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The yellow-flowering plant Cladanthus arabicus (L.) Cass., commonly called Arabian Cladanthus or palm springs daisy, is typical of the West Mediterranean region and is particularly abundant in Morocco. The plant is used in traditional Moroccan medicine for the treatment of diabetes and other ailments. Over the past 20 years, this abundant wild plant has been neglected from a phytochemical viewpoint. For the first time, the present review provides a survey of the pharmacological properties reported from extracts of C. arabicus and from essential oils derived from the aerial parts, mainly antimicrobial, antioxidant, and anti-inflammatory properties. The main bioactive natural products are discussed, with a focus on two rare sesquiterpenes of major interest, which are abundant in the stems and leaves: the 6,12-guaianolide cladantholide and the germacranolide sintenin. These sesquiterpene lactones and their analogues are presented to highlight their properties, extraction or total synthesis, and their therapeutic benefits. They both represent convenient biosourced precursors for the synthesis of derivatives. Sintenin may be used as a starting material for the design of hemi-synthetic germacradienolide-type costunolide or parthenolide derivatives. The 6,12-guaianolide scaffold of cladantholide offers opportunities to design novel arglabin derivatives. The therapeutic potential of the neglected and under-utilized plant Cladanthus arabicus and its original phytochemicals shall be explored further.

The white berry bush, officially Flueggea virosa (Roxb. ex Willd.) Royle is a medicinal plant distributed throughout tropical areas and traditionally used in Africa, India and China. Root decoctions are used to treat abdominal pain, whereas extracts from the aerial parts serve to treat liver and urinary diseases, inflammatory pathologies and diabetes, among other pathologies. Plant extracts have revealed antiparasitic, antimicrobial, antiepilepsy, antidiabetic, anticancer and analgesic effects. Three main categories of phytochemicals were isolated from F. virosa: polyphenols, with the lead product bergenin; terpenoids, such as the flueggenoids and related podocarpane-type diterpenoids; and many alkaloids derived from securinine and norsecurinine. A remarkable feature of S. virosa is the production of norsecurinine oligomers, including macromolecular tetramers and pentamers, such as fluevirosinines. The most potent anticancer alkaloid in the family is the dimeric indolizidine flueggine B, which was identified as a potential binder to α/β-tubulin dimer, which is a known target for securinine. This review highlights the diversity of phytochemicals identified from S. virosa and the potential therapeutic benefits of dimeric alkaloids. Studies are encouraged to further investigate the therapeutic properties of the lead compounds but also define and finesse the nutritional profile of the edible fruit.

Abstract Background Telmisartan (TLT) is a prototypic angiotensin receptor blocker largely used to treat hypertension worldwide. In addition to its cardioprotective effects, TLT presents pleiotropic activities and notably displays noticeable anti-inflammatory and antitumor effects. The repression of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint may be implicated antitumor action of TLT, as it is the case with many other compounds equipped with a biphenyl moiety. We have used molecular modeling to compare the interaction of TLT and derivatives with the PD-L1 dimer protein. Results Two molecules, TLT-dimer and TLT-acylglucuronide, were found to form more stable complexes with PD-L1 than TLT itself. In parallel, the docking analysis performed with a series of 12 sartans led to the identification of Olmesartan as a potential PD-L1 binder. The stacked biphenyl unit of Olmesartan positions the molecule along the groove delimited by the two protein monomers. The flanking tetrazole and imidazole moieties, on each side of the biphenyl unit of Olmesartan, contribute favorably to the protein interaction via specific hydrogen bonding interactions. Conclusions The computational analysis suggests a possible binding of Olmesartan to PD-L1 dimer and thus offers novel perspectives for the design of small molecules capable of interrupting the PD-1/PD-L1 immune checkpoint. Experimental studies are warranted to validate the hypothesis. Graphical abstract

Clitocine (CLT) is an atypical nitro-containing pyrimidine nucleoside bearing a ribofuranosyl moiety attached to the exocyclic 4-amino position. It has been isolated first from the fungus Clitocybe inversa and then from fruiting bodies of Leucopaxillus giganteus. Two intramolecular hydrogen-bonds between adjacent amino and nitro groups on the pyrimidine unit confer a planar structure to the pseudo-tricyclic core of the molecule, thus facilitating stacking interactions with aromatic amino acid or the nucleobases. Over the past thirty years, a variety of CLT analogues have been synthesized, including amino derivatives acting as potent inhibitors of adenosine kinase, and a variety of other molecules all described here. The antitumor action of the mushroom extracts and purified CLT has been evidenced in murine models. The capacity of CLT to reduce tumor cell proliferation, to trigger apoptosis and to inhibit tumor growth in mice have been associated with a drug-induced modulation of the NF-κB and Akt pathways, notably with a down-regulation and proteasome-dependent degradation of anti-apoptotic protein Mcl-1. The potential targeting of an upstream protein effector, possibly the kinase Akt, is discussed. Moreover, CLT can promote translational readthrough of stop codons. This emerging mechanism reinforces further the interest of the natural product to address different types of cancers and nonsense mutation-related genetic disorders. Altogether, the review provides an overview of the history of CLT, from its chemical discovery in fungi to the identification of its anticancer activities and different mechanisms of action. Research prospects are proposed to better delineate the mode of action of this original natural product and to promote mycomedicine.

