixanthone B, cudraxan- was evident in the results, and it was concluded that thone B, and cudracuspixanthone D (Figure 8) molecules with a highly conjugated ketone system showed significant to moderate NO production showed greater cytotoxicity than others. The inhibitory activity. They concluded that the position conjugated system was proposed to act in a Michael of the hydroxyl groups in the structure is pivotal for addition fashion to induce apoptosis [5]. Later, ano- the activity. Compounds with catechol moieties ther group reported 17 prenylated caged xanthones exhibited better inhibitory potential, being more from the same species and analyzed their inhibitory antioxidant in nature. Moreover, the position and the potential against α-glucosidase enzyme. Only two type of the prenyl group also alter the inhibitory compounds with ethoxy and methoxy groups at potential considerably. position 10 were found to be active against the enzyme, while all other compounds did not show any 2.4 Xanthones with caged skeleton inhibitory potential [30]. Interestingly, YANG et al. [31] isolated 11 caged polyprenylated xanthones from the Some xanthones with caged skeletons have also been same plant. These molecules showed significant reported from natural sources (Figure 9). cytotoxic activities against HeLa, A549, HCT-116, and

O OH OH O OH O O OH HO HO O

O O O O O OH O 1,7-dihydroxy-3,4-dimethoxy xanthone 1,7,8-trihydroxy-3-methoxy xanthone 1,3-dihydroxy-7,8-dimethoxy xanthone

OH O OH OH O OH O O OH HO O

O O O O O O O OH 1,7,8-trihydroxy-3,4-dimethoxy xanthone 1,5,8-trihydroxy-3-methoxy xanthone 1-hydroxy-3,7,8-trimethoxy xanthone

Figure 7 Representative alkoxylated xanthones

O OH O OH O OH HO

HO O OH HO O O O OH OH OH

isocudraniaxanthone A isocudraniaxanthone B cudraxanthone H

O OH O OH O OH HO

O OH HO O O HO O O OH OH

1,3,5-trihydroxy-4-prenyl xanthone cudratricusxanthone K dulxanthone B

Figure 8 Representative prenylated xanthones 172 ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192

COOH COOH

O O O O O O O O O O O O

O OH O OH O OH desoxymorellin morellic acid gambogic acid

OHC

O O O O O O O O OH O O OH

O OH O OH O OH

dihydroisomorellin hanburin forbesione

Figure 9 Representative caged-skeleton xanthones

HepG-2 cancer cell lines and inhibited the xanthones [33]. Griffipavixanthone, a xanthone dimer proliferation of the HUVEC cell line. Furthermore, isolated from G. oblongifolia was found to induce morellic acid, gambogenin, and isogambogenic acid apoptosis in human non-small-cell lung cancer H520 [34] showed comparable anti-angiogenic activities with cells with an IC50 value of 3.03 μM . This compound less toxicity than gambogic acid. Gambogenin has also exhibited anti-bacterial potential against showed anti-angiogenic activity with no toxicity at various strains [35]. The xanthone-chromane adducts concentrations in the range of 8 μM to 16 μM. (versixanthones A-F), isolated from A. versicolor Gambogic acid, morellic acid, gambogenin, and showed significant cytotoxic potential against seven [36] isogambogenic acid also inhibited the migration of cancer cell lines with IC50 ranging from 0.7 to 14.0 μM . HUVEC at a concentration of 0.5 μM. It was therefore Xanthone adducts: dicerandrol A, dicerandrol B, concluded that gambogenin can act as a strong anti- deacetylphomoxanthone B, and penexanthone A, [31] angiogenesis agent . isolated from Phomopsis sp. showed significant cytotoxicity against five different cancer cell lines [37]. 2.5 Xanthone dimers/trimers/adducts Literature survey suggests that xanthones are mostly antioxidative or cytotoxic. However, several Xanthones were also found as dimers, trimers, or xanthone derivatives have also been reported to have adducts, exhibiting interesting biological potential anti-bacterial and anti-inflammatory activity. In most (Figure 10). ROTINSULU et al. [32] isolated xanthone cases, the antioxidant nature of xanthones accounts dimers from Aspergillus sp. and evaluated the protein tyrosine phosphatase 1B inhibitory potential of a 2,4’- for their diverse pharmacological potential. Consid- linked tetrahydroxanthone dimer, known as ering the therapeutic importance of xanthones, sev- eral metabolomics methods have been developed for secalonic acid F1. The reported IC50 value for the compound is 5.9 μM as compared to the positive the quantitative and qualitative analysis of their ma- jor plant sources [38, 39]. The SAR studies of these mo- control (oleanolic acid) which showed IC50 value of 1.1 μM [32]. Garcinoxanthones B and C, isolated from lecules have encouraged synthetic chemists to carry G. mangostana, significantly reduced the NO out synthetic modifications, in order to enhance the production in LPS-stimulated RAW264.7 cells, with activity of the natural molecule [40]. The profound bio- IC50 values of 11.3 and 18.0 μM, respectively. logical potential of xanthones offers the scientific Moreover, garcinoxanthone C significantly inhibited community an opportunity to search for these mo- the iNOS protein expression [32]. Austradixanthone, lecules in nature, as well as to prepare some synthet- an O- linked xanthone dimer was reported from a ic derivatives. An overview of the isolated xanthone mixed culture of Aspergillus and austroafricanus, derivatives (aglycons) was given in Table 1. along with other monomeric xanthones. However, the dimer did not show any cytotoxic potential 3 Xanthone Glycosides against the murine lymphoma L5178Y cell lines and bacterial cultures, as compared with the monomeric The basic skeleton of xanthone may be substituted ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192 An Updated Review on Natural Xanthones and Their Glycosides 173

OH O OH CO Me 2 OH O OH OH O O O CO Me HO 2 OH O O OH O O H CO Me OH O OH 2 MeO C MeO C O OH 2 2 O HO O CO Me 2 O OH H OH O

