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DOI: 10.1055/s-0043-1775461
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Small Molecules in Medicinal Chemistry

Sustainable Approaches for the Synthesis of Functionalized Xanthene Derivatives with Anticancer Activities Using Modern Green Tools at Room Temperature: Less Energy and More Efficiency

Sasadhar Majhi∗
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Abstract

Functionalized xanthenes occupy an important position in medicinal chemistry due to their wide range of pharmacological properties. The xanthene skeleton is present in various bioactive natural products such as mulgravanols A and B, hermannol, (+)-myrtucommulone D, homapanicones A and B, blumeaxanthene II, acrotrione, etc. Important xanthene-based drugs, including propantheline bromide, methantheline, phloxine B, etc., are available on the market. Thus, much effort has been dedicated to generating or modifying xanthenes as crucial O-heterocyclic compounds. Recently, the development of efficient processes for the synthesis of xanthene derivatives using modern techniques has received significant attention in an effort to overcome the disadvantages of traditional methodologies. Aligned with the sixth principle of green chemistry, in which minimum energy is needed to perform synthetic methods at ambient temperature with optimum productivity, this account focuses on green, room-temperature strategies for the synthesis of xanthenes with anticancer activities using modern synthetic methodologies.

1 Introduction

2 Synthesis of Functionalized Xanthene Derivatives through Green Strategies at Room Temperature

3 Medicinal Perspectives on Functionalized Xanthene Derivatives as Anticancer Agents

4 Conclusion

5 List of Abbreviations


#

Key words

bioactive O-heterocycles - functionalized xanthenes - ambient conditions - anticancer agents - sustainable chemistry - medicinal impact

Biographical Sketch

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Sasadhar Majhi received both his B.Sc. (Honours) degree in chemistry and his M.Sc. (organic specialization) from Visva-Bharati University (a Central University), with an academic record rated brilliant. He earned his M.Phil in chemistry in 2009 and subsequently obtained a Ph.D. from Visva-Bharati University under the supervision of Prof. Goutam Brahmachari in the area of natural products. He currently serves as an assistant professor in the Department of Chemistry (UG & PG Department) at Triveni Devi Bhalotia College, Raniganj, West Bengal, India. His major research interests include the isolation and structural elucidation of natural products, semisynthetic derivatives, total synthesis, biological activities and sustainable chemistry. He is the co-author of the books entitled ‘Semisynthesis of Bioactive Compounds and their Biological Activities’ (Elsevier, 2024), ‘Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products’ (World Scientific Publishing, 2023) and ‘Green Chemistry and Sustainability: A Unified Approach’ (Narosa, 2022). In addition, he is one of the editors of the book entitled ‘Science and Technology: A Concise History and Evolution’.

1

Introduction

Xanthenes are valuable tricyclic O-heterocyclic compounds characterized by a dibenzo[b,e]pyran nucleus.[1] They are an important class of oxygen-containing condensed aromatic systems and are structurally related to xanthones.[2] Xanthenes have received significant attention owing to their wide range of therapeutic and biological activities,[1] [3] and their derivatives have been broadly applied in different fields such as textiles, electrooptical devices, dyes, food industries, and biomedical devices.[4] The xanthene scaffold occurs in various naturally occurring bioactive compounds such as (+)-myrtucommulone D, mulgravanols A and B, hermannol, homapanicones A and B, acrotrione, blumeaxanthene II, etc.,[5–9] and play a significant role in drug discovery and development.[10] Important xanthene-based drugs are available on the market, including methantheline (antispasmodic), propantheline bromide (antimuscarinic), phloxine B (photosensitizer in antimicrobial photodynamic therapy), etc.[11] [12] Furthermore, owing to their photochemical and photophysical characteristics, xanthenes hold an important position as dyes.[12] The parent compound is xanthene (or 9H-xanthene) in which a pyran ring is combined with a benzene ring on both sides, itself being an obscure compound.[13] However, functionalized xanthene derivatives, particularly 9-substituted xanthenes, represent an important class of heterocycles, demonstrating impressive medicinal applications and excellent biological activities such as antiviral,[14] antiparasitic,[15] antipsychotic,[16] antifungal,[17] analgesic,[18] and anticonvulsant.[19] Thus, several methodologies and catalysts have been reported for the synthesis of xanthene derivatives.[20] [21] [22] [23] [24] [25] However, most documented methodologies utilize toxic reagents, harmful solvents, and strong protic acids as catalysts. The main drawbacks of traditional methods are prolonged reaction times, low yields, difficulties in isolating pure products, impractical scaling up for manufacturing, and harsh reaction conditions.[26] Hence, the current scenario demands the development of novel, green synthetic strategies for generating functionalized xanthene derivatives.

The sixth principle of green chemistry is devoted to the ‘design of energy efficiency’.[27] According to this principle, less/minimum amounts of energy are needed to perform a particular synthetic method with optimum productivity as well as less environmental and economic impacts.[28] The most beneficial route to save energy is to develop methodologies that take place at ambient temperature and pressure.[29] [30] [31] [32] Various methods have been reported for the generation of bioactive synthetic and natural molecules under ambient conditions.[33–39] One of the major causes of death on this planet is cancer, accounting for around 10 million fatalities in 2020, with statistics revealing that by 2040 cancer occurrence will continue to increase, with nearly 29.5 million cases annually.[40–44] Thus, this account focuses on the eco-friendly synthesis of functionalized xanthene derivatives using modern techniques like electrochemistry, mechanochemistry, light irradiation, and ultrasound as alternative energy sources at room temperature. In addition, this study highlights important named reactions for the construction of xanthene derivatives at room temperature as sustainable methodologies.

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Scheme 1 Construction of 9H-xanthen-9-yl amide derivatives using electrochemistry

# 2

Synthesis of Functionalized Xanthene Derivatives through Green Strategies at Room Temperature

This section highlights methods for the efficient room-temperature construction of functionalized xanthene derivatives using electrochemistry, mechanochemistry, photochemistry, sonochemistry, named reactions, etc.

2.1

Applications of Electrochemistry in the Synthesis of Functionalized Xanthene Derivatives at Room Temperature

2.1.1

Synthesis of Amidated Xanthene Derivatives

Recently, significant interest has been devoted to generating amide bonds as amides are one of the most common functional groups in bioactive molecules.[45] Interestingly, of the 37 new drugs approved by the Food and Drug Administration (FDA) in 2022, 11 are small molecules comprising of at least one amide bond.[46] Traditional approaches for the synthesis of amides frequently require activated acylation reagents.[47] Hence, researchers have shifted their attention to the direct amidation of C(sp3)–H bonds due to growing concerns linked to sustainable chemistry.[48] The past decade has witnessed substantial developments in electrochemistry as this technique furnishes more sustainable, reactive, and selective methodologies compared to conventional protocols.[49] [50] In 2023, Li et al. achieved a sustainable method for constructing amidated xanthene derivatives 3 through the direct electrochemical amidation of xanthene (1) with benzamides 2 at room temperature (RT) (Scheme [1]).[51] The electrochemical C(sp3)–H amidation took place in an undivided cell under constant current conditions (15 mA) using a platinum anode, a graphite cathode, n Bu4NClO4 (0.1 M) as the electrolyte in a mixed solvent (CH3CN/HFIP, v/v = 9:1) at RT for 3 hours. The authors initiated the study by taking xanthene as a reaction partner with benzamides to furnish the targeted products in yields of up to 99% under direct anodic oxidation. An augmentation study of the solvent hexafluoroisopropanol (HFIP) was implemented for this reaction. Elimination or substitution of HFIP with methanol (CH3OH) led to decreased yields (from 99% to 36%).[51]