Among bryophytes, the Plagiochila genus represents a large group of leafy liverworts with over 500 species. Plagiochilins A to X are sesquiterpenoids isolated from Plagiochila species. The lead compound plagiochilin A (Plg-A), endowed with anticancer and antiparasitic properties, has been characterized as a potent mitosis inhibitor, acting selectively at the late stage of cytokinesis termed abscission. The compound perturbs the dynamics of microtubules, blocking cell cycle progression and triggering the death of malignant cells. Based on the compound’s mechanism of action and by analogy with other natural products bearing a dihydro-pyrone moiety, we postulated that Plg-A could bind to the pironetin site of α-tubulin. A molecular docking analysis was performed to compare the bindings of all 24 plagiochilins to α-tubulin and to establish structure–binding relationships. The identification of Plg-E and Plg-G as the best binders in the series highlighted the importance of the C13-OH or C=O group for α-tubulin recognition. This observation led to the testing of the natural-product ester plagiochilin A-15-yl n-octanoate and the corresponding alcohol (Plg-OH), both identified as robust α-tubulin binders. The study provides a rationale to potentially explain the mechanism of action of Plg-A and to guide the design of new derivatives.

The medicinal plant Securinega virosa (Roxb ex. Willd) Baill., also known as Flueggea virosa (Roxb. ex Willd.) Royle, is commonly used in traditional medicine in Africa and Asia for the management of diverse pathologies, such as parasite infections, diabetes, and gastrointestinal diseases. Numerous alkaloids have been isolated from the twigs and leaves of the plant, notably a variety of oligomeric indolizidine alkaloids derived from the monomers securinine and norsecurinine which both display anticancer properties. The recent discovery that securinine can bind to tubulin and inhibit microtubule assembly prompted us to investigate the potential binding of two series of alkaloids, fluevirosines A–H and fluevirosinine A–J, with the tubulin dimer by means of molecular modeling. These natural products are rare high-order alkaloids with tri-, tetra-, and pentameric norsecurinine motifs. Despite their large size (up to 2500 Å3), these alkaloids can bind easily to the large drug-binding cavity (about 4800 Å3) on α-tubulin facing the β-tubulin unit. The molecular docking analysis suggests that these hydrophobic macro-alkaloids can form stable complexes with α/β-tubulin. The tubulin-binding capacity varies depending on the alkaloid size and structure. Structure-binding relationships are discussed. The docking analysis identifies the trimer fluevirosine D, tetramer fluevirosinine D, and pentamer fluevirosinine H as the most interesting tubulin ligands in the series. This study is the first to propose a molecular target for these atypical oligomeric Securinega alkaloids.

Most fungi generate secondary metabolites essential to their growth or used as chemical defense systems. They produce a large variety of small molecules, notably alkaloids containing an isoindolinone unit in the form of small bicyclic cichorine-type molecules more or less substituted, up to the form of extended, heavily substituted tri- or tetra-cyclic molecules equipped with one or two prenyl side chains. An extended family of more than 170 isoindolinone derivatives produced by mycelial or endophytic fungi has been identified and analyzed. These isoindolinone derivatives include many series such as the andicichorines, aspergillinines, caputmedusins, clitocybins, daldinans, emerimidines, emeriphenolicins, entonalactams, erinaceolactams, erinacerins, fendlerinines, marilines, meyeroguillines, stachartins, stachybotrins, stachybotrysams, sterenins, xylactams, and others compounds endowed with pharmacological properties described here. The family also includes isoindolinone dimers, notably potent fibrinolytic compounds, such as those designated Stachybotrys microspora triprenyl phenol (SMTP) with the lead product SMTP-7 (orniplabin) currently developed for the treatment of stroke. The repertoire of isoindolinone-based natural products produced by fungi is large (in contrast that of vascular plants) and comprises products with marked anti-inflammatory, antiviral, or anticancer activities. All these fungal isoindolinone-based products can be exploited for their medicinal properties and to guide the design of functionalized analogues targeting different enzymes or pathways. The chemical or biosynthetic access to these products is evoked and the most potent derivatives are underlined. Altogether, the review offers an exhaustive repertoire of isoindolinones of fungal origin and their pharmacological properties.

Introduction: The quest for small molecule inhibitors of the PD-1/PD-L1 checkpoint continues in parallel to the extensive development of monoclonal antibodies directed against this immune checkpoint. Drug screening strategies are being set up to identify novel PD-L1 inhibitors. Methods: A virtual screening based on molecular docking with the PD-L1 protein dimer has been performed to identify a new binder. Binding of the identified ligand to PD-L1 has been validated experimentally using a microscale thermophoresis (MST) assay. The cellular effect of the compound was evidenced using a fluorescence resonance energy transfer (FRET) assay based on activation of tyrosine phosphatase SHP-2. Results: We have identified the potent Wnt/β-catenin inhibitor KYA1797K as a weak PD-L1 binder. Molecular docking suggested that the compound can bind to the interface of a PD-L1 dimer, with a geometry superimposable to that of the reference PD-L1 inhibitor BMS-202. The atypical 2-thioxo-4-thiazolidinone motif of KYA1797K, derived from the natural product rhodanine, plays a major role in the interaction with PD-L1. Binding of KYA1797K to recombinant hPD-L1 was validated experimentally, using MST. The drug was found to bind modestly but effectively to hPD-L1. The FRET assay confirmed the weak capacity of KYA1797K to interfere with the activation of SHP-2 upon its interaction with human PD-1. Discussion: Collectively, the data show that KYA1797K could function as a weak modulator of the PD-1/PD-L1 checkpoint. This effect may contribute, at least partially, to the reported capacity of the β-catenin inhibitor to downregulate PD-L1 in cancer cells. The work also underlines the interest to further consider the rhodanine moiety as a chemical motif for the design of new PD-L1 binders.

