Coumarin derivatives as promising anticancer drugs: a comprehensive review from synthesis to anticancer applications

Abstract

Natural products have long been an important source of anticancer drugs. Coumarins are a class of natural products that contain a core structure of benzo-α-pyranone and exhibit a wide range of pharmacological activities. In recent years, coumarin compounds have garnered increasing research attention as anticancer lead compounds. However, issues such as the low solubility, low bioavailability, and poor selectivity of natural coumarins have limited their clinical applications. Research into the synthetic chemistry of coumarins, which could address these issues, has received far less systematic attention than their biological mechanisms. Therefore, this review will explore both aspects in conjunction. This article summarizes the classical synthetic routes for the coumarin core and modern synthetic strategies for various coumarin derivatives, such as transition-metal-catalyzed cross-coupling, multicomponent and one-pot reactions, click chemistry, green and biocatalytic protocols, and metal complexation. Subsequently, the article discusses the mechanisms of action of the synthesized coumarin derivatives. Structure–activity relationship (SAR) data indicate that the derivatives incorporating nitrogen-containing heterocycles generally exhibit high potency and selectivity, with their IC₅₀ values typically ranging from the low micromolar to nanomolar ranges. Finally, the article discusses future design directions for coumarin derivatives, such as nanocarrier delivery, prodrug design, multi-target approaches, and computer-aided drug design. It is hoped that this article will enable readers interested in coumarin anticancer lead compounds to gain a comprehensive understanding of both their chemical synthesis and biological activity in a single resource, thereby providing guidance for the synthesis of coumarin anticancer derivatives.

This review covers the synthesis and biological evaluation of coumarin derivatives, summarizing classical and modern synthetic strategies, structure–activity relationships, and anticancer mechanisms.

1. Introduction

Cancer remains one of the most serious public health challenges of the 21st century, with nearly 20 million new cancer cases and 9.70 million deaths worldwide in 2022. With the aging of the population and increasing exposure to risk factors, it has been estimated that more than 35 million new cancer cases would be diagnosed worldwide every year by 2050.¹ Despite remarkable progress in treatment methods, such as chemotherapy, radiotherapy, immunotherapy, and targeted drugs, drug resistance, systemic toxicity, and an imbalance in the efficacy-toxicity ratio still seriously restrict the clinical effects.² Therefore, there is an urgent need to develop new anticancer drugs with high efficiency, high selectivity, and good safety. Natural products are an important source of anticancer drugs, and a variety of classical anticancer drugs are derived from plants.³ Among the rich library of natural product compounds, coumarin is a potential anticancer drug candidate due to the structural plasticity of its benzo-α-pyranone skeleton and its multi-target pharmacological activities.⁴

Coumarin is widely found in medicinal plants, such as in those of the Apiaceae, Rutaceae, and Fabaceae families. Natural compounds such as osthole, umbelliferone, scopoletin, and imperatorin exhibit rich biological activities. A large number of studies have shown that coumarin and its derivatives could play anti-proliferative roles, induce apoptosis, regulate oxidative stress, and reverse multidrug tolerance in a variety of cancer models, covering breast cancer, colorectal cancer, lung cancer, leukemia, and other tumor types.⁵

The traditional Pechmann, Perkin, and Knoevenagel condensation reactions are the cornerstone of the construction of the coumarin core. However, in order to meet the needs of modern drug discovery for molecular diversity and green synthesis, emerging methods, such as metal-catalyzed cross-coupling, multi-component and one-pot reaction, microwave/ultrasound assistance, and sustainable chemical technology, have been widely developed.⁶ These methods not only accelerate the generation of coumarin derivative libraries but also provide the possibility of fine-tuning the pharmacophore checkpoint and improving the physical and chemical properties of drugs. More importantly, the current reviews on the anticancer activity of coumarins mostly focus on the pharmacological mechanism and lack a systematic review of the synthetic strategies of coumarin derivatives.

In this context, this review introduces the framework and classification of coumarins, focuses on combining classical and modern synthetic strategies, and further explores how synthetic chemistry can help molecular functionalization and anticancer activity optimization. Finally, we analyze the bottlenecks and future directions of current research, aiming to provide a clear chemical-biological bridge for the basic research and new-drug development of coumarins.

2. Core structure and biological activity of coumarin

Coumarins are a class of natural aromatic lactones with a core structure of benzo-α-pyranone (chromen-2-one). They are formed by the conjugation of a benzene ring with an α-pyranone ring.⁷ According to the type of fused ring on the basic framework, the type of substituent, and the substitution position, natural coumarins can generally be divided into four categories: simple coumarins, furanocoumarins, pyranocoumarins, and other complex coumarins⁸ (Fig. 1).

Fig. 1. Classification and main sources of natural coumarins.

2.1. Simple coumarins

Simple coumarins refer to a class of compounds that only undergo substitutions on the parent nucleus of benzo-α-pyrone and are not fused with other ring systems.⁹ The main substitution checkpoints are concentrated at the C-6, C-7 and C-8 positions, and the common substituents include hydroxyl, methoxy, and carboxyl. Representative compounds, such as umbelliferone, esculetin, and scopoletin, are widely distributed in Apiaceae and Rutaceae plants.¹⁰ These compounds exhibit great antioxidant, anti-inflammatory and antitumor activities and serve as the basic parent nucleus for the study of coumarin-derived drugs.

2.2. Furanocoumarins

Furanocoumarins, which are fused to a furan ring on the benzene ring of the coumarin parent core, can be further divided into two types: linear and angular.⁹ The furan ring of linear furanocoumarins is connected to the C-6 and C-7 positions, forming a coplanar tricyclic structure; angular furanocoumarins are connected through the C-7 and C-8 positions to form a “broken-line” fused structure. Furanocoumarins are widely found in Psoralea, Peucedanum and Citrus plants and demonstrate good photosensitivity, anticancer properties and immunomodulatory activities.¹¹

2.3. Pyranocoumarins

Pyranocoumarins refer to a class of compounds that are fused to a pyran ring (or dihydropyran ring) on the benzene ring of the coumarin parent nucleus, forming an additional oxa six-membered ring.⁹ They are often generated by the fusion reaction of the phenolic hydroxyl group at the C-7 position and the isopentenyl group at the C-6 or C-8 position. Representative compounds, including xanthyletin and seselin, are common in Rutaceae and Apiaceae plants. Most of these coumarins exhibit strong hydrophobicity and good cell-membrane permeability, and they show activities in antitumor, antibacterial and neuroprotective assays.¹²

