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Stereodivergent synthesis of S N Ar precursors. Reagents and conditions: (a) 1.0 equiv 1, 3.0 equiv 2, 3 mol% [{Ir(cod)Cl} 2 ], 12 mol% (S)-L, 15 mol% (S)-or (R)-A, 5 mol% Zn(OTf) 2 , 1,2-dichloroethane (0.5 M), 25°C, 20 hours, for (S,R)-3: 59% yield, > 20:1 diastereomeric ratio (d.r.), >99% enantiomeric excess (e.e.), for (R,R)-3: 76% yield, > 12:1 d.r., >99% e.e.; (b) 5 mol% Grubbs II cat., CH 2 Cl 2 , 25°C, 16 hours; (c) 2.3 equiv NaClO 2 , 2.0 equiv NaH 2 PO 4 , 30 equiv 2-methyl-2-butene, tert-BuOH/H2O, 25°C; then 2.0 equiv Me 3 SiCHN 2 , C 6 H 6 /MeOH, 0°C, 90 min; (d) 8.0 equiv KOH, 3.9 equiv I 2 , MeOH, 0°C, 45 min; (e) 4.0 equiv MeMgBr, THF, 25°C, for (S,R)-4: 56% yield over three steps, for (R,R)-4: 56% yield over three steps; see the Supplementary Materials for structures of (S)-L, (S)-A, and (R)-A, as well as for further details.
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Phytochemical studies on the liverwort Radula genus have previously identified the bibenzyl (−)- cis -perrottetinene ( cis -PET), which structurally resembles (−)-Δ ⁹ - trans -tetrahydrocannabinol (Δ ⁹ - trans -THC) from Cannabis sativa L. Radula preparations are sold as cannabinoid-like legal high on the internet, even though pharmacological data...
Contexts in source publication
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... amounts of PETs for biological testing and relied on a SNAr cyclization to assemble the dihydrobenzopyran core (15). Following a stereodivergent step using iridium-and amine-catalyzed aldehyde allylation (1 + 2 → 3), the S N Ar precursors 4 were prepared through ring-closing metathesis, oxidative esterification, and subsequent Grignard addition (Fig. 2). , 12 mol% (S)-L, 15 mol% (S)-or (R)-A, 5 mol% Zn(OTf) 2 , 1,2-dichloroethane (0.5 M), 25°C, 20 hours, for (S,R)-3: 59% yield, > 20:1 diastereomeric ratio (d.r.), >99% enantiomeric excess (e.e.), for (R,R)-3: 76% yield, > 12:1 d.r., >99% e.e.; (b) 5 mol% Grubbs II cat., CH 2 4.0 equiv MeMgBr, THF, 25°C, for (S,R)-4: 56% yield over ...
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... to the identification of CB receptors (17). Thus, the benzyl substituent in PET does not fundamentally alter the binding relationships at CB receptors. In [ 35 S]GTPS binding assays, both PETs were partial CB1R agonists such as the 9 -THCs, reaching 60 to 80% of the maximal efficacy of the known full CB1R/CB2R agonist CP55,940 (see Table 1 and fig. S2). At the CB1R functional level, cis-PET was about 10 times less potent than 9 -trans-THC [half maximal effective concentration (EC 50 ) = 406 nM versus 43 nM] ( fig. S2A). Similarly, 9 -trans-THC showed a lower EC 50 value at CB2R compared with cis-PET (12 nM versus 167 nM) ( fig. S2B). cis-PET was slightly more potent at CB2R than ...
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... assays, both PETs were partial CB1R agonists such as the 9 -THCs, reaching 60 to 80% of the maximal efficacy of the known full CB1R/CB2R agonist CP55,940 (see Table 1 and fig. S2). At the CB1R functional level, cis-PET was about 10 times less potent than 9 -trans-THC [half maximal effective concentration (EC 50 ) = 406 nM versus 43 nM] ( fig. S2A). Similarly, 9 -trans-THC showed a lower EC 50 value at CB2R compared with cis-PET (12 nM versus 167 nM) ( fig. S2B). cis-PET was slightly more potent at CB2R than trans- PET, revealing a distinct stereochemical bias toward CB2R over CB1R at the functional level as compared with the corresponding 9 -THCs. At CB2R, all cannabinoids ...