O Secalonic acid F1 Versixanthone A Versixanthone B

OH OH O OH O O OH O O OH O OH O O CO Me CO Me HO 2 2 H OH O OH O O

HO O O O

Versixanthone C Dicerandrol A

O O OAc O OH O OH

OH O OH O

HO O O

Dicerandrol B

Figure 10 Representative xanthone dimers and adducts with different glycosidic moieties, affording even most active compound (66.2 U/mL). Interestingly, all more structural diversity to this amazing class of the glycosidic compounds showed better radical organic molecules. Both O- and C-glycosides of scavenging potential than their corresponding agly- xanthones have been reported in the literature. cons. Another, more obvious, trend observed among Different glycosidic analogues of xanthones, such as the molecules was the degree of hydroxylation. More glucopyranosyl, xylopyranosyl, and rhamnopyranosyl the compound is oxygenated, the more antioxidant have been identified from nature (Figure 11). potential it displays. However, the hydroxyl groups at Structure-Activity relationship of these glycosides C-1 and C-8 do not alter the activity, as they are in- suggests that the presence of these moieties enhance tramolecularly hydrogen bonded with the ketone at the overall biological potential of the xanthone C-9 [48]. Mangiferin has also exhibited α-glucosidase molecule as compared with its aglycons. However, (IC50 = 296 μM), AChE (IC50 = 43.4 μM), and there are instances where the activity is suppressed. COX-2 inhibitory activity [119-121]. Several cytotoxic, LUO et al. [25] isolated 10 glycosidic xanthones neuroprotective, hepatoprotective, and anti-HBV from Swertia mussotii. 3,5,6,8-tetrahydroxyxanthone- xanthone glycosides have also been reported from 1-C-β-D-glucoside exhibited the highest antioxidant natural sources. potential with an ORAC value of 75.8 U/mL at a con- Table 2 listed the xanthone glycosides reported centration of 6.25 μM. Mangiferin was the second recently from different plant and microbial species. A 174 ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192

Table 1 Natural xanthones and their biological potential S. No. Compound Source Biological Activity Reference

1 Dicerandrol A Phomopsis sp. Cytotoxic [37]

2 Dicerandrol B Phomopsis sp. Cytotoxic [37]

3 Deacetylphomoxanthone B Phomopsis sp. Cytotoxic [37]

4 Penexanthone A Phomopsis sp. Cytotoxic [37]

Garcinia xanthochymus, Hypoglycemic, Anti- 5 12β-Hydroxy-des-D-garcigerrin A [35, 41, 42] Garcinia dulcis bacterial 6 Garcinoxanthone B Garcinia xanthochymus Hypoglycemic [41] Garcinia xanthochymus, Garcinia dulcis, Garcinia Hypoglycemic, Cytotoxic, 7 6-Deoxyjacareubin [35, 41, 43, 44] nujiagensis, Calophyllum Antifungal symingtonianum 8 Atroviridin Garcinia xanthochymus Hypoglycemic [41] 1,2,5,6-Tetrahydroxy-4-(1,1- 9 dimethyl-2-propenyl)-7-(3- Garcinia xanthochymus Hypoglycemic [41] methyl-2-bu-tenyl)xanthone 1,5,6-Trihydroxy-7,8-di(3-methyl- 10 2-butenyl)-6′,6′- Garcinia xanthochymus Hypoglycemic [41] dimethylpyrano(2′,3′:3,4)xanthone Garcinia cowa, Garcinia schomburgkiana, Garcinia xanthochymus, Garcinia Antioxidant, Cytotoxic, 1,7-Dihyroxyxanthone dulcis, Hypericum 11 EFGR-tyrosine kinase [19, 21, 22, 42, 45-47] (euxanthone) petiolulatum, Polygala inhibition, Anti-bacterial sibirica, Hypericum attenuatum, Garcinia succifolia Garcinia schomburgkiana, Garcinia dulcis, Hypericum 1,3,7-Trihydroxyxanthone Antioxidant, α-glucosidase 12 petiolulatum, Polygala [21, 24, 25, 35, 45, 46, 48] (gentisein) inhibition sibirica, Garcinia atroviridis, Swertia mussotii Garcinia schomburgkiana, 1,3,6,7-Tetrahydroxyxanthone 13 Garcinia benthami, Garcinia Antioxidant, Anti-bacterial [19, 27, 45] (norathyriol) succifolia 14 (±)-Doitunggarcinone L Garcinia propinqua cytotoxic [49] Garcinia propinqua, 15 (±)-Isobractatin cytotoxic [49, 50] Garcinia eugenifolia 16 (±)-3-O-methylneobractatin Garcinia propinqua cytotoxic [49] Garcinia propinquaGarcinia 17 (±)-Neobractatin cytotoxic [49, 51] bracteata 18 (±)-3- O –methylbractatin Garcinia propinqua cytotoxic [49]

19 (±)-Bractatin Garcinia propinqua cytotoxic [49] Calophyllum soulattri, 20 Ananixanthone Calophyllum teysmannii, Cytotoxic, Anti-TMV [7, 52, 53] Garcinia oligantha ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192 An Updated Review on Natural Xanthones and Their Glycosides 175

Table 1 Continued

S. No. Compound Source Biological Activity Reference

Calophyllum soulattri, 21 Trapezifolixanthone cytotoxic [52, 54] Garcinia mangostana Calophyllum brasiliense, Hypericum attenuatum, cytotoxic, NO production 22 Jacareubin Garcinia lancilimba, [22, 43, 55-57] inhibition Garcinia cowa, Garcinia nujiagensis

23 Fuscaxanthone J Garcinia fusca α-glucosidase inhibition [58]

24 Fuscaxanthone K Garcinia fusca α-glucosidase inhibition [58]

Garcinia fusca, Garcinia α-glucosidase inhibition, 25 Cowanin [47, 58] cowa Anti-bacterial Garcinia fusca, Garcinia α-glucosidase inhibition, 26 Cowanol [47, 58] cowa Anti-bacterial 1,3-Dihyroxy-6,7-dimethoxy-2,8- 27 Garcinia fusca α-glucosidase inhibition [58] diprenylxanthone

28 Cowagarcininone E Garcinia fusca α-glucosidase inhibition [58]

α-glucosidase inhibition, Garcinia fusca, Cratoxylum AGE inhibition, Anti- cochinchinense, Garcinia 29 α-Mangostin oxidant, Pancreatic lipase [47, 58-68] cowa, Garcinia mangostana, inhibition, Anti-bacterial, Mesua beccariana Anti-plasmodial Garcinia fusca, Garcinia α-glucosidase inhibition, 30 Cowaxanthone [47, 58] cowa Anti-bacterial

