The wide anticancer activity of xanthones is produced by caspase activation, RNA binding, DNA cross-linking, as well as P-gp, kinase, aromatase, and topoisomerase inhibition. This anticancer activity depends on the type, number, and position of the attached functional groups in the xanthone skeleton. This review discusses the recent advances in the anticancer activity of xanthone derivatives, both from natural products isolation and synthesis methods, as the anticancer agent through in vitro, in vivo, and clinical assays.

The Anticancer Activity of Xanthone Derivatives

Among the heterocyclic compounds, hundreds of xanthone derivatives have been isolated, synthesized, and evaluated as anticancer agents. The latest review article on the anticancer activity of xanthone derivatives was reported by Na in 2009. From that report, unfortunately, an updated review on the anticancer activity of xanthone derivative has not been available yet, as of today. This review, to a certain extent, provides a brief update on the research and development of xanthone derivatives, both from natural products isolation and synthesis methods, such as the anticancer agent through in vitro, in vivo, and clinical assays. The name of it was coined by J.C. Roberts in 1961. The word “xanthone” comes from the word for the color yellow, “xanthos” (ξανθ??, Greek), since the compounds are commonly obtained as yellow solids. The first reported xanthone derivative was gentisin, which was isolated from the roots of Gentiana lutea in 1821. Xanthone with an IUPAC name of 9H-xanthen-9-one is a heterocyclic compound with a dibenzo-γ-pyrone framework, with a basic molecular formula of C13H8O2. It is well-known to have “privileged structures” because this simple tricyclic compound exhibits wide biological activities. The wide biological activities of xanthone derivatives are caused by their ability to bind with multiple protein receptors. It was reported that xanthone derivatives also exhibit antimicrobial, antidiabetic, antioxidant, antiviral, anti-Alzheimer, anti-inflammatory, and anti-tyrosinase activities. Updates on these biological activities of xanthone derivatives have been available recently.[1]

Further improvement in the synthesis of xanthone derivatives recently focused on heterogeneous catalysis and microwave-assisted organic synthesis (MAOS). Heterogeneous catalysis is desirable in the green chemistry approach for our sustainable future, as the heterogeneous catalyst material demonstrates a faster synthesis process, a higher product yield, and a milder reaction condition. Moreover, heterogeneous catalyst material can be recovered for further reusability purposes. On the other hand, the MAOS technique has been widely employed in the synthesis of xanthone derivatives, as the required reaction time is significantly shortened, together with dramatic improvement in the product yield and selectivity. The MAOS synthesis of xanthone derivatives from salicylic acid with resorcinol, pyrogallol, cresol, and phloroglucinol gave the corresponding xanthone derivatives in 72–98% yield within 5 min reaction time. Palladium-catalyzed acylation reaction can be used for the formation of xanthone skeleton from salicylaldehyde and dihalotoluene in 41–81% yield. The tert-butylammonium hydroxide (TBAOH) as the base has been employed in water-based reaction under MAOS technique to give a quantitative yield of 2-methylxanthone within 4 min. In 2020, metal-free synthesis of benzo[c]xanthone from 1,3-diarylketone was reported by Liang et al., employing 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in dimethylsulfoxide (DMSO) solution. The attraction of H-α with DBU leads to the cyclization reaction to form the γ-pyrone scaffold within 30 min in 78–93% yield.

Another recent approach to synthesize xanthone derivatives was reported by Steingruber et al., employing salicylaldehyde and dibromobenzene derivatives using palladium nanoparticles. High yield (up to 88% yield), as well as high regioselectivity reaction, were achieved within 30 min reaction time in which the nanopalladium catalyst can be used up to four consecutive cycles without losing its activity. The xanthone derivatives act as anticancer agents through several mechanisms of action. First, activation of caspase proteins induces the apoptosis of cancer cells. Second, inhibition of protein kinases leads to the proliferation of cancer cells. Third, inhibition of aromatase enzyme leads to the inhibition of breast cancer cells’ growth. Fourth, prostaglandin PG-E2 inhibition is another mechanism for the anticancer activity of xanthone derivatives. The PG-E2 is a lipid biomolecule that is involved in the inflammation, angiogenesis, apoptosis, and proliferation of cancer cells.

