Investigation of the microwave‐assisted condensation of anthranilic acid derivatives with ethylpiperidine isothiocyanates into 2‐thioxoquinazolin‐4‐ones revealed an intramolecular cyclization into 2,3‐dihydro‐5H‐thiazolo[2,3‐b]quinazolinones. The study of reaction parameters demonstrated that temperature is a key factor controlling this transformation, while anthranilic acid substituents further modulate the reaction outcome. Here we report the promotion of the intramolecular cyclization to thiazoloquinazoline at high temperatures (200°C), whereas lower temperature (125°C) selectively favors the formation of 2‐thioxoquinazolin‐4‐one in good yield. These findings provide refined conditions for the synthesis of 2‐thioxoquinazolin‐4‐one derivatives and expand the way to synthesize 2,3‐dihydro‐5H‐thiazolo[2,3‐b]quinazolinone derivatives of potential medicinal interest.

Six 1,4-disubstituted pyrazoles linked to a benzenesulfonamide and a benzodioxane unit have been synthesized through a copper(I)-catalyzed formal [3+2] cycloaddition (32CA) reaction of alkynes with 3-arylsydnones. The Cu-catalyzed sydnone-alkyne cycloaddition (CuSAC) procedure has been optimized to promote the formation of the pyrazole ring and to deliver in three steps the six target compounds 5a-f, fully characterized by 1H/13C-NMR and mass spectrometry (EIMS). Ten solvent conditions were evaluated. The reaction proceeded most efficiently in the presence of copper(II) sulfate pentahydrate in aqueous t-butanol in the presence sodium acetate, to reach a yield of 96%. The mechanism of the Cu(I)-catalyzed reaction has been studied within the Molecular Electron Density Theory (MEDT). This rection is a domino process that consists in a Cu(I)-catalyzed formal [3+2] cycloaddition followed of an extrusion of CO2 yielding the final pyrazole. The capacity of heterocyclic compounds 5a-f to interact with human cyclophilin A (Cyp A), which is a host cofactor for hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1), and with the HIV-1 protein gp120-CD4 was evaluated using molecular docking. Compounds 5a,b,d,f showed a satisfactory protein binding capacity. The physicochemical and metabolic properties of the compounds were also evaluated in silico. These predictions provide important information to guide future design in this series of potential antiviral agents.

Immune checkpoint inhibitors have emerged as one of the most promising approaches for cancer immunotherapy. Several injectable monoclonal antibodies targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway are used to treat solid tumors. The development of orally active small molecules remains a challenge. In this context, we describe new pyrazolone derivatives bearing a chlorophenyl moiety aimed at targeting PD-L1 dimers. Ten new compounds with nanomolar affinities for PD-L1 were identified and among them, six were able to reactivate proliferation of CTLL-2 cytotoxic T-cells. The best compounds were further characterized for their capacity to modulate PD-L1 dimerization and their interaction with PD-L1 dimers, by microscale thermophoresis and molecular docking, respectively. Novel symmetric bis-pyrazolones with a high affinity for PD-L1 protein were also obtained. The 2,4-dichlorophenylpyrazolone scaffold offers novel perspectives to design PD-L1-targeting agents for the treatment of cancer.

The cold-water siliceous sponge Geodia barretti, largely present in the North Atlantic Ocean, notably around Scandinavian costs, plays important roles in carbon and silicon cycling in the deep-sea. The demosponge provides a reservoir for numerous microorganisms. Bioactive natural products have been isolated from this sponge, in particular the indole alkaloid barettin discovered forty years ago. Barettin and analogues, notably 8,9-dihydrobarettin, 8,9-dihydro-8-hydroxybarrettin, bromobenzisoxalone barettin, and geobarrettins A-B, contribute to the maintenance of the sponge stability and security (anti-fouling) and the regulation of its microbial environment. The four indole alkaloids 6-bromo-8-hydroxyconicamin, 6-bromoconicamin, and geobarrettin C-D are also implicated in the defense of the sponge against physical and biochemical aggressions. Altogether, these ten natural products are essential to the sponge life. The present review presents a survey of the chemistry and biology associated with Geodia barretti. The pharmacological properties of (dihydro)barettin, notably their antioxidant and anti-inflammatory properties, are discussed, as well as the synthetic processes set up to produce these diketopiperazine derivatives. Their molecular targets and mechanism of action are also discussed. The review takes the sponge G. barretti from the depths of knowledge and brings barettin and analogues to the surface, with the hope of guiding future research in this field.