31 Garbogiol Garcinia fusca α-glucosidase inhibition [58]

1,3-Dihydroxy-2-(2-hydroxy-3- 32 methylbut-3-enyl)-6,7-dimethoxy- Garcinia fusca α-glucosidase inhibition [58] 8-(3-methylbut-2-enyl)xanthone (5′S,8′S)-1,3,5,8- Tetrahydroxyxanthone(7-2′)- Protection against 33 Gentianella acuta [28] 1,3,5,8-tetrahydroxy-5′,6′,7′,8′- myocardial cell injury tetrahy-droxyxanthone 1,3,5S,8S-Tetrahydroxy-5,6,7,8- Protection against 34 Gentianella acuta [28] tetrahydroxyxanthone myocardial cell injury 1,7-Dihydroxy-3,4- Gentianella acuta, Polygala Protection against 35 [21, 28] dimethoxyxanthone sibirica myocardial cell injury Protection against Gentianella acuta, Garcinia myocardial cell injury, 36 1,3,5-Trihydroxyxanthone dulcisSwertia patens, Antioxidant, intestine [28, 35, 46, 69, 70] Hypericum petiolulatum contraction tension reduction Protection against 37 Demethylbellidifolin Gentianella acuta [28] myocardial cell injury Protection against 38 Bellidifolin Gentianella acuta [28] myocardial cell injury 176 ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192

Table 1 Continued

S. No. Compound Source Biological Activity Reference

Garcinia cowa, Calophyllum Cytotoxic, AGE inhibition, teysmannii, Cratoxylum 39 β-Mangostin Anti-plasmodial, Anti- [7, 47, 59-61, 68] cochinchinense, Garcinia bacterial mangostana Tyrosine phosphatase 1B 40 Secalonic acid F1 Aspergillus sp. TPU1343 [32] inhibition Tyrosine phosphatase 1B 41 Secalonic acid F Aspergillus sp. TPU1343 [32] inhibition 42 Garcisubellone Garcinia subelliptica Anti-inflammatory [26] Garcinia subelliptica, 1,4,5-Trihydroxyxanthone Anti-inflammatory, Anti- 43 Garcinia xanthochymus, [26, 35, 42] (Subelliptenone G) bacterial Garcinia dulcis 44 7-O-Demethyl mangostanin Garcinia mangostana Cytotoxic [54]

45 Xanthochymusxanthone B Garcinia xanthochymus PTP1B Inhibition [42] Garcinia xanthochymus, 46 Symphoxanthone Anti-bacterial [42] Garcinia dulcis Garcinia xanthochymus, 47 Subelliptenone F α-Glucosidase Inhibition [35, 42] Garcinia dulcis 48 Dulcisxanthone J Garcinia dulcis Anti-bacterial [35]

49 Garciniaxanthone C Garcinia dulcis Anti-bacterial [35]

50 Garciniaxanthone A Garcinia dulcis Anti-bacterial [35]

51 Subelliptenone B Garcinia dulcis Anti-bacterial [35]

52 1-O-methylglobuxanthone Garcinia dulcis Anti-bacterial [35]

53 Globuxanthone Garcinia dulcis Anti-bacterial [35]

54 1-O-methylsymphoxanthone Garcinia dulcis Anti-bacterial [35]

55 Griffipavixanthone Garcinia dulcis Anti-bacterial [35]

56 Garciniaxanthone D Garcinia dulcis Anti-bacterial [35] Antioxidant, Intestine Hypericum petiolulatum, contraction tension 57 1,3,5,8-Tetrahydroxy xanthone Gentianella acuta, Swertia [25, 46, 48, 70] reduction, α-glucosidase mussotii inhibition 1,7,8-Trihydroxy-3,4-dimethoxy 58 Swertia mussotii α-glucosidase inhibition [25] xanthone 59 Calycinoxanthone D Hypericum petiolulatum Antioxidant [46] 3,6,7-Trihydroxy-1- 60 Hypericum petiolulatum Antioxidant [46] methoxyxanthone 61 2-Methoxyxanthone Hypericum petiolulatum Antioxidant [46]

62 1-Hydroxy-7-methoxyxanthone Hypericum petiolulatum Antioxidant [46] 5H-furo[3,2-b]xanthen-5-one-2,3- 63 dihydro-4,7-dihydroxy-2-(1-hydr- Hypericum petiolulatum Antioxidant [46] oxy-1-methylet-hyl)

64 Neobraclatone A Garcinia bracteata Cytotoxic [51] ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192 An Updated Review on Natural Xanthones and Their Glycosides 177

Table 1 Continued

S. No. Compound Source Biological Activity Reference

65 Neobraclactone B Garcinia bracteata Cytotoxic [51] 1,7-Dihydroxy-5,6- 66 Polygala sibirica Anti-bacterial [21] dimethoxyxanthone 6-Hydroxy-1,7- 67 Polygala sibirica Antioxidant [21] dimethoxyxanthone

68 1,7-Dihydroxyxanthone Polygala sibirica Antioxidant [21]

69 Cratoxanthone A Cratoxylum cochinchinese Cytotoxic [59]

70 Cratoxanthone B Cratoxylum cochinchinese Cytotoxic [59]

71 Mangostanaxanthone IV Garcinia mangostana Cytotoxic, AGE inhibition [60, 61]

6-Acetyl-1,5-dimethoxy-3- 72 Swertia binaculata Reductase inhibition [71] methylxanthone 6-Acetyl-5-hydroxy-1-methoxy-3- 73 Swertia binaculata Reductase inhibition [71] methylxanthone 6-Acetyl-3-hydroxy-1,5- 74 Swertia binaculata Reductase inhibition [71] dimethoxyxanthone Anti-inflammatory, 75 Cudratricusxanthone A Cudrania tricuspidata [72-74] Cytotoxic, PTP 1B inhibition

76 Isogentisin Cudrania tricuspidata NO production inhibition [23]

77 Isocudraniaxanthone A Cudrania tricuspidata NO production inhibition [23]

78 Isocudraniaxanthone B Cudrania tricuspidata NO production inhibition [23]

NO production inhibition, 79 Cudracuspixanthone A Cudrania tricuspidata PTP 1B inhibition, Anti- [23, 74, 75] proliferative NO production inhibition, 80 Cudraxanthone L Cudrania tricuspidata [23, 74] PTP 1B inhibition Cudrania tricuspidata, 81 2-Deprenylrheediaxanthone B NO production inhibition [22, 23] Hypericum attenuatum

82 8-Prenylxanthone Cudrania tricuspidata NO production inhibition [23]