Structure, Activity, and Drug Likeness Analysis

Inflammation is the body’s self-protective response to multiple stimulus, from external harmful substances to internal danger signals released after trauma or cell dysfunction. Many diseases are considered to be related to inflammation, such as cancer, metabolic disorders, aging, and neurodegenerative diseases. Current therapeutic approaches include mainly non-steroidal anti-inflammatory drugs and glucocorticoids, which are generally of limited effectiveness and severe side-effects. Thus, it is urgent to develop novel effective anti-inflammatory therapeutic agents. Xanthones, a unique scaffold with a 9H-Xanthen-9-one core structure, widely exist in natural sources. Till now, over 250 xanthones were isolated and identified in plants from the families Gentianaceae and Hypericaceae. Many xanthones have been disclosed with anti-inflammatory properties on different models, either in vitro or in vivo. Herein, we provide a comprehensive and up-to-date review of xanthones with anti-inflammatory properties, and analyzed their drug likeness, which might be potential therapeutic agents to fight against inflammation-related diseases.[2]

Xanthones have been implicated in biological activities and chemical isolation, as well as total synthesis. In the last decade, increased reports of xanthones as potential anti-inflammatory reagents have been challenged in the phytochemical, pharmacological, and synthetic community to innate challenges of the construction of this class of natural products. However, although most of the recent research has concentrated on anti-inflammatory activities in vitro and their mechanisms, in vivo information is still restricted and lacks good-quality preclinical models to make a further step in clinical application. More efforts should be paid to verify the therapeutic effects of xanthones using in vivo animal models. Besides mangiferin and α-mangostin, there is a hint of the emergence of studies from other xanthones concerning the discovery of drug candidates.

So far, there are still limited data available on the bioavailability of xanthones. The lack of toxicity studies on xanthones does not negate its importance, as the safety and efficacy of drugs are related to each other. Future structure–activity relationship studies on simplified fragments of the members of this natural product family are also necessary to ascertain both the key features related to activity and the mode of action of these natural products. Ongoing exciting results remain to be discovered and reviewed. Future research on the chemistry and biology on anti-inflammatory xanthones looks very bright and challenging, and with tremendous therapeutic applications.

Xanthone Hybrid for Potent Anti-Inflammatory Effects

Inflammatory responses, while essential for host defence, can precipitate chronic pathologies when sustained. The polyphenolic entity xanthone is distinguished by its capacity to modulate inflammation, notably via the inhibition of the COX-2 enzyme and associated inflammatory pathways. Additionally, heterocyclic frameworks such as pyrazole, triazole, and imidazole are recognised for their anti-inflammatory attributes. This investigation was conducted to engineer and synthesise a series of novel hybrid-xanthone molecules with enhanced anti-inflammatory capabilities. Utilising computational docking strategies, these hybrid-xanthone variants were virtually screened against the COX-2 enzyme structure (PDB ID:1CX2), and the 10 leading candidates were identified based on their binding affinities.

The best percentage inhibition was shown by compound A127(3-(5′(1,2,4-Triazole)-pentyloxy)-1,6,8-trihydroxy xanthone), A11(3-(1′-(1,2,4-Triazole)-methyloxy)-1,6,8-trihydroxy xanthone) and A119(3-(1′-(1,2,4-Triazole)-methyloxy)-1,6,8-trihydroxy xanthone) as 60?±?0.31, 58.57?±?0.023, and 57.14?±?0.21 respectively. Spectroscopic characterisation of the compounds was achieved through UV, IR, NMR, and Mass spectrometry techniques. The investigation revealed that out of the synthesised cohort, nine compounds exhibited favourable in silico profiles, and half of these manifested substantial anti-inflammatory efficacy in both in vitro and in vivo models, outperforming the reference standard. These hybrid-xanthone molecules demonstrated precise COX-2 inhibition and maintained an acceptable safety margin in vivo, underscoring their therapeutic promise as anti-inflammatory agents.

References

[1]Kurniawan YS, Priyangga KTA, Jumina, Pranowo HD, Sholikhah EN, Zulkarnain AK, Fatimi HA, Julianus J. An Update on the Anticancer Activity of Xanthone Derivatives: A Review. Pharmaceuticals (Basel). 2021 Nov 11;14(11):1144.

[2]Feng Z, Lu X, Gan L, Zhang Q, Lin L. Xanthones, A Promising Anti-Inflammatory Scaffold: Structure, Activity, and Drug Likeness Analysis. Molecules. 2020 Jan 30;25(3):598.

[3]Karmakar, Shreyasi et al. “Design and Development of Xanthone Hybrid for Potent Anti-Inflammatory Effects: Synthesis and Evaluation.” Journal of cellular and molecular medicine vol. 29,6 (2025): e70477.