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... the known full CB1R/CB2R agonist CP55,940 (see Table 1 and fig. S2). At the CB1R functional level, cis-PET was about 10 times less potent than 9 -trans-THC [half maximal effective concentration (EC 50 ) = 406 nM versus 43 nM] ( fig. S2A). Similarly, 9 -trans-THC showed a lower EC 50 value at CB2R compared with cis-PET (12 nM versus 167 nM) ( fig. S2B). cis-PET was slightly more potent at CB2R than trans- PET, revealing a distinct stereochemical bias toward CB2R over CB1R at the functional level as compared with the corresponding 9 -THCs. At CB2R, all cannabinoids were inefficient partial agonists despite their nanomolar receptor binding affinities. No relevant ef- fects on the ...
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... Sciences (Waltham, MA, USA). WIN55,212, AA (5Z,8Z,11Z, 14Z-eicosatetraenoic acid), AA-d8 (5Z,8Z,11Z,14Z-eicosatetraenoic- 5,6,8,9,11,12,14,15-d8 acid), AEA (N-(2-hydroxyethyl)-5Z,8Z,11Z,14Z- eicosatetraenamide), AEA-d4 [N-(2-hydroxyethyl-1,1,2,2-d4)-5Z,8Z, 11Z,14Z-eicosatetraenamide], 2-AG (5Z,8Z,11Z,14Z-eicosatetraenoic acid, 2-glyceryl ester), 2-AG-d5 (5Z,8Z,11Z,14Z-eicosatetraenoic acid, 2-glyceryl-1,1,2,3,3-d5 ester), linoleoyl ethanolamide [LEA or N-(2-hydroxyethyl)-9Z,12Z-octadecadienamide], LEA-d4 [N-(2- hydroxyethyl-1,1,2,2-d4)-9Z,12Z-octadecadienamide], oleoyl ethan- lonamide [OEA or N-(2-hydroxyethyl)-9Z-octadecenamide], OEA-d4 [N-(2-hydroxyethyl-1,1,2,2-d4)-9Z-octadecenamide], palmitoyleth- anolamide [PEA or N-(2-hydroxyethyl)-hexadecanamide], PEA-d5 [N-(2-hydroxyethyl)-hexadecanamide-15,15,16,16,16-d5], PGE 2 (9-oxo-11,15S-dihydroxy-prosta-5Z,13E-dien-1-oic acid), PGE 2 - d4 (9-oxo-11,15S-dihydroxy-prosta-5Z,13E-dien-1-oic-3,3,4,4-d4 acid), PGD 2 (9,15S-dihydroxy-11-oxo-prosta-5Z,13E-dien-1-oic acid), progesterone (PROG or 4-pregnene-3,20-dione), PROG-d9 (progesterone-2,2,4,6,6,17,21,21,21-d9), and corticosterone (11,21- dihydroxy-pregn-4-ene-3,20-dione) were obtained from Cayman Chemicals Europe (Ann Arbor, MI, USA). Guanosine triphosphate (GTP) and guanosine diphosphate (GDP) were purchased from Sigma (St. Louis, Missouri, USA). ...
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... material for this article is available at http://advances.sciencemag.org/cgi/ content/full/4/10/eaat2166/DC1 Fig. S1. Radioligand displacement assay using [ 3 H]CP55,940 and membranes from CHO cells stably transfected with human CB1R and CB2R, respectively. Fig. S2. [ 35 S]GTPS binding curves for THC and PET stereoisomers on human cannabinoid receptors. Fig. S3. LC-MS/MS quantifications of the NAEs OEA, PEA, and LEA in the brain of BALB/c male mice 1 hour after intraperitoneal injection of cannabinoids. Fig. S4. LC-MS/MS quantification of 9-trans-THC, cis-PET, and trans-PET in plasma of BALB/c ...
