Xanthones are chemical substances in higher plants, marine organisms, and lower microorganisms. The most prevalent naturally occurring sources of xanthones are those belonging to the families Caryophyllaceae, Guttiferae, and Gentianaceae. Structurally, xanthones (9H xanthan-9-one) are heterocyclic compounds with oxygen and a γ-pyrone component. They are densely packed with a two-benzene ring structure. The carbons in xanthones are numbered from their nucleus and biosynthetic construct. They have mixed shikimate-acetate (higher plants) and acetate-malonate (lower organisms) biosynthetic origins, which influence their classification. Based on the level of oxidation of the C-ring, they are classified into monomers, dimers, and heterodimers. While based on the level of oxygenation or the type of ring residue, they can be categorized into mono-, di-, tri-, tetra-, penta- and hexa-oxygenated xanthones, bis-xanthones, prenylated and related xanthones, xanthonolignoids, and other miscellaneous xanthones. This structural diversity has made xanthones exhibit considerable biological properties as promising antioxidant, antifungal, antimicrobial, and anticancer agents. Structure-activity relationship studies suggest C-1, C-3, C-6, and C-8 as the key positions that influence the biological activity of xanthones. Furthermore, the presence of functional groups, such as prenyl, hydroxyl, glycosyl, furan, and pyran, at the key positions of xanthones, may contribute to their spectrum of biological activity. The unique chemical scaffolds of xanthones, their notable biological activities, and the structure–activity relationships of some lead molecules were discussed to identify lead molecules as possible drug candidates.
Xanthones are a heterocyclic class of secondary metabolites that are mostly found in lichen, fungi, and higher plant groups. They are formed from dibenzo-γ-pyrone, which is γ-pyrone condensed with two benzene rings. The term “xanthone” was first used by J.C. Robert in 1961. Since these metabolites are typically formed as yellow solids, the word “xanthone” comes from the Greek word “xanthos”, which means yellow tint. The first documented xanthone derivative to be extracted from Gentiana lutea roots was gentian in 1821. The chemical formula of xanthone is C 13 H 8 O 2, and its IUPAC designation is 9H-xanthen-9-one.
Lichens, fungi, plants (Polygalaceae, Moraceae, Gentianaceae, and Guttiferae families), and ferns all contain these tricyclic secondary chemicals. These metabolites are widely distributed in nature and because of their chemical makeup and position of the substituent groups on the aromatic ring, they have a variety of biological actions. Derivatives of xanthones come from two main sources: the marine environment (lower organisms) or naturally occurring sources of higher plants, which can be manufactured and extracted. Researchers have been motivated to extract, separate, and purify these heterocyclic metabolites from their natural origins to prepare them as prospective candidates for drug development due to their unique structural architecture and known pharmacological effects. In the past twenty years, researchers have concentrated on understanding the structure–activity relationship of xanthones to use them effectively in medicine. Numerous xanthone derivatives, both natural and artificial, have been examined and found to offer major health benefits. Xanthones and their derivatives can bind to several protein receptors involved in the etiology of diseases, making them have a wide range of biological activities, including antidiabetic, antioxidative, anti-inflammatory, anticancer, antibacterial, and antithrombotic effects.
