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Synthesis and Antimicrobial Activities of Certain Cannabichromene and Cannabigerol Related Compounds

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Abstract

Cannabichromene homologs, analogs, and isomers as well as the C1-homolog and isomer of cannabigerol were prepared and tested for their antimicrobial and antifungal properties. Spectral data of all compounds synthesized are presented.

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... Secondary metabolites are organic compounds produced by microorganisms and plants that play roles in a number of processes that give the plant or microorganism comparative advantage, may play a role in survival of the microorganism or plant, play a role in the aroma (terpenes), pigmentation and flavour of the plant (flavonoids), and that may have pharmacological/health benefits [80][81][82][83]. In addition to these roles, many cannabinoid-and non-cannabinoid secondary metabolites produced by C. sativa L., are analgesic, antimicrobial, anti-cancer, anti-inflammatory, anxiolytic, antidepressant, relaxant, and antioxidant [35,39,[84][85][86][87][88][89][90][91][92][93][94]. ...
... Table 4 lists particular potential applications of secondary metabolites against oral and dental diseases. Anti-bacterial Analgesic [41,47,48,84,93,117,118,191,211] 4. Abscesses (Cannabidiol and delta9-tetrahydrocannabinol) Anti-bacterial Anti-pruritic [191] 5. Prevention of biofilm attachment on teeth (Cannabidiol and delta9-tetrahydrocannabinol) Anti-bacterial [84,191] 6. Burning Mouth Syndrome (Cannabidiol) Analgesic [191] 7. Oral and Salivary Gland Cancers (Cannabidiol) Anti-cancer Anti-metastatic [191] 8. Periodontitis (most severe form of gum disease) (Cannabidiol, HU-320, delta9-tetrahydrocannabinol, AEA) ...
... Anti-bacterial Anti-inflammatory Analgesic [84,93,117,118,151,211] 10. Gingivitis (Cannabidiol, delta9-tetrahydrocannabinol, Cannabigerol, and HU-320) ...
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Oral and dental diseases are a major global burden, the most common non-communicable diseases (NCDs), and may even affect an individual’s general quality of life and health. The most prevalent dental and oral health conditions are tooth decay (otherwise referred to as dental caries/cavities), oral cancers, gingivitis, periodontitis, periodontal (gum) disease, Noma, oro-dental trauma, oral manifestations of HIV, sensitive teeth, cracked teeth, broken teeth, and congenital anomalies such as cleft lip and palate. Herbs have been utilized for hundreds of years in traditional Chinese, African and Indian medicine and even in some Western countries, for the treatment of oral and dental conditions including but not limited to dental caries, gingivitis and toothaches, dental pulpitis, halitosis (bad breath), mucositis, sore throat, oral wound infections, and periodontal abscesses. Herbs have also been used as plaque removers (chew sticks), antimicrobials, analgesics, anti-inflammatory agents, and antiseptics. Cannabis sativa L. in particular has been utilized in traditional Asian medicine for tooth-pain management, prevention of dental caries and reduction in gum inflammation. The distribution of cannabinoid (CB) receptors in the mouth suggest that the endocannabinoid system may be a target for the treatment of oral and dental diseases. Most recently, interest has been geared toward the use of Cannabidiol (CBD), one of several secondary metabolites produced by C. sativa L. CBD is a known anti-inflammatory, analgesic, anxiolytic, anti-microbial and anti-cancer agent, and as a result, may have therapeutic potential against conditions such burning mouth syndrome, dental anxiety, gingivitis, and possible oral cancer. Other major secondary metabolites of C. sativa L. such as terpenes and flavonoids also share anti-inflammatory, analgesic, anxiolytic and anti-microbial properties and may also have dental and oral applications. This review will investigate the potential of secondary metabolites of C. sativa L. in the treatment of dental and oral diseases.
... Notably, the level of sensitivity of the extracts in qualitative tests is not equipollent since their polarity and solubility change their diffusivity through media [69,70]. However, in many other investigations, the activity of C. sativa was shown against P. aeruginosa [62,[71][72][73][74][75], E. coli [62,67,68,72,[76][77][78][79][80][81][82], Salmonella species [76,80,83,84], Shigella species [76,82], K. pneumoniae [82], Acinetobacter calcoaceticus [79], Morganella morganii [62] and Serratia marcescens [84]. ...