Citations
... Representative analogs from each of these three legends, compounds 5, 11, 13, 14 and 17, were selected, based on IC 50 values of 3.0 µg/mL or <3.0 µg/mL as a cut-off value against MRSA for MIC determination. Among the analogous of stemofuran A (1-5 and 17), pinosylvin (6)(7)(8)(9)(10)(11)(12)(13)(14), and resveratrol (15,16), compound 5, 11, and 17 exhibited the most potent activity against MRSA ATCC 1708, with IC 50 /MIC values of 1.18/2.50 µg/mL, 0.91/1.25 µg/mL, and 0.95/1.25 µg/mL, respectively. ...
... µg/mL, 0.91/1.25 µg/mL, and 0.95/1.25 µg/mL, respectively. In addition, these three analogs (5,11, and 17) were found to be active against E. faecalus ATCC 700221 (VRE) with IC 50 /MIC of 2.27/2.50 µg/mL, 1.17/2.50 ...
Three unique 5,6-seco-hexahydrodibenzopyrans (seco-HHDBP) machaeridiols A–C, reported previously from Machaerium Pers., have displayed potent activities against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium, and E. faecalis (VRE). In order to enrich the pipeline of natural product-derived antimicrobial compounds, a series of novel machaeridiol-based analogs (1–17) were prepared by coupling stemofuran, pinosylvin, and resveratrol legends with monoterpene units R-(−)-α-phellandrene, (−)-p-mentha-2,8-diene-1-ol, and geraniol, and their inhibitory activities were profiled against MRSA ATCC 1708, VRE ATCC 700221, and cancer signaling pathways. Compounds 5 and 11 showed strong in vitro activities with MIC values of 2.5 μg/mL and 1.25 μg/mL against MRSA, respectively, and 2.50 μg/mL against VRE, while geranyl analog 14 was found to be moderately active (MIC 5 μg/mL). The reduction of the double bonds of the monoterpene unit of compound 5 resulted in 17, which had the same antibacterial potency (MIC 1.25 μg/mL and 2.50 μg/mL) as its parent, 5. Furthermore, a combination study between seco-HHDBP 17 and HHDBP machaeriol C displayed a synergistic effect with a fractional inhibitory concentrations (FIC) value of 0.5 against MRSA, showing a four-fold decrease in the MIC values of both 17 and machaeriol C, while no such effect was observed between vancomycin and 17. Compounds 11 and 17 were further tested in vivo against nosocomial MRSA at a single intranasal dose of 30 mg/kg in a murine model, and both compounds were not efficacious under these conditions. Finally, compounds 1–17 were profiled against a panel of luciferase genes that assessed the activity of complex cancer-related signaling pathways (i.e., transcription factors) using T98G glioblastoma multiforme cells. Among the compounds tested, the geranyl-substituted analog 14 exhibited strong inhibition against several signaling pathways, notably Smad, Myc, and Notch, with IC50 values of 2.17 μM, 1.86 μM, and 2.15 μM, respectively. In contrast, the anti-MRSA actives 5 and 17 were found to be inactive (IC50 > 20 μM) across the panel of these cancer-signaling pathways.
... In addition to (-)-trans-Δ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), and the other structurally related molecules found in cannabis plants, the cannabinoid receptors are also targeted by several structurally non-related types of compounds. This diverse group of ligands encompasses endocannabinoids (the endocrine signaling molecules naturally synthesized by humans and other animals 13,14 ), other structurally-distinct plant natural products (termed collectively as phytocannabinoids 15 ), and different types of synthetic compounds (many of which are used as illicit drugs) 16,17 . For simplicity, herein, we use the term cannabinoids to collectively refer to any ligand of CB 1 and CB 2 , regardless of structure or origin. ...
Eukaryotic cells use G-protein coupled receptors to sense diverse signals, ranging from chemical compounds to light. Here, we exploit the remarkable sensing capacity of G-protein coupled receptors to construct yeast-based biosensors for real-life applications. To establish proof-of-concept, we focus on cannabinoids because of their neuromodulatory and immunomodulatory activities. We construct a CB2 receptor-based biosensor, optimize it to achieve high sensitivity and dynamic range, and prove its effectiveness in three applications of increasing difficulty. First, we screen a compound library to discover agonists and antagonists. Second, we analyze 54 plants to discover a new phytocannabinoid, dugesialactone. Finally, we develop a robust portable device, analyze body-fluid samples, and confidently detect designer drugs like JWH-018. These examples demonstrate the potential of yeast-based biosensors to enable diverse applications that can be implemented by non-specialists. Taking advantage of the extensive sensing repertoire of G-protein coupled receptors, this technology can be extended to detect numerous compounds. GPCRs are used for diverse sensing in eukaryotes. Here the authors use GPCRs to construct yeast-based biosensors, focussing on cannabinoids, and use these to screen agonists and antagonists, as well as generate a portable detection device.