In organic synthesis, benzylic C–H functionalization represents a key challenge in terms of chemoselectivity.[52] [53] In a 2023 study, Wang et al. accomplished an environmentally benign Ritter-type amination for the synthesis of functionalized xanthene amides 5 from xanthene (1) and nitriles 4 that involved electrochemical benzylic C–H functionalization at RT without any catalyst or external chemical oxidant under mild conditions (Scheme [2]).[54] This electrochemical process produced the desired amination products by using a graphite felt anode and a graphite felt cathode in the presence of n Bu4NPF6 as the electrolyte under a constant current (8 mA) over 5 hours at RT. The electrochemical conditions controlled benzylic C–H functionalization nicely through C–N bond formation on the xanthene to afford the corresponding coupling products in 50–75% yield. Interestingly, a thioxanthene derivative as the targeted product was achieved in 64% yield.[54]

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Scheme 2 Construction of amidated xanthenes using electrochemistry

# 2.1.2

Synthesis of Xanthen-indole Derivatives

In organic chemistry, coupling reactions are very popular and versatile protocols for generating C–C and C–heteroatom bonds.[55] Conventional coupling reactions like Suzuki–Miyaura, Heck, etc. have a few drawbacks. For example, the catalysts employed in these coupling reactions are frequently costly, operational manipulations are burdensome, waste formation is problematic, and preactivated reactants are required.[56] [57] The preactivation of substrates and the formation of metallic salts as by-products greatly retards the progress of these reactions and leads to serious environmental concerns.[58] Cross-dehydrogenative coupling (CDC) reactions do not require reaction substrates having functional groups since they directly use the C–H bonds of the substrates to form C–C and C–heteroatom bonds.[59] Thus, CDCs benefit from shorter synthetic routes, eliminate unnecessary steps, and are more efficient than traditional coupling reactions.[60]

In 2022, Li et al. demonstrated an eco-friendly protocol for synthesizing xanthen-indole derivatives 7 using an electrochemical cross-dehydrogenative coupling of xanthenes 1 with indoles 6 (Scheme [3]).[61] The electrolysis was performed in an undivided cell at a constant current of 5 mA using a carbon rod anode and a platinum cathode in the presence of n Bu4NPF6, BHT, and CH3OH/CH3CN (1:1) at RT for 3 hours. This method proceeds without an external oxidant, a transition metal, or a catalyst, and leads to excellent regioselectivity with moderate yields (53–88%).[61]

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Scheme 3 Construction of xanthen-indole derivatives using electrochemistry

# 2.1.3

Synthesis of Xanthene-Sulfonated Derivatives

Sulfonylation is an important chemical reaction in which a sulfonyl group is inserted into a molecule.[62] The generation of sulfonated compounds has gained much attention in different fields like agrochemicals, pharmaceuticals, and materials industries because of the unique electronic properties and attractive structure of sulfonyl groups.[63] In 2022, Ma and co-workers developed a green protocol for preparing xanthene-sulfonated derivatives 9 by the reaction of xanthenes 1 with benzene sulfonyl hydrazides 8 that proceeded via the construction of C(sp3)–sulfonyl bonds (Scheme [4]).[64] The electrochemical oxidation-induced direct sulfonylation of the C(sp3)–H bond took place by applying a graphite rod anode and a platinum plate cathode in the presence of n Bu4NI (20 mmol%), DCE/HFIP (v/v = 4:2) and the base Cs2CO3 or MeONa at a constant current of 15 mA at RT for 4.5 hours.

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Scheme 4 Construction of xanthene-9-sulfonated derivatives using electrochemistry

# 2.1.4

Synthesis of Xanthen-amine Derivatives

The arylation of C(sp3)–H bonds is of great significance in constructing C(sp3)–C(sp2) bonds in synthetic organic chemistry.[65] [66] In 2022, Lei and co-workers demonstrated electro-oxidative C(sp3)–H arylation for the construction of xanthen-amine derivatives 11 through the cross-coupling of xanthenes 1 with different electron-rich aniline/amine derivatives 10 (Scheme [5]).[67] The electro-oxidation-induced alkylation was carried out in the presence of carbon rod and platinum electrodes using nBu4NBF4 (0.3 mmol) and TFA in TFE under a constant current of 3 mA at RT (25 °C) for 6 hours under a nitrogen atmosphere. The key merits of this protocol include H2 evolution as the by-product as well as a wide substrate scope.[67]

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Scheme 5 Construction of xanthen-9-amine derivatives using electrochemistry

# 2.1.5

Synthesis of Xanthen-aryl Derivatives

Ouyang et al., in 2022, reported a transition-metal-catalyst-free synthesis of 9-aryl-9H-xanthenes 13 involving electrochemical C(sp3)–H arylation of xanthenes 1 with arenes 12 from readily available heterocyclic aromatic hydrocarbons, N,N-disubstituted anilines, and anisoles through a radical pathway (Scheme [6]).[68] The formation of a series of 9-aryl-xanthene derivatives was made possible using a carbon anode, a platinum cathode, nBu4NBF4 (0.05 M), NHPI, MsOH, and CH3CN under a constant current of 10 mA at RT for 3.5 hours.

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Scheme 6 Construction of 9-aryl-9H-xanthenes using electrochemistry

# 2.1.6

Synthesis of Xanthen-alkyl Derivatives

In synthetic organic chemistry, electrochemical anodic oxidation furnishes an eco-friendly methodology for generating new C–C or C–X bonds (X = N, O, etc.).[69] [70] [71] Notably, electro-oxidative dehydrogenative cross-coupling reactions are attracting enormous attention for the formation of C–C or C–X bonds.[72] [73] Thus, in 2020, Li et al. developed an oxidant-free methodology for the synthesis of functionalized 9-alkyl-9H-xanthenes 15 as valuable molecules via electrochemical dehydrogenative cross-coupling of xanthenes 1 with ketones 14 at RT under mild conditions (Scheme [7]).[74] The electrochemical dehydrogenative cross-coupling occurred in the presence of the electrolyte n Bu4NBF4 (0.05 M), CH3CN as the solvent, and MsOH as the additive in a single compartment cell by utilizing a platinum plate as the cathode and a carbon rod as the anode under constant-current conditions (5 mA) at RT for 2 hours. The electrodes were attempted and when carbon rod anode was replaced by Pt plate or the Pt plate cathode was replaced by carbon rod, the efficiency of this transformation was decreased. Unfortunately, no targeted product could be achieved in the absence of electric current. The reaction efficiency was also influenced by the choice of electrolyte (e.g., such as TBAI, n Bu4NPF6, LiClO4), whilst TBAB reduced the reaction efficacy. Importantly, the targeted xanthenes could not be obtained when no MsOH (additive) was present. This green protocol produces H2 as the only by-product and features high atom economy, constructs a novel C(sp3)–C(sp3) bond through a C–H functionalization process at RT, scalability, excellent functional group tolerance, and is simple to use in pharmaceutical chemistry[74]

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Scheme 7 Construction of 9-alkyl-9H-xanthenes using electrochemistry

A plausible mechanism for the formation of 9-alkyl-9H-xanthenes is shown in Scheme [8].[74]

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Scheme 8 A plausible mechanism for the preparation of 9-alkyl-9H-xanthenes using electrochemistry