... [68], Candida neoformans [73] and Aspergillus [68,105,122] are documented. Antifungal activity is cultivar-dependent [123] and also related to the active compounds' chemical structures [75]. The findings indicate that more intensive study on the fungicidal activity of C. sativa phytoextracts is required for the treatment of fungal infections, especially for external use. ...
... Maximum activity is manifested for CBC type compounds when a methyl or pentyl group is held in the side chain [75]. The activity is enhanced for CBC and CBG-type compounds having a methyl side chain due to saturation of two double bonds in the compounds. ...
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Abstract: Antimicrobial resistance has emerged as a global health crisis and, therefore, new drug discovery is a paramount need. Cannabis sativa contains hundreds of chemical constituents produced by secondary metabolism, exerting outstanding antimicrobial, antiviral, and therapeutic properties. This paper comprehensively reviews the antimicrobial and antiviral (particularly against SARS-CoV-2) properties of C. sativa with the potential for new antibiotic drug and/or natural antimicrobial agents for industrial or agricultural use, and their therapeutic potential against the newly emerged coron-avirus disease (COVID-19). Cannabis compounds have good potential as drug candidates for new antibiotics, even for some of the WHO's current priority list of resistant pathogens. Recent studies revealed that cannabinoids seem to have stable conformations with the binding pocket of the M pro enzyme of SARS-CoV-2, which has a pivotal role in viral replication and transcription. They are found to be suppressive of viral entry and viral activation by downregulating the ACE2 receptor and TMPRSS2 enzymes in the host cellular system. The therapeutic potential of cannabinoids as anti-inflammatory compounds is hypothesized for the treatment of COVID-19. However, more systemic investigations are warranted to establish the best efficacy and their toxic effects, followed by preclinical trials on a large number of participants.
... The formation of the post-condensation products could be prevented when the reaction of citral and olivetol was carried out in refluxing toluene in the presence of tert-butylamine (ElSohly conditions). CBC is obtained in 50-60% yield [20], with abnormal-CBC (18) and the product of bis-chromenylation (19) as major by-product [20]. ...
... The formation of the post-condensation products could be prevented when the reaction of citral and olivetol was carried out in refluxing toluene in the presence of tert-butylamine (ElSohly conditions). CBC is obtained in 50-60% yield [20], with abnormal-CBC (18) and the product of bis-chromenylation (19) as major by-product [20]. ...
... Under acidic conditions, the reaction of citral and olivetol afforded instead cis- 9 -THC as the major reaction product (20), the result of a terpenic-type intramolecular cationic cyclization ( Figure 6) [18,19]. The reaction of citral and olivetol is interesting, and well worth reinvestigation to clarify its mechanistic ambiguities and subtleties. ...
Article
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Cannabinochromene (CBC, 1a) is the archetypal member of a class of more than twenty isoprenylated 5-hydroxy-7-alkyl(aralky)benzo[2H]pyranes first reported from Cannabis sativa L. but also occurring in unrelated plants (Rhododendron species) as well as liverworts and fungi. The chemistry, synthesis, and bioactivity of CBC (1a) is reviewed, highlighting its underexploited pharmacological potential and rich chemistry.
... 631 CBG has antidepressant effects, 633 and a potent 5HT1A receptor antagonist that has been a proposed mechanism for potential antidepressant activity. 631 Benefits have been described for several issues including Huntington's disease, 634 as an appetite stimulant, 635 antibacterial effects against MRSA strains, 367 antifungal effects, 636 psoriasis, 381 inflammatory bowel disease, 637 anti-proliferative/ pro-apoptotic against tumor cell lines of multiple organ systems, 178,179,368,638,639 glaucoma, 630,640 and potential benefit for detrusor overactivity and bladder pain. 641,642 CBC is a potent TRPA1 agonist 177 that may reflect a potential role in analgesia, and a weak AEA reuptake inhibitor. ...