The roots of the plant Cynanchum otophyllum C. K. Schneid (Apocynaceae), known as Qingyangshen in Chinese, are used for a long time as a traditional medicine by different ethnic communities in the Yunnan province (China). The multiple properties and applications of this herbal medicine have been analyzed. C. otophyllum is a perennial herbal liana, nonedible, and generally wild harvested. A cultivation method has been proposed to increase the fruit set level. Qingyangshen is used essentially to treat epilepsy, rheumatism, or other inflammatory diseases. The plant can be found also in diverse polyherbal preparations used in cosmetic or as food supplement (detox products), and in phyto-preparations claimed to reduce hair loss. The plant is a rich reservoir of C-21 steroidal glycosides. Many bioactive compounds have been isolated from this plant and some of them have been pharmacologically characterized, such as otophyllosides, cynotophyllosides, cynanotins, cynotogenins, cynanchins, all briefly evocated here. The plant presents also interesting features in other domains. In particular, leave extracts of C. otophyllum C. K. Schneid contain proteases which are exploited for the local preparation of a cheese-like milk cake. Qingyangshen herbal preparation can be useful to treat epilepsy and inflammation. It has applications beyond medicine in the cosmetic and food industry.

The species Fissistigma oldhamii (Hemsl.) Merr. (Annonaceae) has long been used as a traditional herbal medicine in China to treat diverse human diseases. Decoctions from the roots of the plant (Guā Fù Mù) are used to treat body pain and inflammatory pathologies, such as rheumatic syndromes, sciatica, and osteoarthritis. The phytochemical content of the plant and the associated pharmacological activities have been analyzed. Seventy natural products were identified in the different parts of the plants, namely, the roots, stems, leaves, fruits, and seeds. The compounds comprise many tri- and tetracyclic alkaloids (aporphine-type), anthraquinones, terpenoids, flavonoids, and others. The pharmacological properties of these molecules were analyzed to point out the anti-inflammatory, antioxidant, anticancer, and/or antimicrobial effects, together with the underlying modulated pathways and molecular targets in some cases. The panel of phytoconstituents present in F. oldhamii extracts is large, with the majority of bioactive products identified in the roots and stems. Multiple molecules can contribute to the anti-inflammatory properties of the extracts. Network pharmacology analyses of the phytoconstituents are needed to better delineate the effective components and their targets.

Objective: The mangrove tree Xylocarpus granatum J. Koenig (X. granatum) is a medicinal plant used to treat various diseases in several Asian countries. Many bioactive natural products have been isolated from the plants, particularly several groups of limonoids, including 18 xylogranatins (Xyl-A to R), all of which bear a furyl-δ-lactone core commonly found in limonoids. Based on a structural analogy with the limonoids obacunone and gedunin, we hypothesized that xylogranatins could target the enzyme glycogen synthase kinase-3β (GSK-3β), a major target for the treatment of neurodegenerative pathologies, viral infections, and cancers. Methods: We investigated the binding of the 18 xylogranatins to GSK-3β using molecular docking in comparison with two known reference GSK-3β ATP-competitive inhibitors, LY2090314 and AR-A014418. For each compound bound to GSK-3β, the empirical energy of interaction (ΔE) was calculated and compared to that obtained with known GSK-3β inhibitors and limonoid triterpenes that target this enzyme. Results: Five compounds were identified as potential GSK-3β binders, Xyl-A, –C, -J, –N, and –O, for which the calculated empirical ΔE was equivalent to that calculated using the best reference molecule AR-A014418. The best ligand is Xyl-C, which is known to have marked anticancer properties. Binding of Xyl-C to the ATP-binding pocket of GSK-3β positions the furyl-δ-lactone unit deep into the binding-site cavity. Other xylogranatin derivatives bearing a central pyridine ring or a compact polycyclic structure are much less adapted for GSK-3β binding. Structure-binding relationships are discussed. Conclusion: GSK-3β may contribute to the anticancer effects of X. granatum extract. This study paves the way for the identification of other furyl-δ-lactone-containing limonoids as GSK-3β modulators.

The dried fruits of the plant Forsythia suspensa (Forsythia Fructus: Lianqiao in Chinese) are used in many herbal preparations to treat various diseases or the associated symptoms. Forsythia extracts contain phenylethanoid glycosides (PhGs) such as the forsythosides (Fst A-to-P). The leading products, Fst-A,-B and-F (arenarioside), can be found also in >90 other plants inventoried here. The pharmacological properties of Fst are reviewed, with emphasis on their anticancer, antiviral, and antibacterial activities, which essentially derive from their anti-inflammatory and antioxidant effects. Fst-B functions as a potential binder of the repressor protein Kelch-like ECH-association protein 1 (Keap 1), thus promoting the nuclear translocation of the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) implicated in the subsequent activation of the production of antioxidant enzymes and repression of the oxidative stress. The regulation of the Nrf2/Heme oxygenase-1 pathway is the central piece of the multifaceted mechanism of action of Fst-A/B. Their prominent antioxidant and anti-inflammatory effects support the use of these compounds in different inflammation-related diseases and conditions, from sepsis to neuroprotection and many other pathologies discussed here. In addition, these properties contribute to the antiviral action of the compounds. Fst-A/B displays activities against the influenza A virus and different Fst-containing traditional Chinese medicinal (TCMs) have revealed beneficial effects to combat the current COVID-19 pandemic. The mechanisms whereby Fst-A/B could inhibit viral multiplication are discussed. PhGs likely contribute to the anti-COVID-19 activities reported with several TCM such as Shuang-Huang-Lian oral liquid, Lianhua-Qingwen capsules, and others. This review highlights the pharmacological profile of Fst and illustrates health benefits associated with the use of Forsythia Fructus.