2.4. Other complex coumarins

This class includes some coumarin derivatives with more complex structures, which are mainly manifested by the introduction of aryl or acyl groups at the C-3 or C-4 positions, the formation of dimer or trimer structures, and heterocyclic fusions, such as benzocoumarins.⁹ Most of these compounds exhibit strong enzyme inhibitory or cytotoxic activities. Some are synthetic products, and others are naturally found in plants, such as Calophyllum and Ferula. In recent years, they have been widely used in anticancer, antiviral and molecular probe research.¹³

2.5. Source of natural coumarin and its anticancer activity

To explore the publication trends of coumarin derivatives in the context of anticancer activity, we retrieved data from the Science Citation Index Expanded database of the Web of Science Core Collection. The search was performed using the keywords “coumarin” and “biological activity” (Fig. 2B), as well as “coumarin” and “cancer” (Fig. 3B), covering the period from the database inception to the present. As shown in Fig. 2B, a total of 3223 articles on coumarin and its biological activities were identified. Among them, the antibacterial (antibacterial, antifungal, antimicrobial) and antioxidant activities received relatively extensive attention in the early stage. There were 843 articles directly focusing on the anticancer activity, accounting for approximately 26.16% of the total; the steady increase in publications in this field reflected the rising recognition of coumarin derivatives as promising anticancer candidates. It is evident that the research on coumarin derivatives and their anticancer potential has grown substantially over the past decade.

Fig. 2. . Network co-occurrence of all literature in the Web of Science based on the following keywords: (A) coumarin and (B) biological activity.

Fig. 3. . Network co-occurrence of all literature in the Web of Science based on the following keywords: (A) coumarin and (B) anti-tumor activity.

The benzo-α-pyrone scaffold of the coumarin core endowed these compounds with diverse and significant biological activities, among which their anticancer properties were particularly prominent.¹⁴ A multitude of natural coumarin monomers isolated from medicinal plants—such as Apiaceae, Rutaceae, Daphne spp., and Compositae—had been validated by modern pharmacological investigations as potential antitumor lead structures. Owing to their structural diversity and unique capacity to engage multiple biological macromolecules, these natural products exerted synergistic, multi-targeted antineoplastic effects by disrupting key processes in cancer cell proliferation, survival, migration, and drug resistance.¹⁵

Natural coumarins effectively inhibited unchecked cancer-cell proliferation by inducing cell-cycle arrest. Crucially, many coumarins modulated the expression of Bcl-2/Bax family proteins and activated caspase cascades, thereby triggering intrinsic and extrinsic apoptotic pathways and promoting programmed cell death.¹⁶ In addition, coumarins regulated intracellular redox homeostasis: they protected normal cells through intrinsic antioxidant activity, yet in certain contexts, they selectively induced the excessive accumulation of reactive oxygen species to eliminate malignant cells. Notably, daphnetin was shown to reverse tumor multidrug resistance and significantly enhance the efficacy of traditional chemotherapeutics by inhibiting drug-efflux pumps such as P-glycoprotein.¹⁷ Furthermore, several furanocoumarins exhibited photosensitizing activity, offering natural candidates for photodynamic therapy.

Table 1 summarizes representative natural coumarins, their sources, and their anticancer activities. Natural coumarins suffer from issues such as limited sources, difficulty in purification, and poor selectivity in vivo. In contrast, chemical synthesis allows for the construction of natural coumarin derivatives through rational synthetic routes, thereby optimizing activity, enhancing selectivity, and reducing toxicity. These chemical synthetic routes contribute to the development of a new generation of coumarin-based anticancer drugs.¹⁸

Table 1. Natural coumarins with anti-tumor activity.

Coumarin compound	Source plant (family, genus; representative species)	Anticancer activity (target/mechanism, cancer type, experimental model)	Categories	Reference
Scopoletin	Asteraceae (Compositae), Artemisia genus; Artemisia annua (sweet wormwood)	Cervical cancer	Simple coumarins	102
Esculetin	Oleaceae, Fraxinus genus; Fraxinus rhynchophylla (Korean ash)	Gastric cancer, liver cancer, and pancreatic cancer	Simple coumarins	103
Daphnetin	Thymelaeaceae, Daphne genus; Daphne genkwa (lilac daphne)	Human melanoma; enhances the anticancer effects of anthracycline chemotherapeutic drugs	Simple coumarins	104
Umbelliferone	Apiaceae (Umbelliferae), Ferula genus; Ferula communis (giant fennel)	Hepatocellular carcinoma (HCC), pancreatic cancer, gastric cancer, etc.	Simple coumarins	105
Imperatorin	Apiaceae (Umbelliferae), Angelica genus; Angelica dahurica (Dahurian angelica)	Inhibits colon cancer	Linear furanocoumarins	106
Isoimperatorin	Apiaceae (Umbelliferae), Angelica genus; Angelica dahurica (Dahurian angelica)	Inhibits gastric cancer	Linear furanocoumarins	107
Osthole	Apiaceae (Umbelliferae), Cnidium genus; Cnidium monnieri (Monnier's snowparsley)	Cervical cancer (HeLa cells); activity against colon cancer and lung cancer	Typical furanocoumarins (benzyl substitution)	108
Bergapten (5-methoxypsoralen)	Rutaceae, Citrus genus; Citrus bergamia (bergamot orange)	Inhibits colon cancer	Linear furanocoumarins	109
Xanthotoxin (8-MOP)	Apiaceae (Umbelliferae), Ammi genus; Ammi majus (Bishop's weed)	Neuroblastoma and colon cancer	Linear furanocoumarins	110
Angelicin	Apiaceae (Umbelliferae), Angelica genus; Angelica archangelica (garden angelica)	Liver cancer	Angular furanocoumarins	111
Scoparone	Asteraceae (Compositae), Artemisia genus; Artemisia capillaris (Yin Chen Hao)	Prostate cancer	Simple coumarins	112

Fig. 3B summarizes the keyword co-occurrence network from the coumarin literature. The results indicate that coumarin and its derivatives occupy a central position in the field of anticancer coumarin research. The design and synthesis of coumarin derivatives have become key strategies for enhancing the anticancer potential of coumarin. Coumarin derivatives are associated with mechanisms such as apoptosis induction, modulation of oxidative stress, cell cycle arrest, NF-κB inhibition, and autophagy regulation. In the following sections, we will conduct a systematic analysis of the synthetic methods for these derivatives and discuss their associated antitumor mechanisms.

3. Synthesis method of coumarin mother nucleus

3.1. Classical synthetic methods

3.1.1. Perkin synthesis

The Perkin synthesis is one of the earliest methods for constructing the coumarin core. In 1868, Perkin successfully synthesized coumarin by refluxing salicylaldehyde with acetic anhydride (CH₃COOCOCH₃) at 180 °C, catalyzed by sodium acetate (CH₃COONa). The generally accepted reaction mechanism involves the sodium acetate-catalyzed reaction of salicylaldehyde with acetic anhydride to form o-hydroxycinnamic acid as an intermediate. The subsequent intramolecular condensation (cyclization) of this intermediate yields the coumarin core structure¹⁹ (Fig. 4).