83 Cudracuspixanthone B Cudrania tricuspidata NO production inhibition [23]

84 Cudraxanthone B Cudrania tricuspidata NO production inhibition [23]

85 Cudracuspixanthone D Cudrania tricuspidata NO production inhibition [23]

86 Oblongixanthone D Garcinia oblongifolia Migration inhibition [76]

87 Oblongixanthone E Garcinia oblongifolia Migration inhibition [76]

88 Oblongifolin L Garcinia oblongifolia Migration inhibition [76]

89 Cratosumatranone D Cratoxylum sumatranum Anti-bacterial [77]

90 Pruniflorone N Cratoxylum sumatranum Anti-bacterial [77]

Cratoxylum sumatranum, 91 Macluraxanthone Antioxidant, Anti-bacterial [77, 78] Garcinia propinqua 1,3,6-Trihydroxy-7-methoxy 92 Cratoxylum sumatranum Anti-bacterial [77] xanthone 178 ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192

Table 1 Continued

S. No. Compound Source Biological Activity Reference

Antioxidant, Cratoxylum sumatranum, Gastroprotective, H+ K + - 93 1,3,5,6-Tetrahydroxy xanthone Garcinia achachairu, ATPase inhibition, Anti- [29, 77, 79] Garcinia nobilis ulcer, NO production inhibition, 15-LOX activity

94 Trapezifolixanthone Cratoxylum sumatranum Anti-bacterial [77]

95 Mangostanaxanthone III Garcinia mangostana AGE inhibition [61]

AGE inhibition, Anti- 96 Garcinone C Garcinia mangostana oxidant, Neuroprotective, [61, 62] BBB penetration

97 Garcinone E Garcinia mangostana AGE inhibition [61]

Garcinia mangostana, AGE inhibition, Platelet 98 Rubraxanthone [61, 80] Garcinia griffithii aggregation inhibition AGE inhibition, Pancreatic 99 9-Hydroxycalabaxanthone Garcinia mangostana [61, 65] lipase inhibition

100 Coxanthone A Codonopsis ovata Cytotoxic [81]

101 Coxanthone B Codonopsis ovata Cytotoxic [81]

1-Hydroxy-3,5-dimethoxy 102 Codonopsis ovata Cytotoxic [81] xanthone

103 Swertiperenine Codonopsis ovata Cytotoxic [81]

1,7,8-Trihydroxy-3-methoxy Codonopsis ovata, Swertia Cytotoxic, Antioxidant, α- 104 [25, 48, 81] xanthone mussotii glucosidase inhibition

105 Mckeanianone A Garcinia mckeaniana Anti-malarial [82]

106 Mckeanianone B Garcinia mckeaniana Anti-malarial, Cytotoxic [82]

107 Mckeanianone C Garcinia mckeaniana Anti-malarial, Cytotoxic [82]

108 Bannaxanthone I Garcinia mckeaniana Anti-malarial, [82]

109 Bannaxanthone E Garcinia mckeaniana Anti-malarial, Cytotoxic [82]

1,3,5,7-Tetrahydroxy-8- 110 Garcinia esculenta Anti-inflammatory [83] isoprenylxanthone

111 Garcinoxanthone B Garcinia mangostana NO production inhibition [32]

112 Garcinoxanthone C Garcinia mangostana NO production inhibition [32]

Gastroprotective, H+ K + - 113 7-Preniljacareubin Garcinia achachairu ATPase inhibition, Anti- [29] ulcer 3-Demethyl-2-geranyl-4- 114 Garcinia achachairu Gastroprotective, Cytotoxic [29, 84] prenylbellidypholine 1,5,8-Trihydroxy-4’,5’-dimethyl- 115 2H-pyrane(2,3:3,2)-4-(3- Garcinia achachairu Gastroprotective, Cytotoxic [29, 84] methylbut-2-enyl) xanthone Intestine contraction 116 Gentixanthone A1 Gentianella acuta [70] tension reduction ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192 An Updated Review on Natural Xanthones and Their Glycosides 179

Table 1 Continued

S. No. Compound Source Biological Activity Reference

Intestine contraction 117 Gentixanthone A2 Gentianella acuta [70] tension reduction Intestine contraction 118 Norswertianolin Gentianella acuta [70] tension reduction Intestine contraction 119 Swertianolin Gentianella acuta [70] tension reduction Intestine contraction 120 Triptexanthoside A Gentianella acuta [70] tension reduction 121 Cudratrixanthone P Cudrania tricuspidata Neuroprotective [85]

122 Cudratrixanthone R Cudrania tricuspidata Neuroprotective [85] 1-Hydroxy-2,3,5-trimethoxy 123 Halenia elliptica vasodilation [86] xanthone 1,5-Dihydroxy-2,3-dimethoxy 124 Halenia elliptica vasodilation [86] xanthone Inhibition of RANKL- 125 Acredinone C Acremonium sp. (F9A015) induced formation of TRAP+ [87] -MNCs 126 Oliganthin H Garcinia oligantha Cytotoxic [88]

127 Oliganthin I Garcinia oligantha Cytotoxic [88]

128 Oliganthone B Garcinia oligantha Cytotoxic [88]

129 Gaudichaudione H Garcinia oligantha Cytotoxic [88]

130 Cantleyanone Garcinia oligantha Cytotoxic [88] androgen receptor degradation, Anti-oxidant, 131 Gartanin Garcinia mangostana Neuroprotective, BBB [62, 63, 65, 89] penetration, Pancreatic lipase inhibition 132 Schomburgxanthone A Garcinia schomburgkiana Cytotoxic [90]

133 Norgrolineaxanthone E Garcinia schomburgkiana Cytotoxic [90] 6-Hydroxyethyl-1,3,7-trimethoxy 134 Swertia elata anti-TMV [91] xanthone 6-Acetyl-1,3,7-trimethoxy 135 Swertia elata anti-TMV [91] xanthone 136 Pulmonarxanthone B Swertia elata anti-TMV [91] 1,5-Dihydroxy-3-(2-oxopropyl)-6- 137 Swertia elata anti-TMV [91] methoxycarnonylxanthone 138 Bracthones A Swertia elata anti-TMV [91]