There are six general categories into which xanthones can be categorized: prenylated xanthones, glycosylated xanthone, xanthonolignoids, oxygenated xanthone, xanthone dimers, and miscellaneous xanthones. Among them, oxygenated xanthones are divided into six subclasses based on the number of oxygen atoms they contain (mono-, di-, tri-, tetra-, penta-, and hexa-oxygenated xanthones). In addition, glycosylated xanthones are divided into two subclasses: C-glycosides (xanthones are associated with glycosyl moiety via carbon-carbon bond) and O-glycosides (glycosidic couplings among anomeric C-atom of sugar ring and O-atom of OH-group of xanthone structure). A diverse spectrum of biological actions is demonstrated by xanthone derivatives, both natural and synthetic. As secondary metabolites, xanthones are found naturally in lichens, fungi, various microorganisms, and higher plants. Some of the plants, ferns, and fungus species that contain xanthones are Artocarpus, Anthocleista, Allanblackia, Andrographis, Aspergillus, Bersama, Blackstonia, Calophyllum, Canscora, Centaurium, Chironia, Cratoxylum, Comastoma, Garcinia, Cudrania, Eustoma, Emericella, Frasera, Garcinia, Gentiana, Gentianella, Gentianopsis, Halenia, Hoppea, Hypericum, Ixanthus, Lomatogonium, Mesua, Morinda, Macrocarpaea, Mangrove fungi, Orphium, Peperomia, Pentadesma, Polygala, Penicillium, Phoma, Phomopsis, Rheedia, Rhus, Securidaca, Symphonia, Schultesia, Swertia, Tripterospermum, Vismia, Veratrilla, and Xylaria. Currently undergoing a phase III clinical trial as an anticancer drug, 5,6-dimethylxanthone-4-acetic acid (DMXAA) is a noteworthy molecule with notable antibacterial and antitumor properties and provides a quick overview of its discovery. The literature review unequivocally demonstrated that xanthones have a number of pharmacological activities, including anticholinesterase, α-glycosidase inhibitory activity, anticonvulsant, anthelminthic properties, anti-trypanosomiasis, anti-HIV, anti-hypertensive, anti-inflammatory, antimalarial, antibacterial, anti-enteroviral activity, antiprotozoal, antimicrobial and antioxidant activity, and antithrombotic activity. Most notably, a number of xanthone derivatives have gained clinical appeal because of their molecular target locations on certain enzymes, including acetylcholinesterase, topoisomerase, p-glycoprotein, and α-glycosidase, as well as protein-protein interactions like p53-murine double minute 2 (MDM2). Though later withdrawn in 2014, the Food and Drug Administration (FDA, USA) approved amlexanox in 1996 for use as an anti-inflammatory, immunomodulatory (to treat stomach ulcers caused by aphthous ulcers), anti-allergic, and anticancer agent. Thus, an attempt has been made to compile current and quantifiable data on a wide range of naturally occurring xanthone and derivatives and their biological implications in this review.
The study involved an extensive literature search through various scientific databases (including Google Scholar, PubMedCentral, SciFinder, Scopus, and Web of Science) for information on naturally occurring xanthones. For the literature review, the following were the inclusive criteria: naturally occurring xanthones, history of xanthones, classes of xanthones, biosynthesis of xanthones, biological activities of xanthones (antifungal, antibacterial, anticancer, coagulant, antioxidant, anti-inflammatory, and anti-HIV/AIDS effects), and structure–activity relationship of xanthones. Exclusive criteria included a search for classes of compounds other than xanthones. All chemical structures were drawn using ACD/ChemSketch (Freeware) version 2021.1.1 (Advanced Chemistry Development, Inc., Toronto, ON, Canada).
De Koning and Giles discovered bikaverin, a wine-red pigment that was separated from many species of the fungi Fusarium, Gibberella, and Mycogone, in 1988. Bikaverin contains a quinone moiety, which may be responsible for its biological properties, such as antiprotozoal and antitumor activities. The first report of natural xanthone, Gentisin (1,7-dihydroxy-3-methoxyxanthone), came from the higher plant Gentiana lutea in 1821, while the first prenylxanthone derivative, tajixanthone, was isolated from the fungus, Aspergillus stellatus in 1970.
In 1971, Bikaverin and norbikaverin were discovered by Kjaër and associates. Using trifluoroacetic anhydride (TFAA) in combination with the synthesized naphthalene derivative (I) and the aryl acid (II), de Koning et al. first introduced the carbonyl bridge to form the xanthone nucleus. This resulted in the intended product being produced as a single regioisomer (III) in a 51% yield. Palladium on carbon in the presence of hydrogen under pressure was then used to deprotect the compound, affording the phenol (IV) an 80% yield. Using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to oxidize the phenol (IV) resulted in the surprise production of the spiro compound (V) in a 61% yield. With the use of aqueous trifluoroacetic acid (TFA), the spiro compound was hydrolyzed to the required trione (VI) in a 94% yield. Pyrolytic isomerization of the trione (VI) resulted in a 93% yield of the xanthone-based chemical. The mechanism of the DDQ-facilitated reaction that results in the creation of the spiro compound has not been thoroughly explored since this synthesis. Investigating this innovative synthesis’s versatility was also necessary, especially regarding more electron-poor precursors. Owing to the wide diversity of biological activities exhibited by xanthones, it is critical to identify a flexible synthetic strategy that can support a variety of xanthone ring structures.
From the natural source point of view, over 2000 xanthones have been reported from marine organisms, the lower and higher plants. Higher plants are the most common sources of this unique group of compounds, comprising over 20 plant families, including Gentianiaceae, Guttiferae (Clusiaceae), Hypericaceae, Moraceae, and Polygalaceae, and over 120 species. Among the common higher plants with xa