Fig. 4. . Synthetic strategy of the coumarin parent nucleus.

However, the traditional Perkin method suffers from drawbacks, such as high reaction temperature, long duration, numerous side reactions, and low yield. To address these issues, various modifications have been introduced to improve the efficiency of the classical Perkin reaction. These include the use of alternative catalysts, optimization of reactant stoichiometry, and the application of microwave irradiation to accelerate reaction rates and increase yields.^20,21 For instance, John Kallikat et al. synthesized a series of coumarin derivatives using aromatic aldehydes or ketones with 2-cyanoacetic acid, catalyzed by triethylamine in a solvent mixture of propylphosphonic anhydride and n-butyl acetate.²⁰ Wang et al. reported the synthesis of 3-arylcoumarins (featuring substituents on the coumarin core) via the Perkin reaction using substituted salicylaldehydes and arylacetic acids, catalyzed by sodium acetate in acetic anhydride.²² Compared to conventional heating, the aforementioned improved strategies effectively overcome the limitations of the original Perkin method. They offer enhanced yields, clean reaction profiles, and reduced reaction times, establishing this approach as an efficient route for synthesizing both the coumarin core and its derivatives.

3.1.2. Knoevenagel synthesis

As an improvement over the Perkin method, Knoevenagel was proposed in 1894 for the synthesis of the coumarin core via the reaction of salicylaldehyde with active methylene-containing acetic acid derivatives under weak base catalysis²³ (Fig. 4). This method is particularly suitable for salicylaldehydes bearing electron-donating substituents. Subsequent studies identified other effective catalysts, including pyridine, piperidine, and choline chloride, which also improved yields.²⁴ The Knoevenagel method typically offers advantages such as low reaction temperatures, short reaction times, and high yields.

Recent refinements of this method continue to emerge. Khan et al. successfully synthesized 3-substituted coumarin derivatives in ethanol using salicylaldehyde and α-substituted ethyl acetates, catalyzed by phenyliodine(iii) diacetate (PhI(OAc)₂).²⁵ This method is environmentally friendly and operationally simple, and it features mild conditions, broad substrate scope, good functional group tolerance, and high yields. Shakil et al. prepared coumarin compounds by reacting salicylaldehyde with diethyl malonate in ethanol at 10 °C for 24 hours using zinc oxide (ZnO) as the catalyst.²⁶ A key advantage is the reusability of the ZnO catalyst (prepared in methanol) for multiple cycles, reducing costs. Morris et al. demonstrated the utility of the Knoevenagel method in synthesizing complex coumarins.²⁷ They condensed 4-(diethylamino) salicylaldehyde with ethyl nitroacetate to obtain 3-nitro-7-(diethylamino)coumarin. This intermediate was then subjected to nitro-group reduction with SnCl₂, followed by diazotization and azido substitution, yielding 3-azido-7-(diethylamino)coumarin.

The Knoevenagel synthesis is one of the most commonly used and efficient classical methods for coumarin synthesis, particularly for 3-substituted derivatives, owing to its relatively mild conditions, high yields, and broad substrate adaptability, especially for compounds with active methylene groups. The development of novel catalysts has further enhanced its efficiency and sustainability.

3.1.3. Wittig synthesis

The Wittig synthesis involves the reaction of a substituted salicylaldehyde with (ethoxycarbonylmethylene) triphenylphosphorane (the ethoxycarbonyl-stabilized phosphorus ylide) in a Wittig reaction (Fig. 4). This first generates an ethyl *o*-hydroxycinnamate intermediate. Subsequently, this ester intermediate undergoes intramolecular ester exchange (or ester condensation) and cyclization under specific conditions (heating, light irradiation, or acid catalysis) to afford the coumarin core.²⁸ This method generally proceeds under mild conditions and provides high yields. Pierre Neveu et al. brominated 2,4-dihydroxybenzaldehyde in acetic acid to obtain 3,5-dibromo-2,4-dihydroxybenzaldehyde (60% yield).²⁹ This compound was then reacted with the phosphorus ylide in toluene under reflux for 3 hours to yield ethyl 3,5-dibromo-2,4-dihydroxycinnamate (60% yield). Final cyclization under laser irradiation furnished 6,8-dibromo-7-hydroxycoumarin. This method offers good yields, operational simplicity, and mild conditions. H. Ishii et al. dissolved 3,6-dimethoxysalicylaldehyde and the phosphorus ylide in N,N-diethylaniline and heated the mixture under reflux at 215 °C for 30 minutes, achieving 5,8-dimethoxycoumarin in an excellent yield of 91%.³⁰

The Wittig synthesis provides an efficient route for constructing the C3–C4 double bond of coumarins. It is particularly advantageous when complex or sensitive substituents need to be pre-introduced onto coumarin's benzene ring. Its strengths lie in relatively mild conditions, good stereoselectivity, typically forming the trans olefin intermediate, and high yields, making it a powerful tool for synthesizing coumarins with specific substitution patterns.

3.1.4. Pechmann synthesis

The Pechmann reaction, first reported by Hans von Pechmann, gives the coumarin core in a single step³¹ (Fig. 4). This reaction involves the condensation of phenol or its derivatives with β-keto esters, catalyzed by Lewis acids, such as H₂SO₄, BF₃·Et₂O, or AlCl₃. The method is simple and often gives good yields, but it also generates considerable by-products and needs large amounts of acidic catalysts.

To get around these issues, many newer studies have looked for cleaner, more efficient catalysts. Sun et al. used PBr₃ as a Lewis acid.³² Bandgar et al. made 3-carboxycoumarins from Meldrum's acid derivatives under microwave irradiation with natural kaolin catalysts (EPZ10 and EPZG).³³ Zhang et al. reported a choline-based ionic liquid that is cheap, reusable, and effective for condensing resorcinol with β-keto esters.³⁴ Samadizadeh et al. prepared a magnetic nanoparticle-supported sulfonic acid (MNESA) that worked well for phenol and ethyl acetoacetate at 90 °C without solvent; the catalyst could be separated easily and reused at least five times.³⁵

Overall, the Pechmann synthesis remains popular because the starting materials are cheap and easy to handle, the operation is straightforward, and the cyclization is efficient. Current work is moving toward recyclable solid acids or ionic liquids that avoid the corrosion, waste, and tedious work-up of traditional strong acids, making the process greener and more atom-economical.

3.2. Expansion and innovation in core synthesis strategies

Several new routes to the coumarin core have been reported in recent years, moving beyond the classical Pechmann and related condensations. These new methods often rely on different reaction mechanisms or unusual starting materials, and some of them allow substituents to be introduced directly during ring formation.