139 Vieillardixanhone Swertia elata anti-TMV [91]

140 Dalienxanthone A Phomopsis sp. Cytotoxic [92]

141 Dalienxanthone B Phomopsis sp. Cytotoxic [92]

142 Dalienxanthone C Phomopsis sp. Cytotoxic [92] 180 ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192

Table 1 Continued

S. No. Compound Source Biological Activity Reference

3,8-Dihydroxy-4-(2,3-dihydroxy-1- 143 hydroxymethylpropyl)-1-metho-xy Phomopsis sp. Cytotoxic [92] xanthone 144 Oliganthin E Phomopsis sp. Cytotoxic [92] 145 Cratoxylumxanthone D Phomopsis sp. Cytotoxic [92] Scopulariopsis sp., 146 AG1-B4 Cytotoxic [93, 94] Aspergillus sp. Anti-oxidant, Neuroprotective, BBB 147 γ-Mangostin Garcinia mangostana [62, 63, 65] penetration, Pancreatic lipase inhibition 4-Chloro-1,5-dihydroxy-3- 148 hydroxymethyl-6- Alternaria sp. Anti-fungal [95] methoxycarbonyl-xanthen-9-one Garcinia mangostana, Antioxidant, RXR α 149 Garcinone D [63, 96] Cratoxylum cochinchinense transcriptional activity 150 6-Methoxy-bispyrano xanthone Garcinia mangostana Antioxidant [63] 3,6-Dihydroxy-1,4,8-trimethoxy 151 Kielmeyera variabilis Anti-bacterial [97] xanthone 3,5-Dihydroxy-4-methoxy 152 Kielmeyera variabilis Anti-bacterial [97] xanthone 3,4-Dihydroxy-6,8-dimethoxy 153 Kielmeyera variabilis Anti-bacterial [97] xanthone 3,4-Dihydroxy-2-methoxy 154 Kielmeyera variabilis Anti-bacterial [97] xanthone 5-Hydroxy-1,3-dimethoxy 155 Kielmeyera variabilis Anti-bacterial [97] xanthone 4-Hydroxy-2,3-dimethoxy 156 Kielmeyera variabilis Anti-bacterial [97] xanthone 157 Kielcorin Kielmeyera variabilis Anti-bacterial [97] 158 3-Hydroxy-2-methoxy xanthone Kielmeyera variabilis Anti-bacterial [97] 159 2-Hydroxy-1-methoxy xanthone Kielmeyera variabilis Anti-bacterial [97] 160 Smeathxanthone A Garcinia mangostana Pancreatic lipase inhibition [65] 161 Tovophyllin A Garcinia mangostana Pancreatic lipase inhibition [65] 1,7-Dihydroxy-3-methoxy-2-(3- 162 Garcinia mangostana Pancreatic lipase inhibition [65] methylbut-2-enyl) xanthen-9-one Streptomyces 163 Chrestoxanthone A Anti-fungal [98] chrestomyceticus Streptomyces 164 Chrestoxanthone B Anti-fungal [98] chrestomyceticus Streptomyces 165 Chrestoxanthone C Anti-fungal [98] chrestomyceticus Streptomyces 166 Albofungin Anti-fungal [98] chrestomyceticus ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192 An Updated Review on Natural Xanthones and Their Glycosides 181

Table 1 Continued

S. No. Compound Source Biological Activity Reference

Streptomyces 167 Chloroalbofungin Anti-fungal [98] chrestomyceticus Garcinia lancilimba, 168 Xanthone V1a Cytotoxic [43, 56] Garcinia nujiagensis 1,5,6-Trihydroxy-3,7-dimethoxy 169 Garcinia lancilimba Cytotoxic [56] xanthone 170 Epigambogic acid A Garcinia hanburyi α-Glucosidase inhibition [30] 171 Epigambogic acid B Garcinia hanburyi α-Glucosidase inhibition [30] 3,4,6,8-Tetrahydroxy-2-prenyl 172 Garcinia paucinervis Anti-proliferative [99] xanthone 1,3,5-Trihydroxy-2-prenyl 173 Garcinia paucinervis Anti-proliferative [99] xanthone 1,3,7,8-Tetrahydroxy-2-prenyl 174 Garcinia paucinervis Anti-proliferative [99] xanthone Calophyllum RXR α transcriptional 175 2,5-Dihydroxy xanthone [20] membranaceum inhibition Calophyllum RXR α transcriptional 176 1,2,8-Trimethoxy xanthone [20] membranaceum inhibition 177 Cylindroxanthone A Garcinia cylindrocarpa Cytotoxic [100] 178 Genticin Gentiana lutea Anti-proliferative [101] 1-Hydroxy-2,3,4,5-tetramethoxy 179 Gentiana lutea Anti-proliferative [101] xanthone 180 Swertirin Gentiana lutea Anti-proliferative [101] 181 Methylswertinin Gentiana lutea Anti-proliferative [101] 182 Versixanthone A Aspergillus versicolor Cytotoxic [36] 183 Versixanthone B Aspergillus versicolor Cytotoxic [36] 184 Versixanthone C Aspergillus versicolor Cytotoxic [36] 185 Versixanthone D Aspergillus versicolor Cytotoxic [36] Cytotoxic, Topoisomerase I 186 Versixanthone E Aspergillus versicolor [36] inhibition 187 Versixathone F Aspergillus versicolor Cytotoxic [36] 188 Mangosenone F Garcinia mangostana Cytotoxic [102] Lipid accumulation 189 Preshamixanthone Emericella variecolor [103] inhibition 190 Pruniflorone H Rhamnus cathartica Anti-microbial [104] 191 δ-Mangostin Garcinia mangostana Anti-plasmodial [67] 192 3,16-Oxyguttiferone A Symphonia globulifera Cytotoxic [105] 193 1,16-Oxyguttiferone Symphonia globulifera Cytotoxic [105] 194 Hypexanthone A Hypericum chinense Cytotoxic [106] 195 Cowaxanthone G Garcinia cowa Cytotoxic [57] 1,5,6-Trihydroxy-2-prenyl-6’,6’- Garcinia cowa, Garcinia 196 dimethyl-2H-pyrano(2’,3’:3,4)- Cytotoxic, Antioxidant [57, 107] merguensis xanthone 182 ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192