# 2.1.7

Synthesis of Xanthen-azole Derivatives

The xanthen-9-amine motif is important and occurs in various pharmaceuticals, bioactive molecules, and materials.[75] Thus, the formation of these molecules attracts increasing attention in organic synthesis.[76] The most familiar approach for the synthesis of xanthen-9-amines comprises C–H amination of xanthenes with nitrene precursors using a transition-metal catalyst.[77] However, this strategy suffers from a few limitations, including the necessity for substrate prefunctionalization and the generation of toxic waste and heavy metal residues.[78] One of the most powerful methods for generating xanthen-9-amines is the direct C–H/N–H dehydrogenative cross-coupling of xanthenes.[79] In 2019, Song et al. disclosed a green methodology for accessing xanthen-9-amine derivatives 17 in moderate to excellent yields (40–98%) through the electrochemical dehydrogenative coupling of xanthenes 1 with azoles 16 (Scheme [9]).[80] This novel strategy was performed in an undivided cell with a platinum plate cathode and a carbon rod anode under constant-current conditions (10 mA), using n Bu4NBF4 as the electrolyte, CH3CN as the solvent, and MsOH as the promotor under an air atmosphere. This transformation runs at RT for 2 hours under metal-free and additional oxidant-free conditions, and is effective for a wide scope of both xanthenes and N–H-free azoles such as pyrazoles, tetrazoles, triazoles, and imidazoles. Interestingly, a Brønsted acid improved the reaction, providing a conceptually and mechanistically new synthetic complement for construction of the C–N bond.[80]

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Scheme 9 Construction of xanthen-9-azole derivatives using electrochemistry

# 2.1.8

Synthesis of N-Alkoxy-N-xanthen-9-amides

In organic synthesis, the cross-dehydrogenative coupling has appeared as a promising tool because of its step- and atom-economy, along with the avoidance of prefunctionalization of the substrates.[81] As C–N bonds are crucial structural moieties in materials science, natural products, agrochemicals, and pharmaceuticals, C–N bond formation occupies a central position among different C–heteroatom bonds.[82] Thus, in industrial and academic research, novel, effective, sustainable, and selective methods for the formation of C–N bonds have always generated significant interest.[83] In 2018, Zeng et al. reported an electrochemical protocol for the construction of N-alkoxy-N-xanthen-9-amide derivatives 19 involving C–N bond formation via dehydrogenative cross-coupling at room temperature under environmentally benign conditions (Scheme [10]).[84] The electrochemical cross-coupling reaction of xanthenes 1 with N-alkyloxyamides 18 was executed in a single-compartment cell equipped with a carbon anode and a carbon cathode in the presence of the inexpensive redox catalyst ferrocene (Fc) (0.5 mmol), the additive Na2CO3 and the supporting electrolyte LiClO4 in combination with CH3CN/DCM (v/v = 2:1) over 5.5–9 hours to afford functionalized xanthene derivatives at RT in up to 77% yield. The dehydrogenative cross-coupling reaction may progress through an amidyl radical, which is evident from cyclic voltammetry and control experiments.[84]

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Scheme 10 Construction of N-alkoxy-N-xanthen-9-amide derivatives using electrochemistry

# 2.1.9

Synthesis of Xanthene-1,8(2H)-dione Derivatives

The xanthene-1,8(2H)-dione motif has gained interest due to its remarkable biological and pharmacological properties.[85] Thus, different methods have been documented to synthesize these compounds.[86] In 2012, Mirza and Samiei disclosed a convenient methodology for the preparation of various xanthene-1,8(2H)-dione derivatives 22 in yields of 75–95% from different benzaldehydes 20 and dimedone (21), which involved the electroreduction of dimedone at a platinum electrode (Scheme [11]).[87] The electrosynthesis was carried out in an undivided cell with a graphite anode and a Pt sheet as the cathode, employing sodium acetate as an electrolyte in water/acetonitrile solution under a constant current (10 mA) at RT for 5 hours.

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Scheme 11 Construction of xanthene-1,8(2H)-diones using electrochemistry

#
# 2.2

Applications of Mechanochemistry in the Synthesis of Functionalized Xanthene Derivatives at Room Temperature

2.2.1

Synthesis of Dibenzo[a,j]xanthene and Xanthene-dione Derivatives

Mechanochemistry has appeared as a green technique in chemistry to decrease or even entirely avoid solvent use.[88] Besides, mechanochemical synthesis includes many merits such as low energy consumption, reduced waste treatment, a simple operational technique, and large-scale manufacturing.[89] Poly(aluminum chloride) has received significant interest as an inorganic, high molecular weight material, owing to its low cost, simple preparation, ready availability and its effectiveness for water treatment. In addition, it consists of unique electrical properties and a characteristic polynuclear Al-O structure.[90] [91] Poly(aluminum chloride) serves as Lewis acid and is a reliable and environmentally safe catalyst due to its rich metal cation structure.[92]

In 2022, Liu et al. disclosed a green methodology by utilizing the reaction of benzaldehydes 20 and β-naphthol (23) for the synthesis of dibenzo[a,j]xanthenes 25 as well as cyclohexane-1,3-diones 24 for the synthesis of xanthene-dione derivatives 26 in the presence of catalytic materials (polymeric aluminum chloride (PAC) and silica gel) under mechanical grinding at room temperature (RT) (Scheme [12]).[92] For example, to a grinder were added the benzaldehyde 20 (1.0 mmol), the cyclohexane-1,3-dione 24 (2.0 mmol), PAC (0.05 g), and silica gel (0.4 g), and the mixture was ground at 50 Hz for the required period of time. In this process, two events were performed by mechanical ball milling. Firstly, it enables polymeric aluminum chloride and silica gel to be assembled into new composites. Secondly, it behaves as a driving force for the catalytic reaction to take place. Importantly, the complex procedure for the preparation for catalytic materials was eliminated by this one-pot catalytic method. This catalyst (PAC-silica gel) comprises broad applicability (21 substrates) and high stability (six cycles). The role of a co-catalyst was played by the silica gel. Moreover, density functional theory was used to verify the mechanism of action of the catalyst.[92] Different techniques including XPS (X-ray photoelectron spectroscopy), SEM (scanning electron microscopy), HRTEM (high-resolution transmission electron microscopy), and FTIR (Fourier transform infrared) were applied to explore the catalytic active sites because of the unpredictability of the catalytic mechanism occurring under mechanical ball milling.[92]

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Scheme 12 Construction of dibenzo[a,j]xanthene and xanthene-dione derivatives using mechanochemistry

The augmentation of a greener protocol for the generation of heterocyclic compounds, particularly biologically potent xanthene and derivatives, has received much attention recently due to their potential activities.[93] [94] The mechanochemistry approach in organic synthesis, particularly reductions, oxidations, and metal-catalyzed bond-forming reactions, is popular as a green technique owing to fewer drawbacks compared to traditional approaches (e.g., low yields, harsh reaction conditions, harmful solvents, and catalysts).[95,96] In another study, Azizi et al. developed a sustainable methodology for the quick and quantitative construction of dibenzo[a,j]xanthene derivatives 25 by the reaction of aldehydes 20 (1 mmol) and β-naphthol (23) (2 mmol) in the presence of sulfonated graphitic carbon nitride (Sg-CN) (10 mol%) at RT for 10–20 minutes under ball-milling conditions (Scheme [13]).[97] From a green chemistry perspective, the present ball-milling procedure is very attractive due to solvent-free conditions, high atom economy, excellent yields (99%), improved catalytic activity, and the reusability of the catalyst (four consecutive cycles).