Chandra et al. developed a one-pot synthesis of benzo[h]coumarins from α- or β-naphthols, affording a fused core with a 4-ester group in 31–75% yield.³⁶ The reaction is simple, runs under mild conditions, and tolerates a range of substrates.

A more mechanistically distinct approach uses Pd-catalysed C–H activation. Trost et al. reported that phenols and propiolate esters underwent intermolecular annulation to form the coumarin core in one step.³⁷ The active palladium species is still debated; Trost favours Pd⁰, while Kitamura et al. propose Pd²⁺ for a related angelicin synthesis,³⁸ but both versions give high atom economy. This route bypasses the usual condensation step and constructs the ring via direct C–H functionalisation.

Microwave irradiation can also speed up the classic Pechmann reaction. Liu et al. used zirconium(iv) sulfate tetrahydrate to catalyse the condensation of resorcinol with ethyl acetoacetate under microwave irradiation (500 W) for 12 min, affording 7-hydroxy-4-methylcoumarin in 87.5% yield.³⁹ This is essentially a green, accelerated version of the Pechmann process.

For 4-substituted coumarins, Du et al. found that cinnamic acid derivatives can be oxidatively cyclised using a PIDA/I₂ system, without any transition metal.⁴⁰ The procedure is straightforward and offers a mild route to 4-substituted cores that are otherwise difficult to access. Higashida et al. showed that even unactivated polycyclic aromatic hydrocarbons can be converted directly into coumarins via TiO₂-photocatalysed oxidative aromatisation in acetonitrile.⁴¹ This is a radical departure from phenol- or aldehyde-based approaches, greatly expanding the range of possible starting materials.

These methods complement the classical Pechmann synthesis by offering alternative mechanisms, relatively mild conditions, or access to different substitution patterns.

3.3. Rationale for synthetic route selection

Practical routes for coumarins would typically be based on considerations of chemoselectivity, tolerance of functional groups, generality, and synthetic efficiency. For example, since the intended target contains a coumarin core, access to this core scaffold would be readily available through Pechmann condensation, which affords access to 4-substituted coumarins from phenols in one step using β-keto esters. However, this method may require strong acids and heat, which could prevent its use in acid-sensitive substrates. Alternatives could include the Knoevenagel condensation, which proceeds under relatively mild conditions and is considerably tolerant of different substrate variations arising from aldehydes and active methylenes. The alkene side chain could be formed using the Wittig reaction, which would provide the expected stereochemistry, providing primarily trans-alkenes when using stabilized ylides. On the other hand, the Perkin reaction would likely be ruled out early due to the presence of hydroxyl groups on the intended target, since the required use of anhydrides and heat would result in decomposition. For the late-stage diversification of biaryl linkages, such as C-8, on coumarins, palladium-catalyzed Suzuki–Miyaura cross-coupling reactions would allow access to a diverse library of compounds without impacting sensitive lactone groups. Negishi or Stille cross-coupling variants would likely be eliminated from consideration based on the required moisture-free conditions for organozinc reagents and the generation of toxic by-products from organotin reagents. The Suzuki reaction is also advantageous due to the ready availability of many boronic acids, as well as mild reaction conditions that are even compatible with aqueous workups.

4. Modern synthesis strategies of anticancer coumarin derivatives

Modern synthetic chemistry has moved beyond the mere construction of the coumarin core: contemporary strategies emphasize late-stage diversification, atom economy, sustainability, and direct access to hybrid architectures that combine the coumarin scaffold with other pharmacophores.⁴² These capabilities are especially valuable for anticancer lead discovery, where the rapid generation of focused libraries and the facile installation of polar, lipophilic or recognition motifs are critical for tuning potency, selectivity and ADME properties. Below, we summarize six contemporary synthetic avenues that have most directly enabled the discovery and optimization of anticancer coumarins (Fig. 5).

Fig. 5. Synthetic strategies of typical coumarin derivatives.

4.1. Transition-metal-catalyzed approaches

The application of transition-metal catalysis has reshaped the synthetic landscape of coumarin derivatives. This paradigm empowers the precise installation of diverse functional groups to construct intricate, fused ring systems.⁴³ Among the most impactful methods are palladium-catalyzed cross-coupling reactions, Suzuki–Miyaura, Sonogashira, and Heck reactions, which allow the direct functionalization of the coumarin core with aryl or alkyne units. Transition-metal-catalyzed cross-coupling reactions have been widely employed to install diverse aryl or heteroaryl groups at key positions of the coumarin core. Trost et al. developed a palladium-catalyzed atom-economic approach, in which phenols and alkynoates underwent cyclization through net C–H functionalization to furnish coumarins, providing a direct route to substituted coumarin frameworks without requiring prefunctionalized aromatic substrates.³⁷ These transformations introduce lipophilic or electron-deficient heteroaryl groups at key positions, modulating bioactivity.⁴⁴

Beyond traditional cross-coupling, Pd- or Ni-catalyzed C–H activation/annulation strategies further expand structural diversity by enabling the construction of fused aromatic systems.⁴⁵ For instance, the one-step assembly of the pyrone ring via the Pd-carbonylation of ortho-hydroxyaryl enones with alkynes provides access to 3,4-disubstituted coumarins, which are inaccessible by classical methods. The strategic value of these metal-catalyzed approaches is underscored by structure–activity relationship (SAR) analyses, which highlight the critical influence of substituents on cytotoxic efficacy. In coumarin–artemisinin hybrids, the nature and position of substituents on the coumarin moiety can significantly influence anticancer activity, as demonstrated by structure–activity relationship studies on related hybrid systems.⁴⁶ Such modifications are readily achieved through transition-metal-catalyzed reactions, including chlorination or cross-coupling with methyl boronic esters, enabling precise late-stage functionalization. The installation of groups such as 3-chlorophenyl or 4-methylbenzyl at the C-3 position can improve cellular uptake and target engagement, illustrating how transition-metal catalysis provides a versatile platform for generating coumarin analogues with optimized anticancer profiles through strategic structural elaboration.⁴⁷

4.2. Multicomponent and one–pot reactions

Multicomponent reactions (MCRs) are used to construct more complex coumarin-based hybrids using transition-metal-mediated methods. MCRs combine the coumarin skeleton with heterocyclic moieties in a single step to enhance anticancer activity.^48,49 For example, various coumarin–imidazo [1,2-a] pyridine hybrids have exhibited strong antiproliferative activity against multiple cancer cell lines.⁵⁰