Phytolacca: (Shanglu) is a well-known traditional herbal medicine that has been used for thousands of years in China. Phytolacca is also used worldwide in different traditional phyto-medicines and homeopathic preparations. The present work reviewed advances in the traditional uses, plant origin, chemical constituents, pharmacology, and medicinal properties of Phytolacca. Phytolacca is usually made from the roots of Phytolacca acinosa and P. esculenta, but the invasive plant P. americana (American pokeweed) is also widely used. Different types of medicinal products made with Phytolacca are available, as well as various types of Phytolacca extracts, showing a range of pharmacological activities including antioxidant, anti-inflammatory, anti-parasitic, antifungal, anticancer, and insecticidal effects. The marked anti-inflammatory activity of Phytolacca extracts supports its use in treating diseases such as arthritis, nephritis, and rheumatism, as well as in combatting cancer. Several bioactive natural products have been identified from Phytolacca, including glycosylated saponins such as esculentosides and phytolaccosides, as well as a few flavones (cochliophilin A) and phytosterols (α-spinasterol), which contribute to Phytolacca’s anti-inflammatory and/or anticancer effects. A quality evaluation of Phytolacca-based extracts and products is highly recommended; nevertheless, the use of Phytolacca can be encouraged to help regulate cytokine production and combat inflammatory diseases.

The steroidal alkaloid cyclovirobuxine D (Cvb-D) is the active principle of the oral drug huangyangning used for many years in China for the treatment of cardiovascular and cerebrovascular diseases. The drug is listed in the Chinese pharmacopeia. Recent studies have revealed that this unsung alkaloid also displays anticancer properties in vitro and in vivo. The drug activates several signaling pathways, and notably represses phosphorylation of proteins EGFR, ERK, Akt, mTOR. Thereby, Cvb-D exerts antiproliferative and antimetastatic activities. In the present review, the anticancer effects of Cvb-D and related natural products isolated from Buxus species have been analyzed. The molecular targets of Cvb-D are unknown at present, but hypotheses are formulated based on the signaling pathways modulated by the drug and the analogy with other compounds. Proteins EGFR and CTHRC1, implicated in the antiproliferative action of Cvb-D, could be considered as upstream targets. A bolder assumption is also formulated with the metastasis-associated protein S100A4 as a potential co-target for Cvb-D. This review aims to shed light on the anticancer properties of Cvb-D and to encourage further mechanistic studies with this drug with a good safety profile and a recognized anti-cardiovascular efficacy.

Summary: An analysis of the implication of the PD-1/PD-L1 immune checkpoint in periodontitis is provided with the objective to propose a novel therapeutic approach. An exhaustive survey of the literature has been performed to answer two questions: (1) Is there a role for PD-1 and/or PD-L1 in the development of periodontitis? (2) Which natural products interfere with the checkpoint activity and show activity against periodontitis? All online published information was collected and analyzed. The pathogenic bacteria Porphyromonas gingivalis, through its membrane-attached peptidoglycans, exploits the PD-1/PD-L1 checkpoint to evade immune response and to amplify the infection. Three anti-inflammatory natural products (and derivatives or plant extracts) active against periodontitis and able to interfere with the checkpoint were identified. Both curcumin and baicalin attenuate periodontitis and induce a down-regulation of PD-L1 in cells. The terpenoid saponin platycodin D inhibits the growth of P. gingivalis responsible for periodontitis and shows a rare capacity to induce the extracellular release of a soluble form of PD-L1, thereby restoring T cell activation. A potential PD-L1 shedding mechanism is discussed. The targeting of the PD-1/PD-L1 immune checkpoint could be considered a suitable approach to improve the treatment of chronic periodontitis. The plant natural products curcumin, baicalin and platycodin D should be further evaluated as PD-1/PD-L1 checkpoint modulators active against periodontitis.

Abstract Nagilactones are tetracyclic natural products isolated from various Podocarpus species. These lactone-based compounds display a range of pharmacological effects, including antifungal, anti-atherosclerosis, anti-inflammatory and anticancer activities reviewed here. The most active derivatives, such as nagilactones C, E and F, exhibit potent anticancer activities against different cancer cell lines and tumor models. A comprehensive analysis of their mechanism of action indicates that their anticancer activity mainly derives from three complementary action: (i) a drug-induced inhibition of cell proliferation coupled with a cell cycle perturbation and induction of apoptosis, (ii) a blockade of the epithelial to mesenchymal cell transition contributing to an inhibition of cancer cell migration and invasion and (iii) a capacity to modulate the PD-L1 immune checkpoint. Different molecular effectors have been implicated in the antitumor activity, chiefly the AP-1 pathway blocked upon activation of the JNK/c-Jun axis. Nag-C is a potent inhibitor of protein synthesis binding to eukaryotic ribosomes and inhibition of different protein kinases, such as RIOK2 and JAK2, has been postulated with Nag-E. The literature survey on nagilactones highlights the therapeutic potential of these little-known terpenoids. The mechanistic analysis also provides useful information for structurally related compounds (podolactones, oidiolactones, inumakilactones) isolated from Podocarpus plants.