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Scheme 13 Construction of dibenzo[a,j]xanthene derivatives using mechanochemistry

A plausible mechanism for preparing xanthene derivatives 25 using an Sg-CN catalyst under ball-milling conditions is shown in Scheme [14]. The ball-milling produces mechanochemical energy, which promotes the breaking and generation of chemical bonds during organic reactions.[97] [98] The heterogeneous acidic Sg-CN catalyst initially activates a carbonyl group on the aromatic aldehyde through a strong coordination bond. Nucleophilic addition of β-naphthol (23) on the activated carbonyl group of the aldehyde 20, followed by dehydration of the intermediate I provides the α,β-unsaturated ketone II through a Knoevenagel condensation. The second β-naphthol (23) underwent Michael addition with ketone II to form the Michael adduct III. Finally, the targeted xanthene derivatives 25 were derived through intramolecular cyclization of intermediate III followed by dehydration of the resulting intermediate IV.[97]

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Scheme 14 A plausible mechanism for the synthesis of dibenzo[a,j]xanthene derivatives using mechanochemistry

# 2.2.2

Synthesis of Benzo[h][1,3]dioxolo[4,5-b]xanthene-5,6(7H)-dione Derivatives

Metal oxide nanoparticles, especially PbO nanoparticles (NPs), attract wide attention from organic chemists. PbO NPs are cheap, non-corrosive, readily accessible and give higher selectivity in some reactions.[99] [100] In the context of green organic synthesis, the ball-milling technique has gained interest as an eco-friendly strategy.[101] In 2019, Lambat et al. demonstrated the efficient and green synthesis of xanthenedione derivatives 29 in excellent yields (92–97%) via the three-component reaction of aromatic aldehydes 20, 3,4-methylenedioxy phenol (27), and 2-hydroxy-1,4-naphthoquinone (28) in the presence of the mesoporous PbO NPs catalyst over 60 minutes under ball-milling conditions at ambient temperature (Scheme [15]).[102] Aromatic aldehydes with an electron-withdrawing group (e.g., NO2) led to lower product yields, whilst aryl aldehydes containing electron-donating groups (e.g., Me, OH, OMe) enhanced the product yield. Interestingly, no column chromatography was required when using the present methodology as the obtained xanthenediones were instead purified through recrystallization from hot ethanol. Spectroscopic analysis, including 1H and 13C NMR spectroscopy, and melting point analysis confirmed the structures of the synthesized xanthenes.[102]

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Scheme 15 Construction of benzo[h][1,3]dioxolo[4,5-b]xanthene-5,6(7H)-diones using mechanochemistry

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# 2.3

Applications of Photochemistry in the Synthesis of Functionalized Xanthene Derivatives at Room Temperature

2.3.1

Synthesis of Aryl/Hetroaryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-ones

Researchers seek inspired methodologies that minimize environmental impact and maximize productivity to achieve the goal of sustainable chemistry.[103] [104] One of the most promising approaches is visible-light photocatalysis in which organic reactions take place under mild conditions; light energy is used as the driving force.[105] This technique comprises many merits like the use of renewable sunlight, reduction of waste generation, minimization of energy consumption, and higher selectivity than traditional methodologies.[106]

Conventional synthetic protocols for synthesizing xanthene derivatives often include harsh reaction conditions, harmful reagents, high temperatures, and prolonged reaction times.[107] Due to their significant biological activities, green methods are required for the synthesis of xanthene derivatives, and visible-light photocatalysis holds considerable promise in this area. Among different photocatalysts, TiO2 occupies a significant position owing to its non-toxic nature, easy accessibility, and unique photochemical properties.[108] However, TiO2 includes demerits, especially its absorption spectrum, which chiefly exists in the UV range.[109] Currently, organic dyes as are used sensitizers for TiO2 nanoparticles to overcome this barrier and lengthen light absorption into the visible region.[110] The dye-sensitization approach increases the photocatalytic activity of TiO2 and enables effective visible-light-driven organic reactions.

Alotaibi et al. used blackberry dye (BB) as a sensitizer for TiO2 nanoparticles because of its powerful absorption activities in the visible-light range (500 to 600 nm);[111] it shifts energy to the nanoparticles.[112] Because of the wide bandgap of TiO2 nanoparticles, it primarily absorbs UV light (around 380 to 400 nm). However, sensitizing TiO2 nanoparticles with BB dye expands its absorption range into the visible-light region.[113] Hence, in photocatalytic reactions, the use of visible light is more significant.[114] [115] Thus, Alotaibi et al. accomplished the sustainable preparation of xanthene derivatives (12-aryl/hetroaryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-ones) in the presence of the photocatalyst BB dye and TiO2 at RT in 2024 (Scheme [16]).[111] This green technique comprises a multicomponent reaction of various aldehydes 20, 2-naphthol (23), and dimedone (21) in ethanol to afford the desired xanthenes 30 under environmentally benign conditions. A comparative analysis was performed to examine the photocatalytic activities of blackberry-dye-sensitized TiO2 and pristine TiO2 nanoparticles, which revealed that BB dye-TiO2 displays superior photocatalytic activity to pristine TiO2 nanoparticles. This work provided optimized conditions for the photocatalytic synthesis of xanthenes with yields of up to 98%, a light intensity of 100 mW/cm2, a 30-minute reaction time, and a photocatalyst concentration of 1 g/L.[111]

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Scheme 16 Construction of tetrahydrobenzo[a]xanthen-11-ones using photochemistry

# 2.3.2

Synthesis of 2-Substituted/4-Substituted Acyltetrahydroxanthenes and Xanthene ent-Myrtucomvalones E–F

In 2024. Wang et al. demonstrated a unique protocol for the preparation of 2-substituted acyltetrahydroxanthenes 33 and 4-substituted acyltetrahydroxanthenes 32 involving a photoinduced skeletal rearrangement strategy utilizing zero-valent iron as the reducing agent (Scheme [17]).[116] The construction of the functionalized xanthene derivatives was initiated from spiro substrates 31 through myrtucommulone B′ and its analogs. This strategy permits direct asymmetric synthesis as it eliminates racemization. This approach is effective for the first asymmetric total synthesis of the polycyclic xanthenes ent-myrtucomvalones E and F (34 and 35).[116] Besides, biological work revealed that these xanthenes exhibit potential anti-osteosarcoma activity both in vitro and in vivo.[116]

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Scheme 17 Construction of acyltetrahydroxanthenes and xanthene ent-myrtucomvalones E and F using photochemistry

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# 2.4

Applications of Ultrasound in the Synthesis of Functionalized Xanthene Derivatives at Room Temperature

2.4.1

Synthesis of Substituted Xanthen-11-one Derivatives

In green chemistry, ultrasound (US) has emerged as an eco-friendly technology that comprises various merits compared to traditional thermal methods in terms of reaction rates, selectivities, yields, and purities of the desired products.[117] Ultrasound comprises chemical and mechanical effects generally.[118] One of the most powerful strategies is multicomponent reactions (MCRs) to construct various complex molecules using rapid, cheap, and eco-friendly one-pot methods.[119] [120] In 2020, Ghasemzadeh and Ghaffarian developed an environmentally benign protocol that involved the multicomponent reaction of different aldehydes 20, 2-naphthol (23), and dimedone (21) in ethanol/water (1:1) as the solvent in the presence of a CoFe2O4/OCMC/Cu (BDC) nanocomposite (0.002 g) as a useful catalyst for the preparation of tetrahydrobenzo[a]xanthen-11-ones 36 in high yields (83–96%) under ultrasound irradiation at RT for 10–15 minutes (Scheme [18]).[121] The nanocatalyst could be recovered and reused up to 6 times without significant loss of its catalytic activity.