... 643 Sedation, analgesic, and strong anti-inflammatory effects including superiority to phenylbutazone have been shown. 105,202,363,437,[644][645][646] It may have antimicrobial effects against fungi and bacteria including MRSA, 367,636,645 cytotoxicity in cancer cell lines, 368 antianxiety/antidepressant effects, promotion of neurogenesis, 322,647,648 potential use in inflammatory bowel disease, 649 and the ability to reduce THC intoxication symptoms. 650 THCV is a propyl analog of THC. ...
Article
Background.—Comprehensive literature reviews of historical perspectives and evidence supporting cannabis/ cannabinoids in the treatment of pain, including migraine and headache, with associated neurobiological mechanisms of pain modulation have been well described. Most of the existing literature reports on the cannabinoids Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), or cannabis in general. There are many cannabis strains that vary widely in the composition of cannabinoids, terpenes, flavonoids, and other compounds. These components work synergistically to produce wide variations in benefits, side effects, and strain characteristics. Knowledge of the individual medicinal properties of the cannabinoids, terpenes, and flavonoids is necessary to cross-breed strains to obtain optimal standardized synergistic compositions. This will enable targeting individual symptoms and/or diseases, including migraine, headache, and pain. Objective.—Review the medical literature for the use of cannabis/cannabinoids in the treatment of migraine, headache, facial pain, and other chronic pain syndromes, and for supporting evidence of a potential role in combatting the opioid epidemic. Review the medical literature involving major and minor cannabinoids, primary and secondary terpenes, and flavonoids that underlie the synergistic entourage effects of cannabis. Summarize the individual medicinal benefits of these substances, including analgesic and anti-inflammatory properties. Conclusion.—There is accumulating evidence for various therapeutic benefits of cannabis/cannabinoids, especially in the treatment of pain, which may also apply to the treatment of migraine and headache. There is also supporting evidence that cannabis may assist in opioid detoxification and weaning, thus making it a potential weapon in battling the opioid epidemic. Cannabis science is a rapidly evolving medical sector and industry with increasingly regulated production standards. Further research is anticipated to optimize breeding of strain-specific synergistic ratios of cannabinoids, terpenes, and other phytochemicals for predictable user effects, characteristics, and improved symptom and diseasetargeted therapies.
... The phytocannabinoids of C. sativa have been shown to exert potential therapeutic activities in mammalians (Turner et al., 2017). Specifically, CBG exerts anti-inflammatory, neuroprotective and anti-tumor properties (Eisohly et al., 1982), and has been shown to be effective in the treatment of glaucoma, psoriasis, dry-skin syndrome and pain (Olah et al., 2016). In addition, it elicited hyperphagia (Brierley et al., 2016) and attenuated colitis (Borrelli et al., 2013) in mice. ...
... In addition, CBG caused strong reduction in their motility. So far, the activities of CBG have mainly been studied in eukaryotes where it has been found to be neuroprotective, acting as an anti-oxidant (Giacoppo et al., 2017) and exert anti-inflammatory activities (Eisohly et al., 1982). CBG has previously been found to display anti-bacterial properties toward clinical isolates of methicillin-resistant Staphylococcus aureus (Appendino et al., 2008). ...
Article
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Cannabigerol (CBG) is a non-psychoactive cannabinoid naturally present in trace amounts in the Cannabis plant. So far, CBG has been shown to exert diverse activities in eukaryotes. However, much less is known about its effects on prokaryotes. In this study, we investigated the potential role of CBG as an anti-biofilm and anti-quorum sensing agent against Vibrio harveyi. Quorum sensing (QS) is a cell-to-cell communication system among bacteria that involves small signaling molecules called autoinducers, enabling bacteria to sense the surrounding environment. The autoinducers cause alterations in gene expression and induce bioluminescence, pigment production, motility and biofilm formation. The effect of CBG was tested on V. harveyi grown under planktonic and biofilm conditions. CBG reduced the QS-regulated bioluminescence and biofilm formation of V. harveyi at concentrations not affecting the planktonic bacterial growth. CBG also reduced the motility of V. harveyi in a dose-dependent manner. We further observed that CBG increased LuxO expression and activity, with a concomitant 80% downregulation of the LuxR gene. Exogenous addition of autoinducers could not overcome the QS-inhibitory effect of CBG, suggesting that CBG interferes with the transmission of the autoinducer signals. In conclusion, our study shows that CBG is a potential anti-biofilm agent via inhibition of the QS cascade.