The use of ultrasound-assisted MCRs can further enhance the green characteristics of these reactions. Alshabanah et al. reported a three-component synthesis of coumarin derivatives using 4-hydroxycoumarin derivatives, aryl isothiocyanates, and ammonium thiocyanate, affording C-3-functionalized coumarins containing nitrogen- and sulfur-containing heterocyclic motifs.⁵¹ Chitosan-grafted poly(vinylpyridine) was used as a catalyst to successfully synthesize various coumarin derivatives that exhibited good cytotoxic activity in HepG2 liver cancer cells.⁵² This method enabled the efficient functionalization of the C-3 position of coumarin. MCRs provide a simple and efficient route for introducing multiple functional groups into the coumarin core, yielding a variety of coumarin derivatives containing imidazole, pyrazole, or thiadiazole rings.⁵³

4.3. Click chemistry and hybrid conjugations

Building on the theme of efficient molecular assembly, click chemistry—particularly copper(i)-catalyzed azide–alkyne cycloaddition (CuAAC)—has been extensively employed to construct coumarin-based hybrids via stable 1,2,3-triazole linkers.⁵⁴ This modular approach conjugates coumarins with various pharmacophores, such as artemisinin or heterocyclic motifs, enhancing anticancer efficacy through multifunctional design. In one study, coumarin–artemisinin hybrids prepared via CuAAC showed potent activity against colon and breast cancer cells under various conditions.⁵⁵ The substituents on the coumarin scaffold have been shown to influence ROS inhibitory activity and cytotoxicity profiles in cancer cells.⁵⁶

Expanding the scope of this strategy, CuAAC also facilitates the generation of fully synthetic coumarin–triazole libraries. Coumarin–1,2,3-triazole hybrids have been extensively explored as leading-edge anticancer agents, with structural variations at the triazole linker enabling the fine-tuning of activity across different cancer cell lines,⁵⁷ demonstrating the versatility of this approach. Bioisosteric replacement and triazole-tethering strategies have also been applied to coumarin derivatives to improve their pharmacological profiles for anticancer therapy.⁵⁸ Thus, CuAAC represents an efficient strategy for developing multifunctional coumarin hybrids with improved anticancer profiles and multi-target mechanisms.

4.4. Green and sustainable strategies

In parallel with developments in reaction design, the integration of green chemistry principles has significantly enhanced the sustainability and efficiency of coumarin synthesis. Microwave-assisted reactions represent a major advance, as exemplified by CuAAC processes in water or ethanol, which reduce reaction times from hours to minutes. This approach was effectively applied in the preparation of 32 coumarin–triazole hybrids, improving efficiency while minimizing energy use and waste.^59,60

Ultrasound has also emerged as a powerful tool for promoting organic reactions under mild conditions. A solvent-free, ultrasound-promoted synthesis of 3-azolylcoumarins using a chitosan-based catalyst afforded the target products in high yields, showing promising anticancer activity.⁵¹ Microwave-assisted synthesis provides another efficient approach. Bandgar et al. reported a solvent-free, one-pot microwave-assisted synthesis of coumarin-3-carboxylates, demonstrating that microwave irradiation can significantly shorten the reaction time while enabling the rapid construction of functionalized coumarin derivatives.³⁷ Microwave-assisted conditions have also been successfully applied to the synthesis of triazole-containing heterocycles.^61,62 In addition to ultrasound and microwave methods, solvent-free and recyclable catalytic systems have been developed to improve the sustainability of coumarin synthesis. Cholinium ionic liquids have been employed in solvent-free Pechmann condensation as recyclable catalysts, while magnetic nanoparticle-supported catalysts have enabled the efficient preparation of coumarin derivatives under mild conditions.^34,35

These methodologies demonstrate that green techniques not only improve environmental compatibility but also often enhance yield and purity, proving that sustainability and drug development are mutually achievable goals.

4.5. Biocatalytic and enzyme-mediated methods

Beyond conventional and green chemical methods, biocatalysis provides a selective and sustainable route for modifying coumarin scaffolds, introducing chiral or polar groups that are challenging to access via conventional synthesis.⁶³ Recent advances include enzymatic glycosylation, where engineered glycosyltransferases attach carbohydrate units to coumarin cores under mild aqueous conditions.⁶⁴ The resulting glycosides can serve as prodrugs, with enzymatic cleavage in vivo releasing the active aglycone, thereby improving solubility, bioavailability, or targeting.⁶⁵

The potential of biocatalysis extends beyond glycosylation to other strategic modifications. Regioselective hydroxylation by cytochrome P450s or peroxidases, along with reductions by reductases, can introduce functional groups that modulate target interactions.⁶⁶ Although applications in anticancer coumarin development are still emerging, biocatalysis offers a route to stereochemically pure and structurally diverse derivatives.⁶⁷ This approach complements synthetic strategies by providing efficient and green pathways to novel coumarin analogues with potential improvements in tumor selectivity and metabolic stability, representing a promising frontier in coumarin-based drug discovery.⁶⁸

4.6. Metal complexation and coordination chemistry

A particularly innovative approach in coumarin-based drug design involves coordinating coumarin derivatives to metal ions, creating hybrid systems that merge the bioactivity of coumarins with the mechanistic diversity of metal centers.⁶⁹ Palladium(ii) complexes with 4-hydroxycoumarin-derived ligands (C1, C2) exhibited markedly higher cytotoxicity than the free ligands against various cancer cell lines. Complex C1 induced apoptosis in HeLa cells and was proposed to target receptor tyrosine kinases, demonstrating the therapeutic potential of this strategy.⁷⁰

Coumarin–benzimidazole hybrids represent an important class of compounds that have been extensively explored in medicinal chemistry.⁷¹ In related studies, coumarin-substituted benzimidazolium salts have been investigated for their cytotoxic effects against human prostate and ovarian cancer cells.⁷² More broadly, mitochondria play a central role in the regulation of programmed cell death, a process frequently exploited by metal-based anticancer agents.⁷³ Ruthenium(ii)–coumarin complexes also displayed high potency and selectivity, exemplified by a complex with an IC₅₀ of 0.30 µM against NCI–H460 lung carcinoma cells through telomerase inhibition.⁵⁴ These examples illustrate how metal coordination can synergistically enhance coumarin bioactivity, introducing DNA-binding, redox-modulating, or enzyme-inhibiting capabilities while improving target specificity and solubility.⁷⁴ The continued exploration of metal–coumarin complexes promises to yield novel anticancer agents with unique mechanisms of action.⁷⁵

5. Anticancer application of coumarin derivatives

5.1. Anti-proliferative effects (cell-cycle arrest)

Coumarin derivatives can inhibit uncontrolled cell proliferation by interfering with the cell cycle. The cell cycle controls cell growth and division and is divided into four distinct phases: G₁ phase (interphase 1), S phase (DNA synthesis), G₂ phase (interphase 2), and M phase (mitosis). Progression through these phases is regulated by cell cycle protein-dependent kinases and their regulatory cyclins, whose activity is in turn regulated by endogenous CDK inhibitors. The dysregulation of the cell cycle is a key feature of cancer. Inducing cell-cycle arrest is an important strategy for cancer treatment.