# 2.4.2

Synthesis of Dibenzo[b,i]xanthene-tetraones and Dibenzo[a,j]xanthenes

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Scheme 18 Construction of substituted xanthen-11-ones using sonochemistry

An important synthetic procedure for the construction of xanthene derivatives is based on a multicomponent condensation using a Brønsted or Lewis acid.[122] However, traditional protocols include a few limitations such as the use of excess reagents and costly catalysts, poor yields, long reaction times, and the generation of large quantities of waste.[123] Khaligh and Shirini developed a green methodology for the preparation of xanthene derivatives using NSPVPHS (N-sulfonic acid poly(4-vinylpyridinium) hydrogen sulfate) (10 mg) as heterogeneous solid acid catalyst under sonication at RT as a sustainable technique (Scheme [19]).[124] Dibenzo[a,j]xanthenes 25 were obtained by the reaction of aldehydes 20 (1 mmol) and 2-naphthol (23) (2 mmol) at RT for 5–8 minutes, whilst dibenzo[b,i]xanthene-tetraones 37 were prepared from the reaction of aldehydes 20 (1 mmol) and 2-hydroxynaphthalene-1,4-dione (28) (2 mmol) at RT for 6–10 minutes, both under solvent-free ultrasound irradiation. The preparation of xanthenes was carried out by both grinding and heating methods as well as the sonochemical method. This study provides a practical alternative to traditional heating and brings salient developments in the search for novel pathways for generating xanthene derivatives.[124]

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Scheme 19 Construction of dibenzo[b,i]xanthene-tetraones and dibenzo[a,j]xanthenes using sonochemistry

# 2.4.3

Synthesis of 1,8-Dioxo-octahydroxanthene Derivatives

The 5th principle regarding ‘Safer Solvents and Auxiliaries’ and the 6th principle concerning ‘Design for Energy Efficiency’ are very relevant to synthetic organic chemists.[27] In this context, the application of ionic liquids and ultrasound-assisted synthesis is effective in achieving these goals.[125] Raval and co-workers reported the ultrasound-promoted synthesis of functionalized xanthenes 38 through the condensation of various aldehydes 20 with dimedone (21) in the presence of the [cmmim][BF4] (a carboxy-functionalized ionic liquid: 1-carboxymethyl-3-methylimidazolium tetrafluoroborate) at room temperature without any added catalyst in good yields (78–92%) over 30–85 minutes (Scheme [20]).[126] The reusability of the ionic liquid provides an advantage to this strategy compared to the traditional acid/base-catalyzed reaction.

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Scheme 20 Construction of 1,8-dioxo-octahydroxanthenes using sonochemistry

A plausible mechanism for the generation of 1,8-dioxo-octahydroxanthenes using sonochemistry is presented in Scheme [21].

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Scheme 21 A plausible mechanism for the formation of 1,8-dioxo-octahydroxanthenes using sonochemistry

The use of sonochemistry with ionic liquids has received much interest as a versatile tool to stimulate different organic transformations under ambient conditions.[127] A green protocol was disclosed by Srinivasan et al. for the preparation of 1,8-dioxo-octahydro-xanthene derivatives 39 in the presence of the imidazolium ionic liquids 1-n-butylimidazolium tetrafluoroborate or [Hbim]BF4 under ultrasonic irradiation at RT (Scheme [22]).[128] This work comprises condensation between different aldehydes 20 (2.0 mmol) and diketone 21 (4.0 mmol), affording improved yields (75–95%) over 30–90 minutes. Methanol serves as a co-solvent in this study.

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Scheme 22 Construction of octahydro-xanthene derivatives using sonochemistry

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# 2.5

Synthesis of Functionalized Xanthene Derivatives at Room Temperature Involving Important Named Reactions

2.5.1

Synthesis of Xanthene Derivatives via an Intramolecular Friedel–Crafts Reaction

In 2021, Yıldız et al. synthesized substituted arylxanthenes through an intramolecular Friedel–Crafts alkylation method in the absence of transition metals by activating alkenes efficiently in the presence of trifluoroacetic acid (TFA) as the catalyst at RT (Scheme [23]).[129] Initially, new unactivated alkenes 44a–l were prepared as the starting materials in four steps through the coupling of phenol for the formation of 2-phenoxybenzaldehyde (41a) from 2-fluorobenzaldehyde (40) (first step); the Grignard reaction of 41a for the formation of secondary alcohol derivative 42a (second step); oxidation of 42a for the formation of ketone derivative 43a (third step); and a Wittig reaction of 43a for the formation of phenoxydiphenylalkene derivative 44a (fourth step), in which the last two steps were carried out at room temperature in 80% and 85% yield, respectively, in order to achieve xanthene derivatives. Next, the construction of substituted 9-methyl-9-arylxanthenes 45a–l was executed from alkenes 44a–l via intramolecular Friedel–Crafts reactions at RT with TFA (10 mol%) as the catalyst within 6–24 hours. This protocol may open new doors for synthesizing xanthene derivatives under mild reaction conditions and utilizes cheap and efficient reagents. The obtained 9-methyl-9-arylxanthene derivatives were examined as native and bioactive products in the field of pharmaceutical chemistry.[129]

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Scheme 23 Construction of 9-methyl-9-arylxanthenes via intramolecular Friedel–Crafts alkylation

A plausible mechanism for constructing substituted 9-methyl-9-arylxanthene derivatives involving o-quinone methide intermediates is presented in Scheme [24].[129] [130]

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Scheme 24 A plausible mechanism for the formation of 9-methyl-9-phenyl-9H-xanthene

In another study, Yıldız et al. explored different organic Brønsted acids, such as l-lactic acid, acetic acid, N-trifylphosphoramide, benzoic acid, trifluoroacetic acid and diphenyl hydrogen phosphate, as catalysts in intramolecular Friedel–Crafts cyclizations for the construction of several new substituted arylxanthenes from carbinols.[131] It was found that N-trifylphosphoramide (10 mol%), as a cheap and non-toxic catalyst, provided the best results at room temperature in CH3CN (a suitable solvent for strong acids owing to its weak solvating power toward anions and its weak basicity).[132] The starting carbinols 46, with an arene-oxy group, effectively delivered substituted 9-arylxanthenes 47 in good yields within 15 minutes by applying the intramolecular Friedel–Crafts cyclization at RT (Scheme [25]). A metal-free Ullmann coupling[133] and a subsequent Grignard reaction afforded the starting materials. It was observed that electron-withdrawing groups such as nitro (NO2) and cyano (CN) provided very low yields (4–5%) due to their high deactivating effect during electrophilic aromatic substitution reactions, whereas electron-donating groups such as methyl and naphthyl gave very good yields (85 to >99%), as they enhanced the rate of the electrophilic substitution. Moreover, halogen-bearing electron-withdrawing groups, especially a 3-Br substituent, furnished very good yields (>99%) during an investigation of the influence of functional groups on the aryl substrate in the intramolecular Friedel–Crafts cyclization.[131]

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Scheme 25 Construction of substituted 9-arylxanthenes via intramolecular Friedel–Crafts cyclization
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Scheme 26 Construction of triazole-linked 1H-dibenzo[b,h]xanthenes via a Knoevenagel condensation

# 2.5.2

Synthesis of Triazole-Linked 1H-Dibenzo[b,h]xanthenes via a Knoevenagel Condensation

In 2019, da Silva et al. disclosed a methodology for the synthesis of xanthene derivatives via the Knoevenagel condensation of 1H-1,2,3-triazole-4-carbaldehydes 48 and lawsone (49) in EtOH/H2O (1:1) (Scheme [26]).[134] The synthetic intermediates 51 were initially prepared from intermediates 50 in good yields. Finally, the targeted 6H-dibenzo[b,h]xanthenes 52 were synthesized in good yields (51–98%) by reacting intermediates 51 with concentrated sulfuric acid at RT for 30 minutes.