... Because these compounds showed only a marginal affinity for CB receptors, they were not taken into account in studies until recently, but it seems that they have a lot of other pharmacological effects with possible applications in the treatment of neurodegenerative diseases, inflammatory disease, cancer, anxiety, and depression [72], as well as infectious diseases, metabolic disorders, and psoriasis [64,109,110]. ...
... It was found that CBG has antibacterial properties against Gram-positive bacteria, mycobacteria, and fungi [109]. Recently, the antibacterial properties of CBG were tested against various methicillin-resistant Staphylococcus aureus (S. aureus) strains of current clinical relevance, and the results were promising [110]. ...
Article
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The most important discoveries in pharmacology, such as certain classes of analgesics or chemotherapeutics, started from natural extracts which have been found to have effects in traditional medicine. Cannabis, traditionally used in Asia for the treatment of pain, nausea, spasms, sleep, depression, and low appetite, is still a good candidate for the development of new compounds. If initially all attention was directed to the endocannabinoid system, recent studies suggest that many of the clinically proven effects are based on an intrinsic chain of mechanisms that do not necessarily involve only cannabinoid receptors. Recent research has shown that major phytocannabinoids and their derivatives also interact with non-cannabinoid receptors such as vanilloid receptor 1, transient receptor ankyrin 1 potential, peroxisome proliferator-activated receptor-gamma or glitazone receptor, G55 protein-coupled receptor, and nuclear receptor, producing pharmacological effects in diseases such as Alzheimer’s, epilepsy, depression, neuropathic pain, cancer, and diabetes. Nonetheless, further studies are needed to elucidate the precise mechanisms of these compounds. Structure modulation of phytocannabinoids, in order to improve pharmacological effects, should not be limited to the exploration of cannabinoid receptors, and it should target other courses of action discovered through recent research.
... Since cannabinoids are phenolics, their antibacterial activity is not surprising; however, their potency and the activity against multidrug-resistant bacterial strains are remarkable. Data on the antibiotic activity of CBC [75], CBG [76], CBD [77], and D 9 -THC [77] have been obtained, and C. sativa preparations have been investigated as topical antiseptic agents. More recently, the potential of the major cannabinoids to address antibiotic resistance to methicillin-resistant ...
Chapter
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Cannabinoids, a class of meroterpenoids derived from the alkylation of an olivetol-like alkyl resorcinol with a monoterpene unit, are the most typical constituents of Cannabis. This class includes over a hundred members belonging to several structural types, mainly differing by the constitution of their terpenoid moiety. The biomedical relevance of cannabinoids transcends the psychotropic properties of Δ9-THC since, because of their anti-inflammatory, analgesic, and antibacterial activity, they show potential in various fields of medicine, addressing unmet needs like the symptomatic mitigation of multiple sclerosis and the treatment of MRSA infections. Research on cannabinoid activities has yielded to the discovery of an entire new class of human receptors, called cannabinoid (CB) receptors, and of their endogenous agonists, collectively named endocannabinoids (EC). Since its discovery in the early 1990s, the EC system has increasingly emerged as a key signaling system involved in a plethora of physiological and pathological functions in mammals. This chapter will provide an overview on this multi-faceted class of natural products.
... 2-geranylhydroquinone and 3-demethylubiquinone Q2 ( Figure 1A) have been synthesized as drugs and they have been reported to have some value as radioprotective and anti-cancer agents 14,15 . Other synthetic geranylphenols, such as 2-geranyl-5methyl resorcinol and 4-geranyl-5-methyl resorcinol ( Figure 1A), showed antimicrobial and antifungal activities [16][17][18][19] . Recently, our research group has developed the synthesis, structural determination and antifungal activity of a series of linear geranylphenols derivatives of 2-geranylhydroquinones, such 2-geranylphloroglucinol ( Figure 1A) [20][21][22][23][24][25][26] . ...