The two related sesquiterpenes curzerene and curzerenone have been found in many plants, notably in the rhizomes of Curcuma species and other Asian medicinal plants and essential oils. These two natural products, present in several traditional Chinese medicines, belong to a family of furanosesquiterpenoids which includes the less stable analogues furanodiene and furanodienone. Synthetic processes have been described to obtain curzere(no)ne and analogues such as epi- and pyro-curzerenone. An overview of the chemistry and pharmacology of these natural products is reported here. Curzere(no)ne display antioxidant and anti-inflammatory properties. They have shown modest but significant activities against distinct viruses, bacteria, and certain parasites, as well as insecticidal properties. They showed an interest also to limit hyperlipidemia and neuroinflammation. But the most promising point refers to their anticancer activities. Curzerenone combines three complementary properties: (i) inhibition of cancer cell survival and proliferation, (ii) reduction of tumor cell migration and invasion, (iii) promotion of T cell activation and proliferation, notably via a down-regulation of the PD-L1 checkpoint. These properties translate into a capacity of curzerenone to reduce markedly tumor growth in vivo. These considerations shall encourage the development of more potent and safer curzerenone derivatives. Small molecules capable of suppressing immune evasion of tumors are actively searched. Curzerenone represents an interesting scaffold, chemically accessible, to design novel regulators of the PD-1/PD-L1 checkpoint. The review highlights the interest for these two natural products in oncology and beyond.

The pyripyropenes A-X represent a family of 24 alkaloids isolated from fungi, mainly Aspergillus and Penicillium species, over the past 30 years. Numerous analogues have been isolated from fungi or (hemi)synthesized to investigate structure-activity relationships. The leader product in the series remains the first identified natural product pyripyropene A (Pyri-A), known as a highly potent and selective inhibitor of acyl CoA:cholesterol acyltransferase 2 (ACAT2). The present review retraces the products history, from their discovery to the characterization of the target engagement, the cellular mechanism of action and bioactivities. In parallel to the identification of naturally occurring pyripyropenes and the synthesis of derivatives, studies have progressed in three directions. First, the development of agricultural insecticides from Pyri-A led to discovery and worldwide commercialization of afidopyropen (Inscalis®) to protect crops against sucking insects. Second, the highly potent and selective targeting of ACAT2, largely expressed in human liver cells notably, drove the design of analogues aimed at regulating cholesterol metabolism for the treatment of metabolic and cardiovascular diseases. Third, the emerging roles of ACAT2 as a regulator of tumor cell proliferation and anticancer immune response call for the development of the pyripyropenes in oncology. A few tumor-active pyripyropene derivatives targeting ACAT2 have been identified recently. The review underlines the evolution of research in this domain, from the fungal production to the insecticidal action, and from the treatment of atherosclerosis to cancers. The pyripyropene saga is alive and well.

Wuyiencin is a broad-spectrum agricultural antibiotic used to control fungal diseases in vegetables and crops. This nucleoside-type natural product has been granted an organic certification in China and is produced industrially. Wuyiencin has shown efficacy against several fungal pathogens, notably Botrytis cinerea and Sclerotinia sclerotiorum via inhibition of protein synthesis essentially. Plant infections by other pathogenic fungi, such as Sphaerotheca fuliginea and Didymella segeticola, can be prevented or treated with wuyiencin alone or in combination with other fungicides. In D. segeticola, wuyiencin functions as an inhibitor of threonine dehydratase implicated in pyruvate production and thus blocks ATP production needed for mycelium growth. It is an eco-friendly biopesticide efficient against fungi, with no major toxicity to the soil bacterial community. But surprisingly, wuyiencin is essentially unknown from a chemical viewpoint. An atypical chemical structure, with a tetra-peroxy side chain N-attached to a cytidine unit, has been reported in two patents only. No structural and chemical data are available on wuyiencin. Consequently, the exact wuyiencin structure is subject to controverse, despite its well-established use and the development of new wuyiencin-containing formulations. The present review underlines the agricultural interest of this product based on its mechanism of action and bioactivities. In parallel, the analysis advocates for the implementation of chemical studies on wuyiencin and drug design approaches.