... Tests on mouse brains showed that this compound is bioavailable and selectively binds to CB1 and CB2 receptors at nanomolar concentrations in vitro. Cis-PET induced similar effects to Δ9trans-THC, including antinociception, hypothermia, catalepsy, and hypolocomotion [111]. ...
... Metabolites such as marchantin A, plagochilin E, and riccardin C exhibit cytotoxic activities against chemoresistant prostate cancer [3,100]. In addition to the aforementioned active compounds, those with antioxidant [135][136][137], anti-inflammatory [138][139][140], psychoactive [111], antiviral [141], muscle-relaxing [142], neuroprotective [142,143], anti-HIV [144], and insecticidal activities can be distinguished [145,146]. Compounds with nematicidal activity have potential in agricultural industry as natural plantprotection products. ...
Bryophytes constitute a heterogeneous group of plants which includes three clades: approximately 14,000 species of mosses (Bryophyta), 6000 species of liverworts (Marchantiophyta), and 300 species of hornworts (Anthocerotophyta). They are common in almost all ecosystems, where they play important roles. Bryophytes lack developed physical barriers, yet they are rarely attacked by herbivores or pathogens. Instead, they have acquired the ability to produce a wide range of secondary metabolites with diverse functions, such as phytotoxic, antibacterial, antifungal, insect antifeedant, and molluscicidal activities. Secondary metabolites in bryophytes can also be involved in stress tolerance, i.e., in UV-absorptive and drought-and freezing-tolerant activities. Due to these properties, for centuries bryophytes have been used to combat health problems in many cultures on different continents. Currently, scientists are discovering new, unique compounds in bryophytes with potential for practical use, which, in the age of drug resistance, may be of considerable importance. The aim of this review is to present bryophytes as a potential source of compounds with miscellaneous possible uses, with a focus on volatile compounds and antibacterial, antifungal, and cytotoxic potential, and as sources of materials for further promising research. The paper also briefly refers to the methods of compound extraction and acquisition. Formulas of compounds were drawn by the authors using ChemDraw software (PerkinElmer, Boston, MA, USA) with reference to data published in various papers, the ACD/Labs dictionary database, PubChem, and Scopus. The data were gathered in February 2022.
... Liverworts are the most abundant phylum, comprising as many as 9000 species with high diversity in their ecology, morphology and genetic variation, and consequently are used the studies of the evolutionary origins of biodiversity and plant chemistry [67,69]. The most commonly recognised Radula species are found in all ecosystems such as trees, rocks, and soils throughout the world, from Antarctica's coastal area to the northern hemisphere and from Australian semi-arid regions to the Amazon rainforest [71]. ...
... (Figure 3) [70,73]. These compounds have opposite stereochemical configuration (a cis configuration) in the cyclohexene ring compared with Δ 9 -trans-THC [71]. Most notably, (-)-cis-PET and its (-)-trans diastereoisomers demonstrated potential agonist toward CB1 and CB2 receptors. ...
... Additionally, a homolog structure stilbene synthase (STS) that was a homolog of olivetolic acid had been characterised. Thus, (-)-cis-PET is a psychoactive cannabinoid from bryophytes, indicating the convergent development of bioactive cannabinoids in plants [71]. Beside PET, a chromene -like structure had been also found in R. laxiramea Steph. ...