Table 1 Continued

S. No. Compound Source Biological Activity Reference

197 Garcimultiflorone E Garcinia cowa Cytotoxic [57] 198 Symphonone H Garcinia cowa Cytotoxic [57] Garcinia cowa, Garcinia 199 Xanthone V1 Cytotoxic [43, 57] nujiagensis 200 Cudratricusxanthone N Cudrania tricuspidata PTP 1B inhibition [74] 1,6,7-Trihydroxy-2-(1,1-dimethyl- 201 Cudrania tricuspidata PTP 1B inhibition [74] 2-propenyl)-3-methoxyxanthone 202 Cudratricusxanthone L Cudrania tricuspidata PTP 1B inhibition [74] 203 Cudraxanthone M Cudrania tricuspidata PTP 1B inhibition [74] 204 Macluraxanthone B Cudrania tricuspidata PTP 1B inhibition [74] 205 Cudraxanthone D Cudrania tricuspidata PTP 1B inhibition [74] RXR α transcriptional 206 Cochinchinone M Cratoxylum cochinchinense [96] activity RXR α transcriptional 207 Cochinchinone N Cratoxylum cochinchinense [96] activity RXR α transcriptional 208 Cochinchinone O Cratoxylum cochinchinense [96] activity RXR α transcriptional 209 Cochinchinone P Cratoxylum cochinchinense [96] activity RXR α transcriptional 210 Cochinchinone Q Cratoxylum cochinchinense [96] activity RXR α transcriptional 211 Cochinchinone R Cratoxylum cochinchinense [96] activity RXR α transcriptional 212 Cochinchinone K Cratoxylum cochinchinense [96] activity RXR α transcriptional 213 Cochinchinone F Cratoxylum cochinchinense [96] activity 1,3,6,7-Tetrahydroxy-8-prenyl RXR α transcriptional 214 Cratoxylum cochinchinense [96] xanthone activity RXR α transcriptional 215 Celebixanthone Cratoxylum cochinchinense [96] activity RXR α transcriptional 216 Toxyloxanthone C Cratoxylum cochinchinense [96] activity RXR α transcriptional 217 Cochinchinone J Cratoxylum cochinchinense [96] activity 218 Pedunxanthone D Garcinia pedunculata Cytotoxic [108] 219 Epi-Isobractatin Garcinia eugenifolia Cytotoxic [50] RXR α transcriptional 220 Gerontoxanthone Maclura cochinchinensis [109] activity RXR α transcriptional 221 Gerontoxanthone B Maclura cochinchinensis [109] activity RXR α transcriptional 222 Cudraxanthone I Maclura cochinchinensis [109] activity ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192 An Updated Review on Natural Xanthones and Their Glycosides 183

Table 1 Continued

S. No. Compound Source Biological Activity Reference

223 Nujiangexanthone C Garcinia nujiagensis Cytotoxic [43] 224 Nujiangexanthone D Garcinia nujiagensis Cytotoxic [43] 225 Nujiangexanthone E Garcinia nujiagensis Cytotoxic [43] 226 Nujiangexanthone F Garcinia nujiagensis Cytotoxic [43] 227 Nujiangexanthone A Garcinia nujiagensis Cytotoxic [43] 228 Nujiangefolin A Garcinia nujiagensis Cytotoxic [43] 229 Nujiangefolin B Garcinia nujiagensis Cytotoxic [43] 230 Cudratricusxanthone E Garcinia nujiagensis Cytotoxic [43] 3,6,8-Trihydroxy-1- Cytotoxic, COX-2 231 Stachybotry sp. [110] methylxanthone inhibition, Antiviral (1R, 2R)-2-Hydroxy-6- 232 (hydroxymethyl)-8-methoxy-9- Phomopsis amygdali Cytotoxic [111] oxo-2,9-dihydro-1H-xanthone 233 1,5,6-Trihydroxy xanthone Garcinia succifolia Anti-bacterial [19] 234 1,6,7-Trihydroxy xanthone Garcinia succifolia Anti-bacterial [19] EFGR-tyrosine kinase 235 1,5-Dihydroxy xanthone Garcinia succifolia [19] inhibition 1-Hydroxy-3,7,8-trimethoxy Anthocleista vogelii, Swertia Antiulcerogenic, 236 [48, 112] xanthone mussotii Antioxidant 237 3-Isomangostin Garcinia mangostana Anti-plasmodial [68] 1,3,5,6-Tetrahydroxy-7-(3- Platelet aggregation 238 Garcinia griffithii [80] methylbut-2-enyl) xanthone inhibition 239 Gambogic acid Garcinia hanburyi Anti-angiogenic, Cytotoxic [31, 113] 240 Morellic acid Garcinia hanburyi Anti-angiogenic [31] 241 Gambogenin Garcinia hanburyi Anti-angiogenic [31] 242 Isogambogenic acid Garcinia hanburyi Anti-angiogenic [31] 1,6,8-Trihydroxy-2,3,4,5- 243 Securidaca longepedunculata Anti-austerity [114] tetramethoxy xanthone 1,6-Dihydroxy-2,3,4,5,8- 244 Securidaca longepedunculata Anti-austerity [114] pentamethoxy xanthone 1,5-Dihydroxy-3-hydroxyethyl-6- 245 Phomopsis sp. Cytotoxic [115] methoxycarbonyl xanthone 1-Hydroxy-3-hydroxyethyl-8- 246 Phomopsis sp. Cytotoxic [115] ethoxycarbonyl xanthone 1,8-Dihydroxy-3,7-dimethoxy 247 Swertia mussotii Antioxidant [48] xanthone 1,7-Dihydroxy-3,8-dimethoxy 248 Swertia mussotii Antioxidant [48] xanthone 1,7-Dihydroxy-3,4,7,8- 249 Swertia mussotii Antioxidant [48] tetramethoxy xanthone 1-Hydroxy-3,4,7,8-tetramethoxy 250 Swertia mussotii Antioxidant [48] xanthone 184 ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192

Table 1 Continued

S. No. Compound Source Biological Activity Reference

1,8-Dihydroxy-7-methoxy 251 Swertia mussotii Antioxidant [48] xanthone 1,7-Dihydroxy-3-methoxy 252 Swertia mussotii Antioxidant [48] xanthone 253 1,3,7,8-Tetrahydroxy xanthone Swertia mussotii Antioxidant [25, 48] 1,3-Dihydroxy-7,8-dimethoxy 254 Swertia mussotii Antioxidant [48] xanthone 1,5,8-Trihydroxy-3,4-dimethoxy 255 Swertia mussotii Antioxidant [25, 48] xanthone 256 Oliganthin E Garcinia oligantha Anti-TMV [53] 257 Oliganthin F Garcinia oligantha Anti-TMV [53] 1,3-Dihydroxy-6-methoxy-2,4- 258 bis(3-methyl-2-buten-1-yl)-9H- Garcinia oligantha Anti-TMV [53] xanthone 259 Merguenone Garcinia oligantha Anti-TMV [53] 260 Merguensinone Garcinia merguensis Antioxidant [107]