Orally-active anticancer small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched. Phenyl-pyrazolone derivatives with a high affinity for PD-L1 have been designed and characterized. In addition, the phenyl-pyrazolone unit acts as a scavenger of oxygen free radicals, providing antioxidant effects. The mechanism is known for the drug edaravone (1) which is also an aldehyde-reactive molecule. The present study reports the synthesis and functional characterization of new molecules (2–5) with an improved anti-PD-L1 activity. The leading fluorinated molecule 5 emerges as a potent checkpoint inhibitor, avidly binding to PD-L1, inducing its dimerization, blocking PD-1/PD-L1 signaling mediated by phosphatase SHP-2 and reactivating the proliferation of CTLL-2 cells in the presence of PD-L1. In parallel, the compound maintains a significant antioxidant activity, characterized using electron paramagnetic resonance (EPR)-based free radical scavenging assays with the probes DPPH and DMPO. The aldehyde reactivity of the molecules was investigated using 4-hydroxynonenal (4-HNE), which is a major lipid peroxidation product. The formation of drug-HNE adducts, monitored by high resolution mass spectrometry (HRMS), was clearly identified and compared for each compound. The study leads to the selection of compound 5 and the dichlorophenyl-pyrazolone unit as a scaffold for the design of small molecule PD-L1 inhibitors endowed with antioxidant properties.

The present analysis retraces the discovery of plagiochilins A-to-W, a series of seco-aromadendrane-type sesquiterpenes isolated from diverse leafy liverworts of the genus Plagiochila. Between 1978, with the first isolation of the leader product plagiochilin A from P. yokogurensis, and 2005, with the characterization of plagiochilin X from P. asplenioides, a set of 24 plagiochilins and several derivatives (plagiochilide, plagiochilal A-B) has been isolated and characterized. Analogue compounds recently described are also evoked, such as the plagiochianins and plagicosins. All these compounds have been little studied from a pharmacological viewpoint. However, plagiochilins A and C have revealed marked antiproliferative activities against cultured cancer cells. Plagiochilin A functions as an inhibitor of the termination phase of cytokinesis: the membrane abscission stage. This unique, innovative mechanism of action, coupled with its marked anticancer action, notably against prostate cancer cells, make plagiochilin A an interesting lead molecule for the development of novel anticancer agents. There are known options to increase its potency, as deduced from structure–activity relationships. The analysis shed light on this family of bryophyte species and the little-known group of bioactive terpenoid plagiochilins. Plagiochilin A and derivatives shall be further exploited for the design of novel anticancer targeting the cytokinesis pathway.

The antitumor drug topotecan (TPT) is a potent inhibitor of topoisomerase I, triggering DNA breaks lethal for proliferating cancer cells. The mechanism is common to camptothecins SN38 (the active metabolite of irinotecan) and belotecan (BLT). Recently, TPT was shown to bind the ribosomal protein L15, inducing an antitumor immune activation independent of topoisomerase I. We have modeled the interaction of four camptothecins with RPL15 derived from the 80S human ribosome. Two potential drug-binding sites were identified at Ile135 and Phe129. SN38 can form robust RPL15 complexes at both sites, whereas BLT essentially gave stable complexes with site Ile135. The empirical energy of interaction (ΔE) for SN38 binding to RPL15 is similar to that determined for TPT binding to the topoisomerase I-DNA complex. Molecular models with the ribosomal protein L11 sensitive to topoisomerase inhibitors show that SN38 can form a robust complex at a single site (Cys25), much more stable than those with TPT and BLT. The main camptothecin structural elements implicated in the ribosomal protein interaction are the lactone moiety, the aromatic system and the 10-hydroxyl group. The study provides guidance to the design of modulators of ribosomal proteins L11 and L15, both considered anticancer targets.

The genus Ruta in the family Rutaceae includes about 40 species, such as the well-known plants R. graveolens L. (common rue) or R. chalepensis L. (fringed rue), but also much lesser-known species such as R. angustifolia Pers. (narrow-leaved fringed rue). This rue specie, originating from the Mediterranean region, is well-distributed in Southeast Asia, notably in the Indo-Chinese peninsula and other territories. In some countries, such as Malaysia, the plant is used to treat liver diseases and cancer. Extracts of R. angustifolia display antifungal, antiviral and antiparasitic effects. Diverse bioactive natural products have been isolated from the aerial parts of the plant, notably quinoline alkaloids and furocoumarins, which present noticeable anti-inflammatory, antioxidant and/or antiproliferative properties. The present review discusses the main pharmacological properties of the plant and its phytoconstituents, with a focus on the anticancer activities evidenced with diverse alkaloids and terpenoids isolated from the aerial parts of the plant. Quinoline alkaloids such as graveoline, kokusaginine, and arborinine have been characterized and their mode of action defined. Arborinine stands as a remarkable inhibitor of histone demethylase LSD1, endowed with promising anticancer activities. Other anticancer compounds, such as the furocoumarins chalepin and rutamarin, have revealed antitumor effects. Their mechanism of action is discussed together with that of other bioactive natural products, including angustifolin and moskachans. Altogether, R. angustifolia Pers. presents a rich phytochemical profile, fully consistent with the traditional use of the plant to treat cancer. This rue species, somewhat neglected, warrant further investigations as a medicinal plant and a source of inspiration for drug discovery and design.