Phytocannabinoids are isoprenylated resorcinyl polyketides produced mostly in glandular trichomes of Cannabis sativa L. These discoveries led to the identification of cannabinoid receptors, which modulate psychotropic and pharmacological reactions and are found primarily in the human central nervous system. As a result of the biogenetic process, aliphatic ketide phytocannabinoids are exclusively found in the cannabis species and have a limited natural distribution, whereas phenethyl-type phytocannabinoids are present in higher plants, liverworts, and fungi. The development of cannabinomics has uncovered evidence of new sources containing various phytocannabinoid derivatives. Phytocannabinoids have been isolated as artifacts from their carboxylated forms (pre-cannabinoids or acidic cannabinoids) from plant sources. In this review, the overview of the phytocannabinoid biosynthesis is presented. Different non-cannabis plant sources are described either from those belonging to the angiosperm species and bryophytes, together with their metabolomic structures. Lastly, we discuss the legal framework for the ingestion of these biological materials which currently receive the attention as a legal high.
... A final issue worth attention is the absolute configuration of a hypothetical non-Cannabis CBD. Thus, CBD from Cannabis has a very high enantiomeric purity with a 3R,4R configuration (p-menthane numbering), 33 but cis-Δ 9 -THC (5) from Cannabis 34 and its phenethyl analogue perottetinene (6) from various Radula species 35,36 have an opposite configuration at C-6a (corresponding to C-4 in the p-menthane numbering system). This suggests that, in the search for non-Cannabis sources of CBD, the relative configuration of the 2 stereogenic centers, as well as the absolute configuration and the optical purity need to be critically evaluated. ...
Reports on the occurrence of cannabidiol (CBD, 1) in non-cannabis plants are critically reviewed. The isolation of 1 from Humulus Kriya (sic) was fraudulent and from Trema orientalis and stevia dubious, while the occurrence of traces of 1 in flax needs additional confirmation. The presence of high concentration of cannabigerol (CBG, 3a) and its corresponding acidic precursor (GBGA, 3b) in Helichrysum umbraculigerum could not be confirmed, but this plant deserves additional attention due to the possible phytocannabinoids accumulation in selected chemotypes.
... Eventually, the evolution of specialized metabolism led to independent biosynthetic pathways that produce similar compounds. For example, the liverwort Radula marginata and other Radula species produce perrottetinene (Toyota et al., 2002) and perrottetinenic acid (Asakawa et al., 2020) an analogue of Cannabis sativa Δ9-tetrahydrocannabinol with similar pharmacological properties (Chicca et al., 2018;Gülck and Moller, 2020). These compounds of liverworts are in fact bisbenzyls that are accumulated in OBs (Hussain et al., 2019) and their biosynthesis evolved in a completely different fashion to that of cannabinoids in vascular plants. ...
Liverworts are known for their large chemical diversity. Much of this diversity is synthesized and enclosed within the oil bodies (OB), a synapomorphy of the lineage. OB contain the biosynthetic enzymes to produce and store large quantities of sesquiterpenoids and other compounds while limiting their cytotoxicity. Recently, there were important biochemical and molecular discoveries related to OB formation, diversity and biochemistry that allows the comparison with other secretory structures of land plants in an evo-devo perspective. In this review, we address and discuss the most recent advances in OB origin, development and function to understand the importance of these organelles in liverwort physiology and adaptation to the changing environment. Our mapping of OB-types and chemical compounds to the current liverwort phylogeny suggests that OB were already present in the most recent common ancestor of liverworts, supporting OB evolved as the first secretory structure in land plants. Still, we require a better sampling to define the macroevolutionary pattern governing the ancestral type of OB. We conclude that current efforts in finding molecular mechanisms responsible for this morphological and chemical diversity of secretory structures will help understand the evolution of each major group of land plants, and open new avenues in biochemical research of bioactive compounds for both bryophytes and vascular plants.
... 1,15,16 The substitution of the alkyl side chain with a phenylpropionyl moiety, in combination with C-6 diastereomerization on 1, could be a potential modification to newly give rise to the production of prostaglandins D 2 and E 2 , with inhibitory effects associated with antineuroinflammation. 4 Thus the expansion of the cannabinoid analogs with C-3 alkyl-chain modifications with/without the isoprenyl unit portion might establish an excellent platform for the further development of therapeutically beneficial cannabinoids. Despite this potential, their complicated structures requiring appropriate stereospecificity, as well as insufficient insights into the biosynthesis of homologues of 1, have hindered further investigations of alkylcannabinoids. ...