The marine alkaloids naamine A and naamidine A were first isolated from a calcareous sponge forty years ago. Since 1987, about 40 related natural products have been discovered in this series, including naamines A-G, isonaamines A-D, naamidines A-K, isonaamidines A-E, pyronaamidine, spironaamidine, and a few other derivatives. The family also includes related imidazole alkaloids such as leucettamines, clathridines, calcaridines, as well as metal-coordinated dimeric products (e.g. (naamidine A)2-Zn and (naamidine J)2-Cu). Altogether, they represent a group of ∼70 imidazole alkaloids all isolated from marine species. Efficient and versatile synthetic processes have been set up to access these products and to design structural analogues. At the pharmacological level, studies have revealed the interest of these products to combat fungal and viral infections, and to treat certain cancers. A complete overview of these imidazole alkaloids, their chemistry, pharmacological properties and mechanisms of action is presented here. In several cases, key molecular targets have been identified, thus facilitating the structure-guided design of analogues and the identification of more potent synthetic analogues. Encouraging data have been reported with a naamidine A-based cream to treat mycosis, and with naamine A derivatives to viral (TMV) infections. In the naamidine J series, potent anticancer derivatives targeting key molecular targets (CSE1L, FDX1, PD-L1) have been characterized. Altogether, the analysis shed light on this family of marine alkaloids of prime medicinal interest, with the objectives to encourage further researches into their mechanism of action and bioactivities.

Bowdichia virgilioides Kunth is a tree largely present in South America, notably in the Cerrado savannah. The species is known for the quality of its dense and resistant wood, used in construction and furnishing. B. virgilioides is also a medicinal plant used, from leaves to roots, for the treatment of various human pathologies (pharyngitis, bronchitis, healing wounds, diabetes, and arthritis). The present review provides an analysis of the scientific literature pertaining to B. virgilioides, with a focus on pharmacological activities. Aqueous and organic extracts have been used to treat inflammatory pathologies and to combat infectious diseases caused by microorganisms and parasites. All phytochemicals at the origin of the bioactivities of extracts have been identified, including 37 terpenoids, 8 alkaloids, 21 flavonoids and 13 other products. All natural products are discussed, with a focus on a dozen compounds with well-documented pharmacological properties and/or a known mechanism of action. Key products include ormosanine (alkaloid), vouacapane (diterpenoid), lupeol (terpenoid), isoquercetin (flavonoid), isocordoin (chalcone), and little-known specific products (bowdichine and bowdenol). The botanical and phytochemical analysis shed light on this valuable Fabaceae species with the objective to promote its preservation and cultivation, as well as further pharmacological investigations aimed at rationalizing its long-established ethnobotanical use.

Background/Objectives. The actin-binding protein EPLIN (epithelial protein lost in neoplasm), also known as LIMA1, contributes to the maintenance of cytoskeleton structure and dynamic. This protein, which interacts with multiple partners to regulate cell adhesion and migration, has been implicated in the progression of solid tumors and in tumor metastasis. Consequently, small molecules binding to EPLIN are actively searched. EPLIN has been characterized as a molecular target for the antitumor antibiotic albacarcin V which affects the cytoskeletal structure and induces cell growth arrest. Methods. We have modeled the binding of albacarcin and naturally occurring derivatives to EPLIN conformers, in order to locate the drug-binding site and to identify additional EPLIN binders. Nineteen compounds were studied, including albacarcins V (vinyl) and M (methyl), five gilvocarcins, four ravidomycins, two chrysomycins, and six related products (including polycarcin and fucomycin). Results. The modeling analysis confirmed the capacity of albacarcin V to bind to EPLIN and identified a few better binders. In particular, ravidomycin V bearing a dimethylamino sugar unit were identified as the best binders in the series, along with the two related anticancer natural products FE35A-B. Structure-binding relationships are discussed. The drug-binding site has been localized near the central residue Asn34 in the conformationally constrained domain between the two zinc-binding regions. Conclusions. This study provides guidance to the design of EPLIN inhibitors based on the ravidomycin core structure.