This is often achieved through the nuanced modulation of cyclins, CDKs, and endogenous CDK inhibitors, effectively putting the brakes on cancer cell division⁷⁶ (Fig. 7). The structural features of coumarins, such as hydroxylation patterns and lipophilic substituents, play a critical role in determining their specificity for different cell cycle phases.¹⁸ For instance, natural coumarins, such as esculetin-8-O-β-arabinoglucoside (EAG) and fraxetin, have been shown to induce G₀/G₁ and G₂/M phase arrest in Jurkat leukemia and colon cancer cells, respectively.⁷⁷ These effects are often mediated by the upregulation of CDK inhibitors, such as p21Waf1/Cip1 and p27Kip1, accompanied by the downregulation of cyclin B and D expression.⁷⁸ The presence of an ortho-hydroxy group enhances the production of reactive oxygen species in mitochondria, leading to G₂/M phase arrest, whereas a glycosyl group promotes cellular uptake and induces G₁ phase arrest. A 4-hydroxycoumarin hybrid containing a thiazole moiety induces cell cycle arrest by activating the p53/p21 pathway while simultaneously inhibiting kinase activity.^79,80 Additionally, hydrophobic side chains at the C-3 position stabilize interactions with cell-cycle regulators, shifting arrest toward the G₁ phase. Thus, strategic structural modifications enable coumarins to selectively disrupt cell-cycle progression and promote apoptotic sensitization in cancer cells.⁸¹

Fig. 7. Coumarin exerting its anticancer effects by regulating the cell cycle and ROS metabolism.

5.2. Apoptosis induction and ROS modulation

The apoptotic effects of coumarin derivatives involve both endogenous and exogenous pathways, in which reactive oxygen species (ROS) play a central role⁸² (Fig. 7). Natural coumarins, such as EAG and flasetin, can elevate intracellular ROS levels, leading to mitochondrial depolarization, cytochrome c release, and caspase-3 activation, thereby inducing apoptosis.⁸³ Flasetin also increases calcium-ion influx and oxidative stress in colon cancer cells, thereby triggering caspase-dependent apoptosis. Synthetic hybrids, such as coumarin–artemisinin conjugates, enhance mitochondrial ROS production through domains with redox activity.⁸⁴ Hydroxyacid-functionalized coumarins can act as histone deacetylase (HDAC) inhibitors while simultaneously inducing p21 expression and triggering apoptosis.⁸⁵ Compared to normal cells, cancer cells have higher basal ROS levels and are therefore more susceptible to coumarin-induced oxidative stress. For example, flavestin generates more ROS in colon cancer cells than in normal colon cells.⁸⁶ Overall, coumarin-induced apoptosis results from the combined action of the Bax/Bcl-2 pathway and ROS-mediated stress pathways.⁸⁷

5.3. Inhibition of angiogenesis and metastasis

Coumarins inhibit tumor progression by specifically targeting and inhibiting angiogenesis and metastasis. Auraptene is a pre-acylated coumarin. By downregulating the matrix metalloproteinases, MMP-2 and MMP-9, auraptene reverses the epithelial–mesenchymal transition and inhibits migration and invasion in melanoma models. This leads to decreased N-cadherin expression and increased E-cadherin expression.⁸⁸ The terpenoid chain of auraptene enhances its lipophilicity and membrane permeability, thereby strengthening its interaction with protease targets.

Decursin inhibits the stability of hypoxia-inducible factor-1α and VEGF signaling, thereby reducing microvascular density in tumor xenografts. Its anti-angiogenic effect is associated with its large angeloyl group, which may facilitate binding to prolyl hydroxylase or ubiquitin ligase complexes.⁸⁹ In addition, some coumarin triazole heterocyclic compounds and their dimers effectively inhibit MMP activity and VEGF-mediated endothelial tube formation.⁹⁰ These findings suggest that hydrophobic substituents (such as heptyl and benzyl groups), acetyl groups and planar aromatic systems can enhance the antimetastatic and anti-angiogenic properties of coumarins.

5.4. Reversal of multidrug resistance (MDR)

Coumarins can overcome multidrug resistance by inhibiting efflux transporters, such as P-glycoprotein (P-gp).⁹¹ Sesquiterpene coumarins from Ferula species—including farnesiferol A and mogoltacin—effectively block P-gp-mediated drug efflux, restoring chemosensitivity in doxorubicin-resistant breast cancer cells. Their bulky terpenoid moieties facilitate binding to transmembrane drug-binding sites.⁹² Synthetic coumarin–quinazolinone hybrids further suppress MDR1 gene expression and enhance intracellular drug accumulation. Additional mechanisms involve the inhibition of ABCG2 and the modulation of detoxifying enzymes, such as glutathione S-transferase.⁹³ The presence of hydrophobic or cationic substituents improves interactions with efflux pumps or related regulators (GSTP1, MRP1).⁹⁴ These structural insights highlight the capacity of coumarins to reverse MDR through multimodal mechanisms.

5.5. Targeting key enzymes and proteins

Coumarin derivatives can exert antitumor effects by targeting key proteins (Fig. 6). Currently available coumarin-based tumor-targeted enzyme inhibitors include topoisomerases, protein kinases, histone deacetylases (HDACs), telomerase, and carbonic anhydrase.⁹⁵ The planar aromatic structure of the tacrolimus-coumarin hybrid facilitates DNA insertion and the inhibition of topoisomerase I, while the C8–C10 alkyl chain between the linking groups optimizes binding affinity to A549 lung cancer cells.⁹⁶ It has been reported that 4-hydroxycoumarin–thiazole hybrids can target the EGFR and PI3K/mTOR signaling pathways, with specific substituents enhancing the inhibition of kinases by strengthening hydrogen bonding interactions.⁹⁷

Fig. 6. Coumarin exerting its anticancer effects through the PI3K/AKT pathway.

In terms of epigenetic regulation, coumarin hydroxyester derivatives effectively inhibit HDAC1/6/8 by chelating zinc ions, restore the expression of tumor suppressor genes, and induce G1 phase arrest by upregulating p21 and inhibiting cyclin D1.⁹⁸ Furthermore, a multi-target strategy has successfully led to the development of coumarin–thiazole derivatives capable of simultaneously inhibiting topoisomerases and inducing ROS-mediated endoplasmic reticulum stress.⁹⁹ The coumarin scaffold serves as a versatile template for developing complex anticancer drugs, helping to address tumor heterogeneity and resistance mechanisms.^100,101

6. Structure–activity relationship insights

Table 2 summarizes the effects of the structure–activity relationships of the synthesized coumarin derivatives on the anticancer activity. In coumarin–chalcone hybrids, the methoxy group on the chalcone aromatic ring enhances the inhibitory effect of coumarin on breast cancer cells. The chloro substituent, on the other hand, enhances the inhibitory activity against cervical and endometrial cancer cell lines. The kinase selectivity and potency of coumarin–heterocyclic conjugates primarily depend on the type and position of the heterocyclic side chain. In acrylamide conjugates, electron-donating groups on the phenylacrylamide moiety can enhance the inhibition of tubulin polymerization. A single nitro substituent on the coumarin bridge group not only confers ROS-mediated cytotoxicity but also enhances the selectivity of the derivatives toward cancer cells. The type of metal in coumarin–metal complexes determines the primary mechanism of action; palladium(ii) complexes can cause DNA alkylation and induce apoptosis at nanomolar concentrations.