... A THC bibenzyl analog was discovered in species of liverwort endemic to New Zealand in 2002 [21] along with other bibenzyl cannabinoids. The cannabinoid known as Perrottetinene is the most widely studied compound identified from the study and has since demonstrated moderate psychoactivity and cannabinoid binding ability [22] . The discovery of these analogues has highlighted the remarkable co-evolution between plant species to develop cannabinoids independently from one another using different biosynthetic pathways [23] . ...
Cannabis has been cultivated and used for millennia by the human race. The original medicinal and industrial uses of cannabis were almost forgotten during the vilification during the early 20th century. However, with renewed focus, interest, and tolerance, this species has found itself in the limelight of its original purpose. Cannabinoids have become a staple in modern holistic medicine and have even found mainstream medicinal applications. Confusion has arisen over the classification of its primary compounds, cannabinoids, as well as to the presence of similar compounds in other plant species. Novel cannabinoids produced legitimately by researchers or illicitly by clandestine chemists have only added to this issue and furthered the need for unification not only in understanding, but also in terminology. This review seeks to define critical terms for cannabinoid chemistry as well provide an introduction to the variety of compounds.
... Despite the similarity between trans-THC and cis-perrottetinene, only recently Chicca et al. reported a study on the in vitro and in vivo pharmacology of the natural cis-perrottetinene and the non-natural trans-perrottetinene [58], also comparing (− )-cis-perrottetinene and typical cannabinoids on CBR1 and CBR2 cannabinoid-like biochemical effects in animals ( Fig. 6). ...
Nowadays cardiovascular diseases (CVDs) are the major causes for the reduction of the quality of life. The endocannabinoid system is an attractive therapeutic target for the treatment of cardiovascular disorders due to its involvement in vasomotor control, cardiac contractility, blood pressure and vascular inflammation. Alteration in cannabinoid signalling can be often related to cardiotoxicity, circulatory shock, hypertension, and atherosclerosis. Plants have been the major sources of medicines until modern eras in which researchers are experiencing a rediscovery of natural compounds as novel therapeutics. One of the most versatile plant is Cannabis sativa L., containing phytocannabinoids that may play a role in the treatment of CVDs. The aim of this review is to collect and investigate several less studied plants rich in cannabinoid-like active compounds able to interact with cannabinoid system; these plants may play a pivotal role in the treatment of disorders related to the cardiovascular system.
... The duration when animals maintain an imposed position reflects catalepsy and was measured by the high bar test, as previously described 23 . Briefly, the mice were retained in an imposed position with their forelimbs resting on a horizontal bar (diameter: 0.5 cm) that was 4 cm above the benchtop, while their hindlimbs on the benchtop. ...
As one of the hallmarks of cancer, metabolic reprogramming leads to cancer progression, and targeting glycolytic enzymes could be useful strategies for cancer therapy. By screening a small molecule library consisting of 1320 FDA-approved drugs, we found that penfluridol, an antipsychotic drug used to treat schizophrenia, could inhibit glycolysis and induce apoptosis in esophageal squamous cell carcinoma (ESCC). Gene profiling and Ingenuity Pathway Analysis suggested the important role of AMPK in action mechanism of penfluridol. By using drug affinity responsive target stability (DARTS) technology and proteomics, we identified phosphofructokinase, liver type (PFKL), a key enzyme in glycolysis, as a direct target of penfluridol. Penfluridol could not exhibit its anticancer property in PFKL-deficient cancer cells, illustrating that PFKL is essential for the bioactivity of penfluridol. High PFKL expression is correlated with advanced stages and poor survival of ESCC patients, and silencing of PFKL significantly suppressed tumor growth. Mechanistically, direct binding of penfluridol and PFKL inhibits glucose consumption, lactate and ATP production, leads to nuclear translocation of FOXO3a and subsequent transcriptional activation of BIM in an AMPK-dependent manner. Taken together, PFKL is a potential prognostic biomarker and therapeutic target in ESCC, and penfluridol may be a new therapeutic option for management of this lethal disease.