The Asian medicinal plant Cipadessa baccifera (Roth) Miq., also known as C. fruticosa or C. cinerascens (Ranabili or Nalbila), has long been used in Ayurvedic medicine to treat dysentery, skin disorders, rheumatism and parasitic infections. Extracts prepared from the leaves, seeds or fruits of the plant have revealed activities against mosquito vectors of parasitic diseases, notably marked larvicidal activities. Plant extracts have shown insecticidal and antibacterial activities, in addition to antioxidant effects. Numerous natural products at the origin of these pharmacological effects have been identified from all parts of the plant, from roots to leaves and seeds. The phytochemical survey presented here led to the identification of about 200 natural products isolated from C. baccifera, including a large majority of limonoids (>170), in addition to steroids, terpenoids, and a few other products. The panel of limonoids is extremely diversified with multiple groups of compounds: cipacinerasins, cipacinoids, cipacyclonone, cipadesins, cipadessains, cipadessalide, cipadonoids, cipafera, cipaferens, cipaferoids, ciparasins, cipatrijugins, cineracipadesins, cinerascenoids, and cipacinerasins. There are a few interesting bioactive products in Cipadessa, such as the anticancer agents cipaferen G and cipacyclonone, and the anti-inflammatory molecules cipadessain D and methyl-angolensate. Other bioactive products are discussed, such as cryptomeridiol, khayasin T, and febrifugin. An overview of Cipadessa phytochemicals is provided here to shed light on this under-valued medicinal plant.

Ziyuglycosides I-II are two glycosylated triterpenoids isolated from the edible medicinal plant Sanguisorba officinalis L. (great burnet). Ziyu-1 is a bidesmosidic saponin whereas its metabolite Ziyu-2 is a monodesmoside. They were initially isolated from the plant roots (Sanguisorbae radix) but they can be found in diverse medicinal plants and polyherbal preparations. This review retraces the origin of the products, discusses synthetic processes to obtain derivatives from the sapogenin precursor pomolic acid, and presents an overview of the pharmacological properties of Ziyu-1/2. The natural products display antitumor properties, with six major anticancer targets identified, including receptor ESRRG, chromobox protein CBX4 and endoplasmic reticulum-associated protein STING, implicated in tumor cell proliferation and immune-regulation. In parallel, anti-inflammatory properties have been evidenced, associated with the targeting of a few other protein targets such as ADP ribosyl cyclase CD38. Altogether, a dozen protein targets have been proposed, mainly based on in silico studies. The interest of the products for skin protection, as cosmeceutical ingredients, and their antibacterial and antiviral effects are also evoked. Formulation products (Ziyu liposomes and nanoparticules) and (hemi)synthetic analogues are discussed. The aim of this study is to promote further researches with these triterpenoids and naturally-occurring or hemisynthetic analogues.

The divalent metal transporter DMT1 (SLC11A2) is implicated in diverse human pathologies including cancers, inflammatory and degenerative diseases. Small molecules targeting this membrane protein are actively searched. Following the identification of the pyranocoumarin praeruptorin A as an inhibitor of ferroptosis that is able to bind to DMT1, we have investigated the interaction of related natural products with DMT1 using molecular modeling to determine structure-binding relationships. Two series of compounds were tested: praeruptorins A-H and qianhucoumarins A-J, all isolated previously from the roots of the Chinese medicinal plant Peucedanum praeruptorum Dunn (Bai-Hua Qian-Hu). The antitumor compound praeruptorin C was identified as the best DMT1 ligand in the series, with a binding capacity largely superior to that of praeruptorin A and also well superior to the reference organoselenium product ebselen, at least from an in silico perspective. Praeruptorin C, and to a lower extent praeruptorins F and H, can form stable complexes with DMT1 upon binding close to the ebselen binding site. Qianhucoumarins C and I were also identified as potential binders. Altogether, the analysis of the 18 natural products enabled identification of structural elements implicated in the target binding process. The curvature of the tricyclic pyranocoumarin scaffold and the angeloyl side chain at position 9 seem to contribute importantly to the protein interaction. An experimental validation is required but the docking study paves the way to the discovery and design of tricyclic coumarin derivatives targeting DMT1.

The fungus Didymella segeticola is a major plant pathogen which causes significant damages to cultures and important economic losses. It is chiefly responsible for leaf spots and leaf blights of tea and tobacco species, and at least seven other plants. Effective measures are taken to detect early the disease and to limit its propagation and its impact on plant culture. However, novel fungicidal and fungistatic agents are needed to combat D. segeticola-induced leaf spot disease. The present review provides an analysis of the top-10 natural and synthetic products active against D. segeticola and the associated molecular targets and/or mechanism of action. The products include (1) ergosterol synthesis inhibitor jiahuangxianjunzuo, (2) protein translation inhibitor zhongshengmycin, (3) succinate dehydrogenase inhibitor boscalid, (4) nitrate reductase inhibitor kasugamycin, (5) β-tubulin binder griseofulvin, (6) DNA-binding agent carvacrol, (7) pyruvate dehydrogenase inhibitor phenazine-1-carboxamide, (8) threonine dehydratase inhibitor wuyiencin, (9) glucose regulator erlvejunzuo, and (10) phosphoenolpyruvate carboxykinase inhibitor ningnanmycin. The potency of the compounds varies significantly, with EC50 values from 0.5 nM (boscalid) to 100 μM (kasugamycin). The diversity of products and their molecular targets underline the multiplicity of approaches currently investigated to tackle leaf spot disease. On this basis, novel products and combinations can be proposed and the battle is going again.