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Background: Previous studies have demonstrated that geranyl metabolites, found mainly in marine organisms, exhibit interesting antimicrobial and antifungal activities. In addition, linear geranyl derivatives have been synthesized as drugs and reported cytotoxic and anticancer activities. Aims: Considering the biological testing and the structural features of these compounds, we evaluated seven linear geranylphenol derivatives on the human breast cancer cell line MDA-MB-231, and the human gastric cancer cell line MKN74. Results: We found that compounds 2, 5 and 7 were cytotoxic for both cancer cell lines. From them, the most potent was compound 2, with an IC50=7.5 μM for MKN74 cells, and compound 7, with an IC50=14.73 μM for MDA-MB-231 cells. By nuclear staining and inmunocytochemistry, we detected that the three compounds induced cell death, and by Western blot analysis, we observed a remarkable decrease in the expression of cyclin D1 and the retinoblastoma protein, key regulators of the cell cycle. Conclusion: Considering that compounds 2 and 7 were the most potent compounds inducing cell death, and were able to decrease the expression of retinoblastoma protein and cyclin D1, proteins usually altered in different types of cancers, they appear as promising therapeutic agents against cancer. Bangladesh Journal of Medical Science Vol.19(3) 2020 p.486-500
... The assumed antimicrobial potential of CBC and CBG [63,64], as well as the in vitro data showing that Δ 9 THC, CBD, CBC, CBN, and CBG are efficient against highly-resistant Staphylococcus aureus strains [65], have not yet translated into any specific therapeutic interventions. The mechanisms of bactericidal action in these cannabinoids is unknown, although some targets of CBC have been discovered. ...
Article
While natural Δ⁹-tetrahidrocannabinol (Δ⁹THC), cannabidiol (CBD), and their therapeutic potential have been extensively researched, some cannabinoids have not been widely investigated. The present article compiles data from the literature that highlights research on and the therapeutic possibilities of lesser known phytocannabinoids, which we have divided into varinic, acidic, and “minor” (i.e., cannabinoids that are not present in high quantities in common varieties of Cannabis sativa L). A growing interest in these compounds, which are enriched in some cannabis varieties, has already resulted in enough preclinical information to show that they are promising therapeutic agents for a variety of diseases. Each phytocannabinoid has a “preferential” mechanism of action, and often target the cannabinoid receptors CB1 and/or CB2. The recent resolution of the structure of cannabinoid receptors demonstrates the atypical nature of cannabinoid binding, and that different binding modes depend on the agonist or partial agonist/inverse agonist, which allows for differential signaling, even acting on the same cannabinoid receptor. In addition, other players and multiple signaling pathways may be targeted/engaged by phytocannabinoids, thereby expanding the mechanistic possibilities for therapeutic use.
... A review of the therapeutic potential of varinic and acidic phytocannabinoids has been recently released [29]. For instance, CBG is considered as antimicrobial [30,31] and as counteracting neuroinflammation by targeting glial cells [32]. Potential to combat amyotrophic lateral sclerosis is based in the actions of a synthetic derivative, VCE-003.2, in the SOD1G93A rodent model of the disease [33,34]. ...
Article
Background Recent approved medicines whose active principles are Δ⁹Tetrahidrocannabinol (Δ⁹-THC) and/or cannabidiol (CBD) open novel perspectives for other phytocannabinoids also present in Cannabis sativa L. varieties. Furthermore, solid data on the potential benefits of acidic and varinic phytocannabinoids in a variety of diseases are already available. Mode of action of cannabigerol (CBG), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabidivarin (CBDV) and cannabigerivarin (CBGV) is, to the very least, partial. Hypothesis/Purpose Cannabinoid CB1 or CB2 receptors, which belong to the G-protein-coupled receptor (GPCR) family, are important mediators of the action of those cannabinoids. Pure CBG, CBDA, CBGA, CBDV and CBGV from Cannabis sativa L. are differentially acting on CB1 or CB2 cannabinoid receptors. Study Design Determination of the affinity of phytocannabinoids for cannabinoid receptors and functional assessment of effects promoted by these compounds when interacting with cannabinoid receptors. Methods A heterologous system expressing the human versions of CB1 and/or CB2 receptors was used. Binding to membranes was measured using radioligands and binding to living cells using a homogenous time resolved fluorescence resonance energy transfer (HTRF) assay. Four different functional outputs were assayed: determination of cAMP levels and of extracellular-signal-related-kinase phosphorylation, label-free dynamic mass redistribution (DMR) and ß-arrestin recruitment. Results Affinity of cannabinoids depend on the ligand of reference and may be different in membranes and in living cells. All tested phytocannabinoids have agonist-like behavior but behaved as inverse-agonists in the presence of selective receptor agonists. CBGV displayed enhanced potency in many of the functional outputs. However the most interesting result was a biased signaling that correlated with differential affinity, i.e. the overall results suggest that the binding mode of each ligand leads to specific receptor conformations underlying biased signaling outputs. Conclusion Results here reported and the recent elucidation of the three-dimensional structure of CB1 and CB2 receptors help understanding the mechanism of action that might be protective and the molecular drug-receptor interactions underlying biased signaling.