Table 2. Anticancer activity and structure–activity relationships of representative coumarin derivatives.

No.	Chemical structure	Chemical structure	IC50 and cell lines	Mechanism	Key structure–activity relationship	Ref.
I. Coumarin–chalcone and chalcone-like hybrids
1	Benzocoumarin–chalcone; 7-methoxybenzocoumarin conjugated with 3,5-dimethoxyphenyl via an enone linker		MCF-7: 6.8 µM; MDA-MB-231 : 8.5 µM; and MCF-10A: non cytotoxic	TNF-α binding inhibition	Methoxy-substituted compounds active against breast cancer; chloro-substituted analogues inactive against breast cancer but active against cervical/endometrial cancer	113
2	Benzocoumarin–chalcone; 7-methoxybenzocoumarin conjugated with 3,4,5-trimethoxyphenyl via an enone linker		MCF-7: 14.4 µM; MDA-MB-231 : 15.7 µM	JNK pathway inhibition	Increasing the number of methoxy groups slightly decreases the activity against MCF.	113
3	Coumarin–chalcone; 8-sec-butyl-3-(ethoxycarbonyl)coumarin+ 4-methylchalcone		HeLa: 7.6 µM; C33A: 4.7 µM	Intrinsic apoptosis; G2/M cell-cycle arrest	—	114
4	Coumarin–thiazole chalcone; coumarin-6-yl linked through a propenone to 4-methylthiazole-2(3H)-thione		MDA-MB-23 : 0.37 µM; MCF 10A: 42.5 µM	Tubulin polymerization inhibition; carbonic anhydrase CA IX/XII inhibition; G2/M arrest and mitochondrial apoptosis	Replacing phenyl with coumarin enhances tubulin inhibition; coumarin mediates CA inhibition, and thiazole-chalcone mediates tubulin inhibition	115
II. Coumarin–nitrogen heterocycle hybrids
5	Coumarin–bis triazole (benzyl series); 5,7-bis-[(1-(2,4 dichlorobenzyl)-1H-1,2,3-triazol-4-yl)-methoxy]-4-methylcoumarin		PANC-1: 7.15 µM; HT29: >100 µM; and H6C: nontoxic	EGFR binding; caspase-dependent apoptosis	The position of the halogen affects activity; a halogen at the 2 position can sterically hinder the hydrogen bonding between the triazole and target.	116
6	Coumarin–bis triazole (phenyl series); 5,7-bis[(1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)-methoxy]-4-methylcoumarin		PANC-1: 6.09 µM; HT29: >100 µM; and H6C: nontoxic	EGFR binding; caspase-dependent apoptosis	Electrostatic/halogen bond between the 3-Cl and EGFR.	116
7	Coumarin–triazole–naphthoquinone hybrid; 4-hydroxycoumarin linked via a propyl triazole to 1,4-naphthoquinone		SCC 9 : 12.29 µM; B16 F10 : 4.93 µM; HCT116 : 6.72 µM; 4T1: 7.63 µM; and HGF: 22.77 µM	ROS-induced apoptosis; caspase-dependent cell death; S-phase arrest; and PKM2 inhibition	The naphthoquinone moiety contributes to both ROS generation and PKM2 inhibition	117
8	1,3,4 Oxadiazole–thioether derivative; 4-methoxyphenyl-oxadiazole-2-thiol linked through a thioether to 1-(4 methoxyphenyl)-ethanone		A549 : 11.20 µg mL−1	CRMP1 protein binding	The best activity is achieved when both the 5 position of the oxadiazole and the phenacyl moiety bear a 4-methoxy group; the N-phenylacetamide-containing thioether analogues are less active than the corresponding phenacyl derivatives	118
9	Coumarin–benzimidazole–thiourea hybrid; 3-(2-oxo-2H-chromen-3-yl)-N-phenyl-1H-benzimidazole-1-carbothioamide		MCF-7: 0.08 µM; NCI–H460 : 0.05 µM; SF-268 : 0.06 µM; and WI-38 : 28.0 µM	Cytotoxic/antitumor activity	The combined coumarin and N-phenylthiourea moieties contribute to the high antitumor activity	119
III. Coumarin–acrylamide/thiazole hybrids (kinase-targeted)
10	4-Hydroxycoumarin–thiazole hybrid; 4-hydroxycoumarin + 4-methylthiazole-5-carboxylic acid ethyl ester (N-unsubstituted)		MCF-7: 6.4 µM; HCT 116 : 20.4 µM; and HepG2: 57.2 µM	EGFR, PI3K, and m-TOR inhibition; S-phase arrest; and apoptosis	N-unsubstituted thiazole is more active than N-methyl or N-ethyl; the carboxylate metabolite displays additional ionic and hydrogen bonds	97
11	4-Hydroxycoumarin–thiazole hybrid; 4-hydroxycoumarin + 3,4-dimethylthiazole-5-carboxylic acid ethyl ester (N-methyl)		HCT 116 : 5.9 µM; MCF 7 : 11.2 µM; HepG2: 41.4 µM; and BJ: non toxic	EGFR, PI3K, and m-TOR inhibition	N-methyl substitution favors HCT 116 activity over MCF 7 compared with 6a	97
12	4-Hydroxycoumarin–thiazole hybrid (azo series); 4-hydroxycoumarin + thiazole + azo(4-bromophenyl)		HCT 116 : 33.8 µM; MCF-7: 12.7 µM; and BJ: >500 µM	Dual EGFR and HDAC1 inhibition; ERK inhibition; G2/M arrest; and apoptosis	Compounds bearing a 4-bromophenylazo group show extremely low toxicity toward normal BJ 1 cells, while other analogues exhibit moderate toxicity toward normal cells	120
13	Coumarin–acrylamide hybrid; 4,8-dimethyl-7-hydroxycoumarin + 3,4,5-trimethoxybenzamide + 4-methoxyphenylacrylamide		HepG2: 1.88 µM; HL 770: lower cytotoxicity than 5-FU	β-Tubulin polymerization inhibition; G2/M arrest; and apoptosis	Compounds bearing an electron-donating group are more active than those with electron-withdrawing groups; the trimethoxybenzamide moiety is the critical pharmacophore for tubulin binding	121
IV. Coumarin–metal complexes
14	4-Hydroxycoumarin–Pd(ii) complex; 3-hydroxyaniline-substituted 4-hydroxycoumarin ligand + Pd(ii)		MIA PaCa 2 : 3.0 µM; A375 : 5.4 µM; HCT116 : 7.0 µM; and MRC 5 : 8.8 µM	Apoptosis induction; receptor tyrosine kinase (RTK) inhibition	Pd(ii) complexes are markedly more cytotoxic than the free coumarin ligand; the meta OH-substituted complex is more active than the para OH analogue across all tested cell lines	70
15	Quinoline–coumarin–Pt(II) complex; 3-(2′-quinolyl)-6-hydroxycoumarin + Pt(II)		A549/DDP: 0.10 µM; HeLa: 0.15 µM; A549 : 35.22 µM; and HL 7702: >150 µM	Mitochondria-targeted apoptosis	Pt4, bearing the 3-(2′quinolyl)-6-hydroxycoumarin ligand, is more potent against A54 than a compound containing the 6,8-dichloro analogue	122
16	Ru(ii)–COUPY conjugate; julolidine-fused CF3 COUPY coumarin attached via an amide bond to a cyclometalated Ru(ii) polypyridyl complex		CT 26: PI (620 nm) > 300 (dark IC50 > 300 µM); and HT 29: PI (740 nm) > 42	Photodynamic therapy; red/NIR light activation; type I + type II ROS generation	Conjugation completely abolishes dark toxicity, while the free Ru complex exhibits significant dark toxicity; the incorporation of COUPY enables NIR (740 nm) photoactivation	123
17	Ru(ii)–COUBPY complex; COUPY coumarin directly integrated into the coordination sphere of a Ru(ii) polypyridyl complex through a bipyridine ligand		CT 26: deep red (645 nm): 7.4 nM (PI > 33 783); green (540 nm): 25 nM (PI > 10 000)	Photodynamic therapy; type I + type II ROS generation	The direct integration of coumarin into the metal coordination sphere (rather than amide conjugation) increases the PI from >300 to >33 000	124
18	Coumarin-based Schiff-base Cu(ii) complex with coordinated imidazole		A549 : 4.6 µM	Partial DNA intercalation; ROS generation; GSH depletion; lipid peroxidation; and hydrolytic DNA cleavage	The Cu(ii) complex operates through a non-cross-resistant mechanism	125
19	cis-N2O2 Pd(ii) complex of a coumarin-derived 3-(1-aminoethylidene)-2H-chromene-2,4-dione ligand		A549 : 9.7 nM; HeLa: 7.8 nM; and K562 : 7.8 nM	DNA alkylation; DNA conformational changes	The cis N2O2 square planar geometry exhibits extremely strong DNA binding and alkylating ability	126