Cryptoconcatones A-L represent a series of 12 dihydropyrone derivatives isolated from the evergreen tree Cryptocarya concinna Hance, which is well distributed in southeast Asia. The lead compound in the series, cryptoconcatone L, has revealed antiproliferative activity against cultured cancer cells but its mechanism of action remains unknown. Based on a structural analogy with the anticancer natural product pironetin, which is well known for binding covalently to α-tubulin and for functioning as a microtubule polymerization inhibitor, we investigated the interaction of cryptoconcatones with tubulin dimers using molecular docking. The α-tubulin binding capacity of each compound was quantified (through calculation of the empirical energy of interaction ΔE) and structure–binding relationships were delineated. Two compounds were found to interact with α-tubulin much more potently than pironetin: cryptoconcatones F and L. In both cases, the facile formation of a covalent bond with Cys316 was evidenced, as observed with the parent compound pironetin. A few other pironetin analogues were investigated, including spicigerolide, which is an analogue of another known α-tubulin binder. Altogether, this study points to the identification of a series of 5,6-dihydro-α-pyrones as α-tubulin-binding agents. The study contributes to a better understanding of the mechanism of action of cryptoconcatones and should help the design of analogues targeting the pironetin site of α-tubulin.

Drugs targeting the cell division cycle kinase 7 (Cdc7) are actively searched for the treatment of different pathologies such as amyotrophic lateral sclerosis and cancer. Cdc7 interacts with multiple protein partners, including protein Dbf4 to form the Dbf4-dependent kinase (DDK) complex which regulates DNA replication initiation. Cdc7 and its activator Dbf4 are over-expressed in some cancers. The antibacterial drug clofoctol (CFT), used to treat respiratory tract infections, has been shown to block Cdc7 kinase activity, acting as a non-ATP-competitive inhibitor, capable of arresting DNA synthesis in cancer cells. We have modeled the interaction of CFT with the DDK complex and identified four potential binding sites at the interface of the Cdc7/Dbf4 heterodimer: at T109 and D128 (Cdc7), V220 and I330 (Dbf4). CFT behaves as an interfacial protein-protein inhibitor of the Cdc7/Dbf4 complex, limiting drug access to the proximal kinase site. Six CFT analogues have been tested for binding to the kinase complex. Two potent binders were analyzed in detail. The CFT structure was modulated to replace the two chlorine atoms with hydroxyl groups. The empirical potential energy of interaction (ΔE) calculated with hydroxylated compounds points to a more favorable interaction with the DDK complex, in particular at D128 site with the compound bearing two ortho-OH groups. Our work contributes to the identification of novel DDK inhibitors. DOI: http://dx.doi.org/10.5281/zenodo.5527211

Extracts of the plant Glycyrrhiza glabra (licorice) are used in traditional medicine to treat malaria. The main active components are the saponin glycyrrhizin (GLR) and its active metabolite glycyrrhetinic acid (GA) which both display activities against Plasmodium falciparum. We have identified three main mechanisms at the origin of their anti-plasmodial activity: (i) drug-induced disorganisation of membrane lipid rafts, (ii) blockade of the alarmin protein HMGB1 and (iii) potential inhibition of the detoxifying enzyme glyoxalase 1 (GLO-1) considered as an important drug target for malaria. Our analysis shed light on the mechanism of action of GLR against P. falciparum.

The para-terphenyl derivative vialinin A (Vi-A), isolated from Thelephora fungi, has been characterized as a potent inhibitor of the ubiquitin-specific protease 4 (USP4). Blockade of USP4 contributes to the anti-inflammatory and anticancer properties of the natural product. We have investigated the interaction of Vi-A with USP4 by molecular modeling, to locate the binding site (around residue V98 within the domain in USP segment) and to identify the binding process and interaction contacts. From this model, a series of 32 p-terphenyl compounds were tested as potential USP4 binders, mainly in the vialinin, terrestrin and telephantin series. We identified 11 compounds presenting a satisfactory USP4 binding capacity, including two fungal products, vialinin B and aurantiotinin A, with a more favorable empirical energy of USP4 interaction (ΔE) than the reference product Vi-A. The rare p-terphenyl aurantiotinin A, isolated from the basidiomycete T. aurantiotincta, emerged as a remarkable USP4 binder. Structure-binding relationships have been identified and discussed, to guide the future design of USP4 inhibitors based on the p-terphenyl skeleton. The docking study should help the identification of other protease inhibitors from fungus.

The medicinal plant Artabotrys hexapetalus (synonyms: A.uncinatus and A. odoratissimus) is known as yingzhao in Chinese. Extracts of the plant have long been used in Asian folk medicine to treat various symptoms and diseases, including fevers, microbial infections, ulcers, hepatic disorders and other health problems. In particular, extracts from the roots and fruits of the plant are used for treating malaria. Numerous bioactive natural products have been isolated from the plant, mainly aporphine (artabonatines, artacinatine) and benzylisoquinoline (hexapetalines) alkaloids, terpenoids (artaboterpenoids), flavonoids (artabotrysides), butanolides (uncinine, artapetalins) and a small series of endoperoxides known as yingzhaosu A-to-D. These natural products confer antioxidant, anti-inflammatory and antiproliferative properties to the plant extracts. The lead compound yingzhaosu A displays marked activities against the malaria parasites Plasmodium falciparum and P. berghei. Total syntheses have been developed to access yingzhaosu compounds and analogues, such as the potent compound C14-epi-yingzhaosu A and simpler molecules with a dioxane unit. The mechanism of action of yingzhaosu A points to an iron(II)-induced degradation leading to the formation of two alkylating species, an unsaturated ketone and a cyclohexyl radical, which can then react with vital parasitic proteins. A bioreductive activation of yingzhaosu A endoperoxide can also occur with the heme iron complex. The mechanism of action of yingzhaosu endoperoxides is discussed, to promote further chemical and pharmacological studies of these neglected, but highly interesting bioactive compounds. Yingzhaosu A/C represent useful templates for designing novel antimalarial drugs.