Aim: The immunosuppressive drug brequinar (BQR) is a potent inhibitor of dihydroorotate dehydrogenase (DHODH) active against autoimmune diseases and viral infections. This oral drug is currently evaluated for the treatment of cancers, notably acute myeloid leukemia to limit the suppressive function of myeloid cells. A combination of BQR and an anti-PD-1 (programmed death-1) antibody has revealed potent antitumor and antimetastatic activities. BQR induced a marked down-regulation of PD-L1 (programmed death-ligand 1) gene expression and a large decrease of PD-L1 protein expression in implanted tumors in mice. Methods: The present study evaluated the capacity of BQR to interact directly with the PD-L1 protein dimer using molecular modeling. Results: Molecular docking experiments revealed a modest capacity of BQR to stabilize PD-L1 dimers. The PD-L1 binding capacities of four known BQR analogs were compared to establish structure-binding relationships. The protein binding was significantly enhanced when the acid function of BQR was replaced with a trifluoroethanol substituent. The interaction was further reinforced when BQR was coupled to a mitochondria-targeted triphenylphosphine (TPP) unit. Among three BQR-TPP hybrids, compound B2 with a short alkyl linker revealed a prominent capacity to interact with PD-L1, superior to that of the reference biphenyl ligand BMS-202. Conclusions: Two PD-L1 binders derived from BQR have been identified and the protein interaction modeled. Our study underlines the possibility of designing novel small molecule ligands targeted to the PD-L1 dimer interface based on the BQR scaffold.

Diketopiperazines (DKPs) are biologically important cyclic dipeptides widespread in nature, associated primarily with microorganisms. This is the case for the 2,5-DKP derivative cyclo(L-Leu-L-Pro) (cLP), also known as gancidin W or PPDHMP, identified from a variety of bacteria and fungi, and occasionally found in food products. The present review retraces the discovery of cLP, its identification in living species, its chemical syntheses, and its biochemical properties. In bacteria, cLP is often associated with other DKPs to serve as a defense element against other microorganisms and/or as a regulator of bacterial growth. cLP plays a role in quorum-sensing and functions as an anticariogenic and antifungal agent. The antimicrobial mechanism of action and molecular targets of cLP are evoked. The interest in cLP for combatting certain parasitic diseases, such as malaria, and cancers is discussed. The capacity of cLP to interact with CD151 and to down-regulate the expression of this tetraspanin can be exploited to reduce tumor dissemination and metastases. The review sheds light on the pharmacology and specific properties of cyclo(L-Leu-L-Pro), which can be useful for the development of a novel therapeutic approach for different human pathologies. It is also of interest to help define the bioactivity and mechanisms of action of closely related DKP-based natural products.

Background/Objectives: Microcolins A–M are cytotoxic marine lipopeptides produced by the cyanobacterium Moorena producens, also known as Lyngbya majuscula. Recent studies have shown that two compounds in the series, microcolins B and H, can form covalent complexes with phosphatidylinositol transfer proteins α and β (PITPα/β) upon the reaction of their α,β-unsaturated ketone group with the thiol group of a key cysteine residue of PITP. These observations prompted us to compare the binding of all microcolins and a few related derivatives (VT01454 and (deoxy)majusculamide D) to PITP to delineate structure–binding relationships. Methods: A molecular docking analysis led to the identification of microcolin E as the potentially best PITPα binder in the series, followed by microcolins B and H and analog VT01454. The computational data agree well with the published experimental results. Results: The binding of microcolin H into a large cavity of PITPα positions its reactive electrophilic α,β-unsaturated ketone close to the thiol of Cys95, enabling the facile formation of a covalent C-S linkage. A similar bonding can occur with the Cys94 of PITPβ. Molecular models of microcolins bound to PITP were compared to identify structural elements chiefly implicated in the recognition process. Conclusions: This computational study provides guidance in the design of microcolin derivatives targeting PITPα/β considered targets for cancer and inflammatory pathologies.

