166 ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192 Contents lists available at ScienceDirect Digital Chinese Medicine journal homepage: http://dcmhi.com.cn 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- Copyright © 2019 Digital Chinese Medicine. Production and hosting by Elsevier B.V. This is an open access article under the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. ZAFAR Salman , et al/Digital Chinese Medicine 2 (2019) 166-192 An Updated Review on Natural Xanthones and Their Glycosides 167 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.