# 2.5.3

Synthesis of Dioxolo[4,5-b]xanthenes via a Diels–Alder Reaction

He and co-workers synthesized 9-functionalized xanthenes, including 9-aryl- and 9-cinnamyl-substituted derivatives, in moderate to high yields (46–89%) at RT (Scheme [27]).[135] The stable ortho-quinone methides 53 underwent Diels–Alder reactions with arynes 54 in THF as the reaction medium, using KF and 18-crown-6 as co-additives, to afford the targeted xanthene derivatives 55 in reaction times of 12–18 hours. Importantly, symmetrical arynes possessing electron-donating, electron-withdrawing or electron-neutral substituents provided good yields of the xanthene derivatives (63–84%), whereas unsymmetrical 4-chloro- and 3-methoxy-arynes underwent Diels–Alder reactions with almost complete regioselectivity, affording yields of 63% and 54%, respectively.[135]

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Scheme 27 Construction of 9-functionalized xanthenes via Diels–Alder reactions

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# 2.6

Miscellaneous

2.6.1

Synthesis of BN-Xanthenes at Room Temperature

Recently, Gilroy et al. constructed a series of BN-substituted xanthenes via directed C–H borylation in the presence of BBr3, followed by electrophilic fluorination utilizing Selectfluor (Scheme [28]).[136] Moreover, these compounds show an afterglow in the solid state at RT ascribable to phosphorescence. The synthesis of BN-xanthenes was initiated from asymmetric aryl ethers 56. Reactions of 2-bromopyridine or 2-chloroquinoline with phenol or 2-naphthol using NaOH afforded ethers 56. Next, BBr2 adducts 57 were obtained by treating BBr3 with i Pr2NEt at 0 °C to RT for 18 hours through directed C–H borylation of substituted 2-phenoxypyridines 56.[137] Adducts 57 slowly decomposed under ambient conditions and purification by column chromatography was not tolerated. Xanthene derivatives 58 were derived in good yields (67–78%) from adducts 57 using one stoichiometric equivalent of Selectfluor in DMSO at RT for 18 hours as a green technique.[138]

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Scheme 28 Construction of BN-substituted xanthenes at RT

# 2.6.2

Synthesis of Xanthene/Thioxanthene-indole Derivatives at Room Temperature

Natural and synthetic products containing xanthene scaffolds show a range of biological activities.[5] Several protocols have been investigated for synthesizing functionalized xanthenes, especially 9-substituted xanthene derivatives.[139] The replacement of the xanthenyl-9-position with an indolyl substituent has gained more interest because of the important therapeutic potential of indole derivatives.[140] In 2020, Wang et al. developed a sustainable strategy for the construction of xanthene/thioxanthene-indole derivatives 60 from xanthen-9-ol or thioxanthen-9-ol 59 using iodine (5 mol%) as an efficient catalyst under mild conditions (Scheme [29]).[141] Xanthen-9-ol or thioxanthen-9-ol 59 in ethanol underwent nucleophilic substitution with indoles 6 to furnish xanthene/thioxanthene-indole derivatives 60 in good to excellent yields (80–98%) at RT in 5 minutes. This methodology displayed good tolerance of functional groups and a broad range of substrates under environmentally benign conditions.

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Scheme 29 Construction of xanthene/thioxanthene-indole derivatives at RT

A possible mechanism for the preparation of xanthene/thioxanthene-indole derivatives is depicted in Scheme [30].

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Scheme 30 A possible mechanism for the formation of xanthene/thioxanthene-indole derivatives at RT

# 2.6.3

Synthesis of Unsymmetrical 9-Arylxanthene Derivatives at Room Temperature

Panda et al. synthesized 9-arylxanthene and 9-arylthioxanthene derivatives using cheap anhydrous FeCl3 (10 mol%) as an efficient catalyst at room temperature.[142] The synthesis of 9-arylxanthenes involves a three-step synthetic route in which the last two steps take place at room temperature. The synthesis started with the formation of 2-arenoxybenzaldehydes 64 by the reaction of aromatic hydroxy compounds 63 and 2-fluorobenzaldehydes 61 or 62 (Scheme [31]).[142] Next, different freshly prepared arylmagnesium bromides were treated with benzaldehydes 64 at RT to give a series of carbinols 65 in high yields (90–96%) after 30 minutes. Finally, carbinols 65 in DCM delivered the desired 9-arylxanthenes 66 in good yields (85–94%) in the presence of the catalyst FeCl3 (10 mol%) at RT over 30 minutes. Moreover, the 9-arylthioxanthenes 71 were also prepared from commercially available 2-fluorobenzaldehyde (67) and benzenethiols 68 as the starting materials by following a similar strategy.[142] In this work, dichloromethane (DCM) was used as a suitable reaction medium due to the toxic nature of benzene.[143]

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Scheme 31 Construction of 9-arylxanthene and 9-arylthioxanthene derivatives at RT

Arynes show significant potential as highly reactive intermediates in organic synthesis, and are present in many natural products.[144] [145] Okuma and co-workers constructed xanthenes and 9-hydroxyxanthenes by reacting salicylaldehydes with benzyne in CH3CN at room temperature through the annulation of arynes.[146] The benzyne was obtained from o-trimethylsilylphenyl triflate in the presence of the CsF. The authors initiated their investigation on the construction of xanthene 74a and xanthone 75a (formed in 42% and 46% yields, respectively) by the reaction of o-trimethylsilylphenyl triflate (72) and salicylaldehyde (73a) using CsF at RT for 13 hours (Scheme [32]). The reaction was further studied for the synthesis of different xanthene derivatives 74 by the treatment of triflate 72 with various substituted salicylaldehydes 73a using CsF at RT (Scheme [32]). When the reaction was performed under basic conditions with K2CO3 in acetonitrile at RT for 15 hours, 9-hydroxyxanthenes 76 were achieved in good yields of 52–91% (Scheme [32]).[146]

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Scheme 32 Construction of xanthenes and hydroxyxanthenes at RT

Table 1 IC50 (μM) Values of Dibenzoxanthenes 77a–c toward HeLa Cancer Cells over 48 Hours

Dibenzoxanthene

Structure

IC50 (μM)

77a

50.6 ± 8.8

77b

26.9 ± 0.8

77c

26.6 ± 1.8

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#
# 3

Medicinal Perspectives on Functionalized Xanthene Derivatives as Anticancer Agents

This section aims to summarize the anticancer activities of functionalized xanthene derivatives.

Cervical cancer is the fourth most frequently occurring female cancer.[147] In clinical practice, a few drugs like carboplatin, cisplatin, and fluorouracil are used to treat cervical cancer.[148] [149] Nevertheless, these drugs include some limitations such as high cytotoxicity, low selectivity, bone marrow suppression, etc.[150] Hence, the current situation demands novel anticervical cancer drugs with low toxicity and high anticancer activity.[151] In pharmaceutical research, benzoxanthene derivatives have gained much attention recently due to their important biological activities, and a few of them were found to be new CCR1 receptor antagonists.[152] In 2024, Liu et al. prepared three novel dibenzoxanthenes 77a–c, and these compounds were investigated for their cytotoxicity against HeLa cells (human cervical carcinoma cell line) (Table [1]).[153] These compounds were able to generate singlet oxygen which was demonstrated by a DBPF (1,3-diphenylisobenzofuran) assay. The substituted compounds 77a–c efficiently inhibited HeLa cell cloning and migration, which was manifested by cell cloning and wound healing assays. The apoptotic mechanism revealed that compounds 77a–c regulated the Bcl-2 family protein, producing abnormal mitochondrial function. Apoptosis, ferroptosis, and pyroptosis are three pathways that are caused by compounds leading to cell death. The results revealed that dibenzoxanthenes displayed high cytotoxicity toward HeLa cells and low cytotoxicity toward normal cells. Hence, such compounds are expected to become powerful drugs for the therapy of cervical cancer.[153] Table [1] lists the IC50 values of dibenzoxanthenes 77a–c.[153]