It is worth noting that among the coumarin derivatives listed in Table 2, those containing nitrogen-containing heterocycles—including triazoles, thiazoles, pyrimidines, oxadiazoles, benzimidazoles, and quinolines—exhibit relatively strong anticancer activities, with IC₅₀ values typically in the low micromolar to nanomolar range. At the same time, these compounds possess more diverse antitumor mechanisms, and the nitrogen-containing heterocyclic-coumarin skeleton may represent the most ideal platform for anticancer drug discovery.

7. Challenges and future directions

Natural coumarins have attracted significant attention due to their anticancer activities. However, natural coumarins have low solubility and bioavailability, and they lack the ability to target tumor cells in vivo. Many natural coumarins also exhibit hepatotoxicity or phototoxicity. Research in the following areas may help address these issues.

7.1. Nanoparticle-based delivery

The encapsulation of coumarins in nano-carriers can dramatically improve solubility and pharmacokinetics. For instance, liposomal coumarin formulations have shown prolonged circulation half-life and enhanced tumor uptake. Wang et al. demonstrated coumarin-loaded micelles that increased water solubility and intracellular delivery, boosting anticancer effects. In vivo, nano-encapsulated coumarins achieve relatively high bioavailability and preferential accumulation in tumors via the EPR effect. Recent examples include coumarin–chitosan nanoparticles and PEGylated liposomes for furocoumarins, which both improve bioavailability and reduce hepatic clearance. Thus, nanomedicine is a promising route to enhance delivery to tumors.

7.2. Prodrug and conjugate design

Attaching solubilizing or targeting moieties to coumarins can address PK issues. Amino acid or sugar conjugates can increase aqueous solubility and exploit transporters. The acetate or phosphate prodrugs of coumarin phenols are examples in development. Hybrid molecules, in which coumarin is linked to another drug or targeting ligand, serve multiple roles: they can improve membrane permeability or direct the compound to cancer cells. For example, the conjugation of coumarins to antibodies or peptides for targeted delivery is being explored. As noted, coumarin–steroid conjugates have been made to target hormone-sensitive tumors, providing both anti-inflammatory and anticancer benefits.

7.3. Computationally aided drug design

SAR analysis has identified key substituents with various anticancer activities and the ability to target cancer cells. A database specific to coumarins can be established based on the characteristics of these substituents. The activity of novel derivatives can be predicted, and lead candidates can be screened.

7.4. Developing multi-target drugs

Coumarins are ideally suited for the development of multi-target drugs. Coumarin–triazole hybrids, coumarin–artemisinin conjugates, and coumarin–uracil or isoindole derivatives can all target multiple cancer signaling pathways. In the context of multidrug resistance, multi-target coumarin drugs may overcome drug resistance.

7.5. Multi-target/cytokine strategies

Rather than single-target ligands, some research advocates the development of coumarins that modulate entire signaling networks. For instance, coumarins that simultaneously inhibit angiogenesis, glycolysis, and DNA repair might be more effective. Network pharmacology analyses suggest combining coumarins with other small molecules to synergistically shut down tumor survival circuits.

In summary, coumarin-based anticancer drug development will rely on tackling pharmacokinetic and toxicity issues via advanced formulation and chemistry while exploiting their intrinsic multi-target potential. Nanotechnology and prodrug design can markedly improve delivery, and SAR-guided synthesis can yield more selective analogues. By integrating coumarins into hybrid drugs and combination regimens, researchers aim to harness their promiscuous binding profile for maximum therapeutic effects. Ongoing studies, including animal models of novel formulations, support this trend. If these strategies succeed, the chemical versatility of the coumarin scaffold could translate into a new generation of anticancer agents.

Conflicts of interest

The authors have declared no conflicts of interest.

Data availability

No primary research results, software or code have been included, and no new data were generated or analysed as part of this review.