1,3,5-Trihydroxy-2-(3-methylbut- Calophyllum 261 Antifungal [44] 2-enyl) xanthone symingtonianum 262 Citreamicin θ A Streptomyces caelestis Anti-bacterial [116] 263 Citreamicin θ B Streptomyces caelestis Anti-bacterial [116] 264 Citreaglycon A Streptomyces caelestis Anti-bacterial [116] 265 Dehydrocitreaglycon Streptomyces caelestis Anti-bacterial [116] 266 Garcinolic acid Garcinia hanburyi Cytotoxic [113] 10α-Ethoxy-9,10-dihydromorellic 267 Garcinia hanburyi Cytotoxic [113] acid 10α-Ethoxy-9,10- 268 Garcinia hanburyi Cytotoxic [113] dihydrogambogenic acid 269 Deoxygaudichaudione A Garcinia hanburyi Cytotoxic [113] 270 Gambogenic acid Garcinia hanburyi Cytotoxic [113] 271 Desoxygambogenin Garcinia hanburyi Cytotoxic [113] 272 Hanburin Garcinia hanburyi Cytotoxic [113] 273 Desoxymorellin Garcinia hanburyi Cytotoxic [113] 274 Garciniacowone Garcinia hanburyi Cytotoxic [113] 275 Norcowanin Garcinia cowa Anti-bacterial [47] 276 Cowagarcinone B Garcinia cowa Anti-bacterial [47] 277 Cowagarcinone D Garcinia cowa Anti-bacterial [47] 278 Cowagarcinon E Garcinia cowa Anti-bacterial [47] 279 Fuscaxanthone A Garcinia cowa Anti-bacterial [47] 280 Fuscaxanthone C Garcinia cowa Anti-bacterial [47] 281 6-O-Methylmangostanin Garcinia cowa Anti-bacterial [47] ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192 An Updated Review on Natural Xanthones and Their Glycosides 185

Table 1 Continued

S. No. Compound Source Biological Activity Reference

282 Cowaxanthone D Garcinia cowa Anti-bacterial [47] 283 Muchimangin G Securidaca longepedunculata Anti-cancer [117] 6,7,11-Trihydroxy-10-methoxy-9- (7-methoxy-3-methyl-1- 284 oxoisochroman-5-yl)-2--methyl- Pyrenacantha kaurabassana Anti-HIV [118] 12-oxo-12H-benzo[b]xanthene-4- carboxylic acid 6,7-Dihydroxy-10,11-dimethoxy-9- (7-methoxy-3-methyl-1- 285 oxoisochroman-5-yl)-2-methyl-12- Pyrenacantha kaurabassana Anti-HIV [118] oxo-12H-benzo[b]xanthene-4- carboxylic acid 286 10-O-Methylmacluraxanthone Garcinia propinqua Anti-bacterial [78]

HO OH OH OH OH HO

HO OH O O O O O O OH

HO O O O OH OH O OH 5-hydroxy-3,46-trimethoxyxanthone-1-O-β-D-glucopyranoside norswertianoline

OH OH OH OH HO HO

OH OH OH OH O O O OH OH O OH HO O O O OH OH HO O OH O OH HO O OH O O HO O O OH OH mangiferin kouitchenside F swertianolin

Figure 11 Representative xanthone glycosides careful probe into SAR of these molecules can guide burst. The quest for xanthones has led to the isolation towards some synthetic manipulations [40], which and identification of several bioactive molecules, may include the hydrolysis of the glycoside, or the se- with properties good enough to be potential drugs in lective conjugation of the aglycons with the sugar near future. Future work on natural products and moiety. synthetic manipulations of the natural xanthones may lead to the discovery of more potent therapeutic 4 Conclusions and Perspectives agents. This paper focused on highlighting the rich sources of these interesting molecules, as well as Xanthones and their sub-classes are important their pharmacological importance, thus giving an products of the nature’s laboratories. They offer great insight into the work already done and the future structural diversity and immense variety in their prospects. This contribution will help the researchers therapeutic ability. Their unique structural skeleton to carry out targeted work in search of more renders them free radical scavenging ability, which is structurally diverse and biologically active important against disorders caused by oxidative xanthones. 186 ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192

Table 2 Natural xanthone glycosides and their biological potential S. No. Compound Source Biological activity Reference

1,8-Dihydroxy-3,6-dimethoxy-xanthone- 1 5-O-[α-L-rhamnopyranosyl-(1’’-2’)]-β-D- Polyonum bellardii Antioxidant [119] glucopyranoside 1-O-[β-D-xylopyranosyl-(1-6)-β-D- 2 glucopyranosyl]-8-hydroxy-3,4,5- Swertia bimaculata α-Glucosidase inhibition [120] trimethoxy xanthone 8-O-[β-D-xylopyranosyl-(1-6)-β-D- 3 glucopyranosyl]-1-hydroxy-3,4,5- Swertia bimaculata α-Glucosidase inhibition [120] trimethoxy xanthone 1-O-[β-D-xylopyranosyl-(1-4)-β-D- 4 glucoyranosyl]-3,8-dihydroxy-4,5- Swertia bimaculata α-Glucosidase inhibition [120] dimethoxy xanthone 3,5,6,8-Tetrahydroxy-xanthone-1-C-β-D- 5 Swertia mussotii Antioxidant [48] glucoside 7-Hydroxy-3,4,8-trimethoxyxanthone-1- 6 Swertia mussotii Antioxidant [48] O-(β-D-glucoside) 6-Hydroxy-3,5-dimethoxyxanthone-1-O- 7 Swertia mussotii Antioxidant [48] (β-D-glucoside) 3,4,7,8-Tetramethoxyxanthone-1-O-(β- 8 Swertia mussotii Antioxidant [48] D-glucoside) 1,8-Dihydroxy-3,4-dimethoxyxanthone- 9 Swertia mussotii Antioxidant [48] 7-O-(β-D-glucoside) 1,8-Dihydroxy-3-methoxyxanthone-7-O- 10 Swertia mussotii Antioxidant [48] (β-D-glucoside) 1-Hydroxy-3,4-dimethoxyxanthone-7-O- 11 Swertia mussotii Antioxidant [48] (β-D-glucoside) 3,7,8-Trimethoxyxanthone-1-O-(β-D- 12 Swertia mussotii Antioxidant [48] glucoside) 7-O-[(α-L-rhamnopyranosyl(1-2)-β-D- 13 xylopyranosyl(1-7))]-1,8-dihydroxy-3- Swertia mussotii Antioxidant [48] methoxy xanthone Swertia mussotii, Bombax ceiba, Swertia Antioxidant, α-Glucosidase 14 Mangiferin chirata, Swertia inhibition, AChE inhibition, [25, 48, 122-124] koitchensis, Pueraria COX-2 inhibition tuberosa 4-C-β-D-Glucopyranosyl-1,3,6,8- 15 tetrahydroxy-7-O-(p-hydroxybenzoyl)- Bombax ceiba Antioxidant [124] 9H-xanthen-9-one (Shamimoside) 8-O-β-D-Glucopyranosyl-6-methyl-1- 16 Penicillium sp. Cytotoxic [125] carboxylate methyl ester xanthone 1,8-Dihydroxy-3-methoxyxanthone 7-O- 17 [α-L-rhamnopyranosyl(1-2)-β-D- Swertia mussotii α-Glucosidase inhibition [25] xylopyranoside] 18 Koitchenside E Swertia koitchensis α-Glucosidase inhibition [120]