The DNA (deoxyribonucleic acid) chain is familiar as the cellular target of different anticancer molecules.[154] The interaction of a drug with a DNA chain comprises a unique role in the pharmacological efficacy and the mechanism of action of a drug. A vital step toward ascertaining the functional mechanism of binding agents is the interpretation of how the complex influences both the structural and mechanical activities of DNA, providing guidance for more selective drug design.[155] In 2024, Chehardoli et al. constructed 17 novel xanthene-1,8-dione derivatives and assessed them for cytotoxic activities against the A549 (lung carcinoma) cell line by employing the MTT assay.[156] Among the synthesized derivatives, compound 78 exhibited the highest cytotoxic activity, with an IC50 value of 34.59 ± 1.84 μM compared to cisplatin (a platinum-based chemotherapy agent) (Figure [1]). Besides, the results of docking studies revealed that compound 78 could interact with DNA strands through the intercalating mechanism, which is the same as that of daunomycin (an antitumor antibiotic).[156]

In medicinal chemistry, xanthene derivatives are significant compounds due to their biological and pharmaceutical activities.[157] Thus, in 2024, Mohareb et al. aimed to explore the preparation of xanthenes and investigate the possibility of their application as anticancer agents.[158] Initially, 2,3-dihydro-1H-xanthen-1-one was prepared by the reaction of 2-hydroxybenzaldehyde and cyclohexan-1,3-dione. Next, fused xanthene derivatives, including pyrimidine, thiophene, thiazole, and isoxazole, were derived from the 2,3-dihydro-1H-xanthen-1-one, and these newly synthesized compounds were assessed for their cytotoxicity. The prepared compounds showed good antiproliferative effects and high activities via inhibition of the tested compounds, depending on the diversity of substituents and the nature of the heterocyclic rings.[158]

In 2024, Wang et al. developed a green methodology for the formation of highly functionalized xanthenes and evaluated 38 of the obtained xanthenes for antitumor activity.[116] The authors synthesized compound 81 (over 350 mg) because of its significant activity against osteosarcoma cells 143B and U2OS. Besides, two highly functionalized xanthene derivatives (79 and 83) displayed remarkable activity with IC50 values of <10 μM. No anti-osteosarcoma activity (IC50 > 50 μM) was observed by 4-substituted acyltetrahydroxanthenes possessing alkylated hydroxy groups, while xanthenes bearing free hydroxy groups (OH), including compounds 79–81, showed promising anti-osteosarcoma activity (IC50 = 2.41–19.79 μM) (Table [2]). Hence, the existence of two free OH groups may be vital for the activity. The presence of an acyl group at the C4 position is more beneficial for anti-osteosarcoma activity in comparison to the C2 position, as compound 81 showed superior activity compared to compound 82.[116]

Table 2 IC50 Values of Xanthenes 79–83 [116]

Xanthene

Structure

U2OS (IC50, μM)

143B (IC50, μM)

79

 4.85

 8.00

80

16.06

19.79

81

 2.41

 3.40

82

26.43

27.27

83

 2.56

 6.18

Recently, researchers designed selective cytotoxic agents to target cancer cells more specifically, to reduce side effects and to minimize effects on healthy cells.[159] In 2023, Abualhasan et al. synthesized several xanthene derivatives and investigated their anticancer activity against colon cancer cells, hepatic cancer cells, and HeLa cells.[160] Among the synthesized compounds, thioxanthene 86 showed remarkable inhibitory activity with an IC50 value of 9.6 ± 1.1 nM against Caco-2 (colon cancer cells), while xanthene 87 displayed strong potency against colon cancer cells with an IC50 value of 24.6 ± 8 nM compared to doxorubicin as a positive control (497 ± 0.36 nM) (Figure [1]). Besides, compound 85 displayed a good inhibition effect with an IC50 value of 161.3 ± 41 nM against Hep G2 (hepatocellular carcinoma) cells, while compound 87 had an IC50 value of 400.4 ± 56 nM (IC50 = 1060 ± 43 nM for doxorubicin as a positive control). Moreover, compound 84 exhibited significant inhibition activity with a percentage inhibition of 96% at a concentration of 0.2 μM.

In 2022, Ma et al. synthesized xanthene-sulfonated derivatives through C(sp3)–H sulfonylation and assessed them for their anticancer activity.[64] The MTT assay was applied to assess the in vitro cytotoxicity of all the synthesized xanthene derivatives against human cancer cell lines. It was evident from the results that most of the obtained compounds, e.g., 88 and 89, displayed good inhibitory activity toward tumor cell lines (Figure [1]).[64] The Bliss method was applied to calculate the final IC50 (a drug concentration killing 50% cells) values.

Globally, gastric cancer is one of the most deleterious cancers.[161] Millions of people die from this deadly cancer in Asia especially. Chemotherapy is one of the most common treatment methods for this cancer. However, this technique comprises many disadvantages like serious side effects, drug resistance, high cost, and a partial lack of targeting specificity.[162] Hence, it is urgent to develop new anticancer drugs with low toxicity and high efficiency that can be used in clinical treatment. Wang et al. synthesized three novel dibenzoxanthenes by oxidizing binaphthols and evaluated the molecular mechanisms of anti-antiproliferation efficacies toward gastric cancer cells in 2020.[163] The results revealed that compounds 90a–c showed strong antiproliferation activity toward gastric cancer cells (SGC-7901) (Figure [1]). These three dibenzoxanthenes showed lower IC50 values, from 0.30 ± 0.07 mM to 0.93 ± 0.10 mM, against SGC-7901 cells compared to other tumor cells like HepG2 (human hepatocellular carcinoma), A549 (human lung carcinoma), Eca-109 (human esophageal cancer), LO2 (human normal cell line), HeLa (human cervical carcinoma), indicating that dibenzoxanthenes are potential new therapeutic agents for SGC-7901 cells (Table [3]).

Table 3 IC50 Values of Dibenzoxanthenes 9a–c [163]

Dibenzoxanthene

IC50 (μM)

SGC-7901

HepG2

A549

Eca-109

LO2

HeLa

90a

0.30 ± 0.07

 5.40 ± 0.67

2.40 ± 0.17

1.00 ± 0.29

 12.0 ± 0.96

3.60 ± 1.26

90b

0.93 ± 0.10

21.68 ± 2.21

5.06 ± 0.20

3.19 ± 0.16

44.93 ± 3.16

6.22 ± 0.16

90c

0.56 ± 0.02

 6.90 ± 0.60

5.62 ± 0.34

3.19 ± 0.30

16.71 ± 0.82

3.57 ± 0.23

In 2020, Napoleon et al. demonstrated the regioselective synthesis of new tetrahydro-dimethyl-xanthene-diones via a three-component domino reaction using ascorbic acid. Twelve of these xanthene derivatives were evaluated for their anticancer activities, since derivatives of xanthene are known to have significant anticancer activities compared to xanthene itself.[164] The authors focused on these synthesized derivatives as an important series of PI3Kinase inhibitors. The obtained derivatives of xanthene-dione were examined for their antioxidant activities as oxidative stress plays a crucial factor in the improvement of cancer in cellular systems. Among the synthesized derivatives, relative percentages of anticancer properties were displayed by compounds 91 and 92: 90.56 ± 1.18 and 93.24 ± 1.80 against MCF-7 (ER-HER2), and 86.25 ± 1.25 and 89.74 ± 1.64 against BT474 (ER+HER2+) (Figure [1]).[164]

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Figure 1 Structures of functionalized xanthene derivatives as anticancer agents

Breast cancer is regarded as a serious global health challenge and is the most diagnosed class of cancer among females, with nearly 2.26 million cases recorded in 2020.[165] However, a complete cure has not been found yet. In 2019, Fimognari et al. synthesized a novel tamoxifen-xanthene hybrid having a rigid structural motif, due to the toxicity and chemoresistance of tamoxifen, and tested it to assess its anticancer activity.[166] Interestingly, compound 93, bearing a rigid xanthene skeleton, displayed the most promising activity with an IC50 value of 12.4 μM toward MCF-7 (breast cancer cell line), which is comparable to tamoxifen (10.4 μM) (Figure [1]).