More than 100 protostane triterpenoids have been isolated from the dried rhizomes of Alisma species, designated Alismatis rhizoma (AR), commonly used in Asian traditional medicine to treat inflammatory and vascular diseases. The main products are the alisols, with the lead compounds alisol-A/-B and their acetate derivatives being the most abundant products in the plant and the best-known bioactive products. The pharmacological effects of Ali-A, Ali-A 24-acetate, Ali-B, Ali-B 23-acetate, and derivatives have been analyzed to provide an overview of the medicinal properties, signaling pathways, and molecular targets at the origin of those activities. Diverse protein targets have been proposed for these natural products, including the farnesoid X receptor, soluble epoxide hydrolase, and other enzymes (AMPK, HCE-2) and functional proteins (YAP, LXR) at the origin of the anti-atherosclerosis, anti-inflammatory, antioxidant, anti-fibrotic, and anti-proliferative activities. Activities were classified in two groups. The lipid-lowering and anti-atherosclerosis effects benefit from robust in vitro and in vivo data (group 1). The anticancer effects of alisols have been largely reported, but, essentially, studies using tumor cell lines and solid in vivo data are lacking (group 2). The survey shed light on the pharmacological properties of alisol triterpenoids frequently found in traditional phytomedicines.

Bladder pathologies, very common in the aged population, have a considerable negative impact on quality of life. Novel targets are needed to design drugs and combinations to treat diseases such as overactive bladder and bladder cancers. A promising new target is the ubiquitous Rho GTPase Rac1, frequently dysregulated and overexpressed in bladder pathologies. We have analyzed the roles of Rac1 in different bladder pathologies, including bacterial infections, diabetes-induced bladder dysfunctions and bladder cancers. The contribution of the Rac1 protein to tumorigenesis, tumor progression, epithelial-mesenchymal transition of bladder cancer cells and their metastasis has been analyzed. Small molecules selectively targeting Rac1 have been discovered or designed, and two of them—NSC23766 and EHT 1864—have revealed activities against bladder cancer. Their mode of interaction with Rac1, at the GTP binding site or the guanine nucleotide exchange factors (GEF) interaction site, is discussed. Our analysis underlines the possibility of targeting Rac1 with small molecules with the objective to combat bladder dysfunctions and to reduce lower urinary tract symptoms. Finally, the interest of a Rac1 inhibitor to treat advanced chemoresistance prostate cancer, while reducing the risk of associated bladder dysfunction, is discussed. There is hope for a better management of bladder pathologies via Rac1-targeted approaches.

Small molecules targeting the PD-1/PD-L1 checkpoint are actively searched to complement the anticancer arsenal. Different molecular scaffolds have been reported, including phenyl-pyrazolone derivatives which potently inhibit binding of PD-L1 to PD-1. These molecules are structurally close to antioxidant drug edaravone (EDA) used to treat amyotrophic lateral sclerosis. For this reason, we investigated the capacity of five PD-L1-binding phenyl-pyrazolone compounds (1–5) to scavenge the formation of oxygen free radicals using electron spin resonance spectroscopy with DPPH/DMPO probes. In addition, the reactivity of the compounds toward the oxidized base 5-formyluracil (5fU) was assessed using chromatography coupled to mass spectrometry and photodiode array detectors. The data revealed that the phenyl-pyrazolone derivatives display antioxidant properties and exhibit a variable reactivity toward 5fU. Compound 2 with a N-dichlorophenyl-pyrazolone moiety cumulates the three properties, being a potent PD-L1 binder, a robust antioxidant and an aldehyde-reactive compound. On the opposite, the adamantane derivative 5 is a potent PD-L1 binding with a reduced antioxidant potential and no aldehyde reactivity. The nature of the substituent on the phenyl-pyrazolone core modulates the antioxidant capacity and reactivity toward aromatic aldehydes. The molecular signature of the compound can be adapted at will, to confer additional properties to these PD-L1 binders.

The barrier-to-autointegration factor 1 (BAF1) protein is a DNA-binding protein implicated in nuclear envelop repair and reformation after mitosis. This nuclear protein is frequently overexpressed in cancer cells and plays a role in the occurrence and development of different tumors. It is a potential therapeutic target for gastric cancer, breast cancer and other malignancies. For this reason, BAF1 inhibitors are searched. The butanolide lactone obtusilactone B (Ob-B) has been found to inhibit VRK1-dependent phosphorylation of BAF1, upon direct binding to the nuclear protein. Taking advantage of the known crystallographic structure of BAF1, we have elaborated molecular models of Ob-B bound to BAF1 to delimit the binding site and binding configuration. The long endoolefinic alkyl side chain of Ob-B extends into a small groove on the protein surface, and the adjacent exomethylene-γ-lactone moiety occupies a pocket comprising to the Ser-4 phosphorylation site of BAF1. Twenty butanolide lactones structurally close to ObB were screened for BAF1 binding. Several natural products with BAF1-binding capacity potentially superior to Ob-B were identified, including mahubanolide, kotomolide B, epilitsenolide D2, and a few other known anticancer plant natural products. Our study provides new ideas to guide the discovery and design of BAF1 inhibitors.

Control of the in-situ polymerization of thick methacrylic laminates is essential to minimize cavitation due to monomer boiling. To this end, a computationally efficient thermochemical model is developed to predict the temperature and degree of monomer conversion during polymerization of a methyl methacrylate (MMA)-based resin in a fibrous preform. The model couples the self-accelerating exothermic free-radical bulk polymerization of MMA (gel effect) with the heat transfer within the preform and to the environment. The predicted temperature profiles are in excellent agreement with experimental data measured during a series of in-situ polymerization tests with different heating conditions and preform thicknesses. Processing diagrams are constructed to reveal the regimes of interest for the production of thick fiber-reinforced methacrylic composites without voids induced by monomer boiling.