... Analgesic and antierythemic effects and the ability to block lipooxygenase were said to surpass those of THC (Evans, 1991). CBG demonstrated modest antifungal effects (ElSohly, Turner, Clark, & Eisohly, 1982). CBG has remarkable anticancer properties in basic research models, it has proved to be an effective cytotoxic in high dosage on human epithelioid carcinoma and is one of the more effective phytocannabinoids against breast cancer (Baek et al., 1998;Ligresti et al., 2006). ...
Chapter
The golden age of cannabis pharmacology began in the 1960s as Raphael Mechoulam and his colleagues in Israel isolated and synthesized cannabidiol, tetrahydrocannabinol, and other phytocannabinoids. Initially, THC garnered most research interest with sporadic attention to cannabidiol, which has only rekindled in the last 15 years through a demonstration of its remarkably versatile pharmacology and synergy with THC. Gradually a cognizance of the potential of other phytocannabinoids has developed. Contemporaneous assessment of cannabis pharmacology must be even far more inclusive. Medical and recreational consumers alike have long believed in unique attributes of certain cannabis chemovars despite their similarity in cannabinoid profiles. This has focused additional research on the pharmacological contributions of mono- and sesquiterpenoids to the effects of cannabis flower preparations. Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas. Additional parts of the cannabis plant provide a wide and distinct variety of other compounds of pharmacological interest, including the triterpenoid friedelin from the roots, canniprene from the fan leaves, cannabisin from seed coats, and cannflavin A from seed sprouts. This chapter will explore the unique attributes of these agents and demonstrate how cannabis may yet fulfil its potential as Mechoulam's professed “pharmacological treasure trove.”
... These effects may be due to the agonistic nature of these compounds with endocannabinoids that compete with CB1 and CB2 receptors [98,132,133]. The pharmacological and therapeutic effects of endocannabinoids and phytocannabinoids are summarized in Table 1 and include antinociceptive, anti-epileptic, cardiovascular, immunosuppressive effects [134], nausea and vomiting, appetite stimulation [135], anticancer [136,137], antimicrobial [138], anti-inflammatory [139], neuroprotective antioxidants [140], and pain therapy [141]. Cannabis is also a potential drug for inflammatory bowel diseases (IBD) [142]. ...
Article
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Cannabis is an annual plant with a long history of use as food, feed, fiber, oil, medicine, and narcotics. Despite realizing its true value, it has not yet found its true place. Cannabis has had a long history with many ups and downs, and now it is our turn to promote it. Cannabis contains approximately 600 identified and many yet unidentified potentially useful compounds. Cannabinoids, phenolic compounds, terpenoids, and alkaloids are some of the secondary metabolites present in cannabis. However, among a plethora of unique chemical compounds found in this plant, the most important ones are phytocannabinoids (PCs). Over hundreds of 21-22-carbon compounds exclusively produce in cannabis glandular hairs through either polyketide and or deoxyxylulose phosphate/methylerythritol phosphate (DOXP/MEP) pathways. Trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are those that first come to mind while talking about cannabis. Nevertheless, despite the low concentration, cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabinodiol (CBND), and cannabinidiol (CBDL) may have potentially some medical effects. PCs and endocannabinoids (ECs) mediate their effects mainly through CB1 and CB2 receptors. Despite all concerns regarding cannabis, nobody can ignore the use of cannabinoids as promising tonic, analgesic, antipyretic, antiemetic, anti-inflammatory, anti-epileptic, anticancer agents, which are effective for pain relief, depression, anxiety, sleep disorders, nausea and vomiting, multiple sclerosis, cardiovascular disorders, and appetite stimulation. The scientific community and public society have now increasingly accepted cannabis specifically hemp as much more than a recreational drug. There are growing demands for cannabinoids, mainly CBD, with many diverse therapeutic and nutritional properties in veterinary or human medicine. The main objective of this review article is to historically summarize findings concerning cannabinoids, mainly THC and CBD, towards putting these valuable compounds into food, feed and health baskets and current and future trends in the consumption of products derived from cannabis.