19 Koitchenside F Swertia koitchensis α-Glucosidase inhibition [120] ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192 An Updated Review on Natural Xanthones and Their Glycosides 187

Table 2 Continued

S. No. Compound Source Biological activity Reference

20 Swertianolin Swertia koitchensis α-Glucosidase inhibition [120] 1-O-[β-D-xylopyranosyl-(1-6)-β-D- 21 glucopyranosyl]-8-hydroxy-3,7- Swertia koitchensis α-Glucosidase inhibition [120] dimethoxy xanthone 3-O-(6-O-α-L-arabinopyranosyl)-β-D- 22 Phomopsis sp. Cytotoxic [126] glucopyranosyl-1,4-dimethoxyxanthone 1,6-dihydroxy-4-methoxy-8-O-[2-(4′- hydroxy-3′-methoxy-E-cinnamyl)-β-D- Comastoma 23 xylopyranosyl-(1-6)-β-D- Hepatoprotective [127] pedunculatum glucopyranosyl]-xanthone (Comastomaside C) 1,4,6-trihydroxy-8-O-[2-(4′-hydroxy-3′- methoxy-Ecinnamyl)-β-D- Comastoma 24 xylopyranosyl-(1-6)-β-D- Hepatoprotective [127] pedunculatum glucopyranosyl]xanthone (comastomaside D) Demethylsterigmatocystin1-(4-O- 25 Aschersonia coffeae Cytotoxic [128] methyl)-β−L-arabinopyranose 8-hydroxy-3,5-dimethoxy-1-O[α-L- 26 arabinofuranosyl-(1→6)-β-D- Centaurium spicatum Cytotoxic [129] glucopyranosyl]-xanthone 8-hydroxy-3,5-dimethoxy-1-O-β-D- 27 Centaurium spicatum Cytotoxic [129] glucopyranosyl-xanthone 1-hydroxy-3,5-dimethoxy-xanthone-6-O- 28 Iris minutiaurea Anti-inflammatory [130] β-D-glucoside 29 Glomerxanthone A Polygala glomerata Neuroprotective [131]

30 Glomerxanthone B Polygala glomerata Neuroprotective [131]

31 Glomerxanthone C Polygala glomerata Neuroprotective [131] 1,3,6,7-Tetrahydroxy-2-C- Antioxidant, α-Glucosidase 32 Swertia mussotii [132] glucopyranoside inhibition 1,3,6,7-tetrahydroxyxanthone 4-C-β- 33 Cyclopia genistoides Pro-apoptotic activity [133] glucoside (Isomangiferin) 34 Norswertianolin Swertia yunnanensis Anti-HBV, HBsAg inhibition [134]

35 Neolancerin Swertia yunnanensis Anti-HBV, HBsAg inhibition [134]

36 Isovitexin Swertia yunnanensis Anti-HBV, HBsAg inhibition [134]

37 6’-O-acetyl mangiferin iris rossii Anti-inflammatory [135]

Acknowledgments Competing Interests

We thank for the funding support from the National The authors declare no conflict of interest. Natural Science Foundation of China (No. 81673579), Hunan Province Universities 2011 Collaborative References Innovation Center of Protection and Utilization of Hu-Xiang Chinese Medicine Resources, and Hunan Provincial Key Laboratory of Diagnostics in Chinese [1] BOONYONG C, PATTAMADILOK C, SUTTISRI R, et al. Medicine. Benzophenones and xanthone derivatives from Garcinia 188 ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192

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天然产物 酮及其苷类成分抗氧化性及其他药用价值的最新研究进展

ZAFAR Salmana, 翦雨青b, 李斌b, 彭彩云b, CHOUDHARY Muhammad Iqbalc, RAHMAN Atta-urc, 王炜b*

a. 白沙瓦大学化学科学研究所，白沙瓦25120，巴基斯坦 b. 湖南中医药大学药学院，中-巴中医药民族医学研究中心，中医药与民族医学创新与 发展国际实验室，湖南 长沙410208，中国 c. 卡拉奇大学国际化学和生物科学中心化学研究所，卡拉奇75270，巴基斯坦

【摘要】许多植物因其新的生物活性分子的发现而受到关注。在新近被发现的几种植物化学物质中， 酮表现出良好的结构多样性和药理价值。 酮有多种结构，但都具有抗氧化性。因此，引起了天然产 物和天然药物化学家研究兴趣。 酮及其苷类化合物具有广泛的生物活性，如细胞毒性、抗炎、抗氧化、 抗菌、神经保护、抗-HIV、酶抑制和降血糖等。这些分子通过清除自由基实现其药用价值。本文介绍了 酮及其糖苷类成分的最新研究进展，总结了其构效关系和作用机制，旨在为 酮及其类似物的进一 步发现提供指导，并为其不同药物制剂的开发提供更好的思路。

【关键词】 酮； 酮苷；抗氧化；自由基清除； 酮二聚体； 酮三聚体