Glycyrrhizin (GLR) is triterpenoid saponin used for the treatment of various of liver and skin diseases. GLR blocks the nucleocytoplasmic translocation of the protein HMGB1, thereby inhibiting its extracellular release and its functions as a damage-associated molecular pattern molecule. Here we have analyzed the interaction with HMGB1 of GLR and its three main metabolites mono-glucuronyl-glycyrrhetinic acid (MGA), glycyrrhetinic acid (GA) and a sulfate metabolite of GA (Cpd 3). We determined the optimized binding configurations (starting from crystallographic data for HMGB1) of the bound 18α- and 18β-epimers to compare the potential energy of interaction (ΔE) and free energy of hydration (ΔG). The molecular modeling shows that GLR and MGA can form much more stable complexes with HMGB1 than the non-glycosylated molecules GA and Cpd 3. The glucuronic acid residue common to GLR and MGA directly attached to the terpenoid core contributes importantly to the protein interaction. 18α-GLR (isoglycyrrhizinate) appeared as a better binder to HMG Box B than 18β-GLR, whereas both epimers bind very well to HMG Box A. The stabilization of HMG Box A through an intramolecular cystine disulfide bond further increases the stability of the GLR-HMG Box A complexes. On the opposite GA and Cpd 3 exhibit a considerably weaker HMG binding capacity. The study provides a detailed in silico analysis of the interaction of GLR with HMGB1; the limitations and biological implications are discussed.

Because electromagnetic (EM) pollution of the environment is becoming such a pervasive issue, highly efficient solutions for EM protection are being keenly sought for. Our approach provides new avenues to simple, compact, and efficient broadband microwave absorbers designed to cancel EM interferences in the microwave range. The paper demonstrates the potential of a clever organization of nanoscale inclusions (carbon nanotubes, graphene, magnetic metallic nanowires or nanoparticles) in polymer matrices for controlling the propagation of microwaves over a wide range of wavelengths (10−3-10−1 m), focusing on broadband absorption. Controlled architectures of polymer composites loaded with various nanofillers, and in particular layered stacks of composite films enable optimization of the absorption bandwidth while preserving the compactness of the structure. First, various carbon-based and metallic nanofillers are synthesized. Next, nanofillers are dispersed in a polymer matrix thanks to melt polymer processing and dispersion techniques. The absorption characteristics of resulting thin composite slabs are first characterized. Various combinations of superposed slabs are then investigated and modeled in order to optimize the absorption of the resulting multilayers. As innovative approach, the performances of the investigated structures are finally compared with the help of a new figure of merit combining the maximum absorption and its bandwidth.

The dried flower buds of the plant Daphne genkwa Sieb. et Zucc. have been largely used in traditional Chinese medicine for the treatment of inflammatory diseases. Numerous diterpenoids have been isolated from the Genkwa Flos (yuanhua in Chinese), including a series of daphnane-type diterpene designated as yuanhuacin (YC, often improperly designated as yuanhuacine) and analogues with a patronymic name. The series includes ten daphnane-type diterpenes: yuanhuacin, yuanhuadin (YD), yuanhuafin (YF), yuanhuagin (YG), yuanhuahin (YH), yuanhuajin (YJ), yuanhualin (YL), yuanhuamin (YM), yuanhuapin (YP), and yuanhuatin (YT). They are distinct from the rare flavonoid yuanhuanin. The series comprises several anticancer agents, such as the lead compound YC, which has revealed potent activity in vitro and in vivo against models of lung and breast cancers. The main signaling pathways implicated in the antitumor effects have been delineated. Protein kinase C is a key factor of activity for YC, but in general the molecular targets at the origin of the activity of these compounds remain little defined. Promising anticancer effects have been reported with analogues YD and YT, whereas compounds YF and YP are considered more toxic. The pharmacological activity of each compound is presented, as well as the properties of Genkwa Flos extracts. The potential toxic effects associated with the use of these compounds are also underlined.

Sesquiterpene lactones (SLs) are abundant in plants and display a large spectrum of bioactivities. The compound britannin (BRT), found in different Inula species, is a pseudoguaianolide-type SL equipped with a typical and highly reactive α-methylene-γ-lactone moiety. The bioproperties of BRT and related pseudoguaianolide SLs, including helenalin, gaillardin, bigelovin and others, have been reviewed. Marked anticancer activities of BRT have been evidenced in vitro and in vivo with different tumor models. Three main mechanisms are implicated: (i) interference with the NFκB/ROS pathway, a mechanism common to many other SL monomers and dimers; (ii) blockade of the Keap1-Nrf2 pathway, with a covalent binding to a cysteine residue of Keap1 via the reactive α-methylene unit of BRT; (iii) a modulation of the c-Myc/HIF-1α signaling axis leading to a downregulation of the PD-1/PD-L1 immune checkpoint and activation of cytotoxic T lymphocytes. The non-specific reactivity of the α-methylene-γ-lactone moiety with the sulfhydryl groups of proteins is discussed. Options to reduce or abolish this reactivity have been proposed. Emphasis is placed on the capacity of BRT to modulate the tumor microenvironment and the immune-modulatory action of the natural product. The present review recapitulates the anticancer effects of BRT, some central concerns with SLs and discusses the implication of the PD1/PD-L1 checkpoint in its antitumor action.