For more than sixty years, the piperidinopropiophenone derivative dyclonine is used as a local anesthetic in human and veterinary medicines. Dyclonine-containing drugs (Dyclone, DycloPro) have been developed as anti-itching medications and pain relievers in dermatology and dentistry. The product is used also as a protectant of mucosal surfaces to facilitate endoscopic examination. In the present review, the history of dyclonine is retraced and its multiple pharmaceutical usages are discussed. Synthetic strategies to obtain dyclonine are summarized. The goal of this study was also to analyze all pharmacological activities of the drug and its molecular targets. Dyclonine is considered a potent and selective antagonist of TRPV3 channels but it inhibits also histone methyltransferase G9a, aldehyde dehydrogenase 2 (ALDH2) and a few other proteins. The contribution of these targets to the drug activities is discussed. The better knowledge of the pharmacology of dyclonine has raised novel opportunities to use the drug for the treatment of neurodegenerative diseases, notably Parkinson disease and Friedreich's ataxia, and to combat drug-resistant cancers, such as chemo-resistant head and neck squamous cell carcinoma and glioblastoma. Preliminary evidence for the activity of dyclonine-containing drug combinations to treat multiple myeloma and solid tumors are discussed. An overview of dyclonine pharmacology is offered. This unsung drug has not finished talked about it.

Highly degraded sterols belonging to the incisterol group have been identified in a large set of microorganisms. The leading product in the family is demethylincisterol A3 (DM-A3), isolated from various fungi and endowed with marked antitumor properties. Since the initial discovery of incisterol from a marine sponge in the 1990s, more than 30 incisterol-type natural products have been identified, essentially from fungi. An overview of these products, their bio-origin, chemical synthesis, and associated pharmacological properties is presented. The series includes diverse incisterol and demethylincisterol derivatives, chaxines, volemolide, different analogues (salimyxins, phellinignincisterols, daedatrin D, inonotoide F, aplykurodinone-1, dendrodoristerol), and a glycoside derivative (xyloneside), all bearing a tetracyclic incisterol framework. An analysis of the anticancer mechanism of the action of DM-A3 underlined the three main components of its activity associated with the (i) inhibition of β-catenin and the Wnt signaling pathway, (ii) inhibition of tyrosine phosphatase SHP2 (IC50 = 6.75 µM) implicated in cancer cell survival and differentiation, and (iii) blockade of α7nAchR activation coupled with inhibition of acetylcholinesterase (IC50 = 11.16 µM). A comprehensive picture of the DM-A3 mechanism of action is discussed, highlighting the uniqueness of the compound as a dual SHP2/AchE inhibitor able to attenuate an inflammatory response through the cholinergic anti-inflammatory pathway. The review shed light on this little-known category of incisterol-type natural products, with the objective of promoting further research into this neglected group of anticancer agents.

Chrysanthemum species represent an economically important group of flowering plants. Many species also present a medicinal interest, notably for the treatment of inflammatory pathologies. This is the case for Chrysanthemum boreale Makino, endemic to Japan and widespread in Eastern Asia. This perennial plant has long been used in folk medicine to treat inflammatory diseases and bacterial infections. An extensive review of the scientific literature pertaining to C. boreale has been performed to analyze the origin of the plant, its genetic traits, the traditional usages, and the properties of aqueous or organic plant extracts and essential oils derived from this species. Aqueous extracts and the associated flavonoids, such as acacetin and glycoside derivatives, display potent antioxidant activities. These aqueous extracts and floral waters are used mainly as cytoprotective agents. Organic extracts, in particular those made from methanol or ethanol, essentially display antioxidant and anti-inflammatory properties useful to protect organs from oxidative damage. They can be used for neuroprotection. Essential oils from C. boreale have been used as cytoprotective or antibacterial agents. The main bioactive natural products isolated from the plant include flavonoids such as acacetin and related glycosides (notably linarin), and diverse sesquiterpene lactones (SLs). Among monomeric SLs, cumambrins and borenolide are the main products of interest, with cumambrin A targeting covalently the transcription factor NF-κB to regulate proinflammatory gene expression to limit osteoclastic bone resorption. The dimeric SL handelin, which is characteristic of C. boreale, exhibits a prominent anti-inflammatory action, with a capacity to target key proteins like kinase TAK1 and chaperone Hsp70. A few other natural products isolated from the plant (tulipinolide, polyacetylenic derivatives) are discussed. Altogether, the review explores all medicinal usages of the plant and the associated phytochemical panorama, with the objective of promoting further botanical and chemical studies of this ancestral medicinal species.