Robbs et al. synthesized xanthene-naphthoquinone derivatives through the multicomponent reactions of aromatic aldehydes, dimedone, and lawsone, and assessed them for their anticancer efficacies against the SCC9 human oral cancer cell line.[167] Among the synthesized derivatives, compound 94 showed the most potent activity with an average IC50 value of nearly 1.45 μM against 3 different OSCC cancer cell lines: SCC4, SCC9, and SCC25; this value is about 90 times greater than that of carboplatin, which is employed as a standard anticancer compound (Figure [1]). It showed no hemolytic activity and about four times the selectivity versus normal NIH3T3 cells, with an IC50 value of ~5.0 μM.

Wang and co-workers generated a new polycyclic bridged-ring xanthene from acetylacetone and the parent dibenzoxanthene via a Michael addition and nucleophilic substitution.[168] Single-crystal X-ray diffraction was applied to confirm the structure of the product 95 (Figure [1]). An MTT assay was used to study cell viability in five tumor cell lines. Morphological analyses along with biochemical assays were used to investigate the cytotoxic activity of compound 95 against BEL-7402 cells. In a comet assay, considerable nuclear damage of BEL-7402 cells was noticed after cells were treated with compound 95, and this compound also caused DNA damage together with S-phase arrest in BEL-7402 cells. This work suggested that BEL-7402 was directly damaged by compound 95 through a ROS-mediated apoptotic mechanism.[168]

Yang and co-workers prepared N-substituted dibenzo[a,j]xanthene-3,11-dicarboxamides and evaluated them for their cytotoxicity.[169] An MTT assay was applied to study the in vitro antitumor activity of the prepared compounds. Potent inhibitory activity toward acute promyelocytic leukemia NB4 cells and human hepatocellular carcinoma cell lines (HepG2, SK-HEP-1, and SMMC-7721 cells) were exhibited by most of the synthesized compounds. Among the prepared compounds, xanthenes 96–98 displayed remarkable inhibitory activities, with IC50 values of 0.52 μM and 0.76 μM, respectively, against NB4 cells, which are much lower compared to that of 5.31 μM of the positive control As2O3 (Figure [1]).[169]


# 4

Conclusion

The xanthene skeleton occurs in a wide range of biologically active natural products and pharmaceuticals. In catalytic chemistry, xanthene derivatives are applied as multifaceted fluorescent materials and are also used in various fields like food industries, electrooptical devices, textile industries, and biomedical devices. Besides, xanthenes show a wide range of therapeutic and biological activities. Thus, several methodologies have been developed for the synthesis of xanthene derivatives. However, conventional protocols suffer from many demerits like prolonged reaction times, low yields, and hazardous conditions. To minimize environmental damage while optimizing efficiency, researchers are exploring new strategies in the field of sustainable chemistry. The most promising approaches are electrochemistry, mechanochemistry, photochemistry, and sonochemistry, which enable efficient syntheses of xanthene derivatives at room temperature under mild conditions, as showcased in this account. Moreover, the present account focuses on the synthesis of xanthene derivatives via important named reactions at room temperature. In addition, medicinal perspectives are provided on the anticancer activities of several xanthene derivatives. It is anticipated that the present account may guide synthetic organic and medicinal chemists working with O-heterocycles by highlighting procedures that can be performed under mild reaction conditions, paving the way for further improvements in this area.


# 5

List of Abbreviations

RT: room temperature

n Bu4NClO4: tetrabutylammonium perchlorate

HFIP: hexafluoroisopropanol

BHT: butylated hydroxytoluene

TFA: trifluoroacetic acid

MsOH: methanesulfonic acid

TBAI: tetra-n-butylammonium iodide

n Bu4NI: tetrabutylammonium iodide

LiClO4: lithium perchlorate

DCE: 1,2-dichloroethane

TFE: tetrafluoroethylene

TBAB: tetrabutylammonium bromide

n Bu4NPF6: tetrabutylammonium hexafluorophosphate

IC50: half-maximal inhibitory concentration

MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide


#
#

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

I would like to thank my father Tarani Majhi and his mother Sadeswari Majhi for their constant inspiration. I am also grateful to Triveni Devi Bhalotia College for providing infrastructure and other facilities.


Corresponding Author

Sasadhar Majhi
Department of Chemistry (UG & PG Dept.), Triveni Devi Bhalotia College, Kazi Nazrul University
Raniganj, West Bengal, 713347
India   

Publication History

Received: 29 January 2025

Accepted after revision: 27 February 2025

Article published online:
30 April 2025

© 2025. Thieme. All rights reserved

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Scheme 1 Construction of 9H-xanthen-9-yl amide derivatives using electrochemistry
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Scheme 2 Construction of amidated xanthenes using electrochemistry
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Scheme 3 Construction of xanthen-indole derivatives using electrochemistry
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Scheme 4 Construction of xanthene-9-sulfonated derivatives using electrochemistry
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Scheme 5 Construction of xanthen-9-amine derivatives using electrochemistry
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Scheme 6 Construction of 9-aryl-9H-xanthenes using electrochemistry
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Scheme 7 Construction of 9-alkyl-9H-xanthenes using electrochemistry
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Scheme 8 A plausible mechanism for the preparation of 9-alkyl-9H-xanthenes using electrochemistry
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Scheme 9 Construction of xanthen-9-azole derivatives using electrochemistry
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Scheme 10 Construction of N-alkoxy-N-xanthen-9-amide derivatives using electrochemistry
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Scheme 11 Construction of xanthene-1,8(2H)-diones using electrochemistry
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Scheme 12 Construction of dibenzo[a,j]xanthene and xanthene-dione derivatives using mechanochemistry
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Scheme 13 Construction of dibenzo[a,j]xanthene derivatives using mechanochemistry
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Scheme 14 A plausible mechanism for the synthesis of dibenzo[a,j]xanthene derivatives using mechanochemistry
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Scheme 15 Construction of benzo[h][1,3]dioxolo[4,5-b]xanthene-5,6(7H)-diones using mechanochemistry
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Scheme 16 Construction of tetrahydrobenzo[a]xanthen-11-ones using photochemistry
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Scheme 17 Construction of acyltetrahydroxanthenes and xanthene ent-myrtucomvalones E and F using photochemistry
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Scheme 18 Construction of substituted xanthen-11-ones using sonochemistry
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Scheme 19 Construction of dibenzo[b,i]xanthene-tetraones and dibenzo[a,j]xanthenes using sonochemistry
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Scheme 20 Construction of 1,8-dioxo-octahydroxanthenes using sonochemistry
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Scheme 21 A plausible mechanism for the formation of 1,8-dioxo-octahydroxanthenes using sonochemistry
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Scheme 22 Construction of octahydro-xanthene derivatives using sonochemistry
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Scheme 23 Construction of 9-methyl-9-arylxanthenes via intramolecular Friedel–Crafts alkylation
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Scheme 24 A plausible mechanism for the formation of 9-methyl-9-phenyl-9H-xanthene
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Scheme 25 Construction of substituted 9-arylxanthenes via intramolecular Friedel–Crafts cyclization
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Scheme 26 Construction of triazole-linked 1H-dibenzo[b,h]xanthenes via a Knoevenagel condensation
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Scheme 27 Construction of 9-functionalized xanthenes via Diels–Alder reactions
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Scheme 28 Construction of BN-substituted xanthenes at RT
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Scheme 29 Construction of xanthene/thioxanthene-indole derivatives at RT
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Scheme 30 A possible mechanism for the formation of xanthene/thioxanthene-indole derivatives at RT
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Scheme 31 Construction of 9-arylxanthene and 9-arylthioxanthene derivatives at RT
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Scheme 32 Construction of xanthenes and hydroxyxanthenes at RT
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Figure 1 Structures of functionalized xanthene derivatives as anticancer agents