... When the reaction is performed following "standard" organic conditions, that is, using toluene as a solvent in the presence of pyrrolidine as a catalyst (Table 1, entry 5), the obtained products, although in marginal yields, are derived from the CBC skeletons 5 and 6, in agreement with previous reports. 11 Finally, the use of gallium and indium catalysts in DCM (Table 1, entries 6−9) led to similar results to those obtained using water and DBSA (Table 1, entry 2), where compounds 3 and 4 were again the major products, but with the significant presence of a third product that was identified as 7. The structure of this tetracyclic adduct was elucidated after extensive 1D and 2D NMR analysis, including a 2D ADEQUATE experience, and unambiguously determined by X-ray crystallography (Figure 1) of the p-bromobenzoate derivative of 7 (7a) obtained via derivatization of the phenol moiety. ...
Article
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We have proven that the biomimetic-like synthesis of cannabinoids from citral and the corresponding phenolic counterpart may well be carried out using water as a solvent. The influence of different additives such as surfactants was also analyzed. Rationalization of the reaction mode and regiochemistry of the processes were provided in terms of "on water" and "in water" reactions. The same reactions were conducted in organic media using Ga(III) salts as catalysts. Worthy of being underlined, an unprecedented formal [2+2+2] process was found to occur between two citral molecules and the corresponding phenolic species in both aqueous and organic environments. Computational studies were performed in order to gain a comprehensive mechanistic and energetic understanding of the different steps of this singular process. Finally, the influence of SDS micelles in the chemical behavior of olivetol and citral was also pursued using PGSE diffusion and NOESY NMR studies. These data permitted to tentatively propose the existence of a mixed micelle between olivetol and SDS assemblies.
... Abbreviations used: IPP, isopentenyl diphosphate; DMAPP, dimethylallyl diphosphate; GPP, geranyl diphosphate; FPP, farnesyl diphosphate; MVA, mevalonate; MEP, methylerythritol phosphate. (Davis and Hatoum, 1983), anti-bacterial and antifungal properties (Eisohly et al., 1982). CBC is also a potent inhibitor of anandamide uptake, an endogenous ligand of CB receptors (De Petrocellis et al., 2011). ...
Article
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Cannabis sativa L. is an important herbaceous species originating from Central Asia, which has been used in folk medicine and as a source of textile fibre since the dawn of times. This fast-growing plant has recently seen a resurgence of interest because of its multi-purpose applications: it is indeed a treasure trove of phytochemicals and a rich source of both cellulosic and woody fibres. Equally highly interested in this plant are the pharmaceutical and construction sectors, since its metabolites show potent bioactivities on human health and its outer and inner stem tissues can be used to make bioplastics and concrete-like material, respectively. In this review, the rich spectrum of hemp phytochemicals is discussed by putting a special emphasis on molecules of industrial interest, including cannabinoids, terpenoids and phenolic compounds, and their biosynthetic routes. Cannabinoids represent the most studied group of compounds, mainly due to their wide range of pharmaceutical effects in humans, including psychotropic activities. The therapeutic and commercial interests of some terpenoids and phenolic compounds, and in particular stilbenoids and lignans, are also highlighted in view of the most recent literature data. Biotechnological avenues to enhance the production and bioactivity of hemp secondary metabolites are proposed by discussing the power of plant genetic engineering and tissue culture. In particular two systems are reviewed, i.e. cell suspension and hairy root cultures. Additionally, an entire section is devoted to hemp trichomes, in the light of their importance as phytochemical factories. Ultimately, prospects on the benefits linked to the use of the -omics technologies, such as metabolomics and transcriptomics to speed up the identification and the large-scale production of lead agents from bioengineered Cannabis cell culture, are presented.
... However, THC is well-documented having anti-inflammatory effects, including for arthritic and inflammatory conditions [15], Alzheimer's disease [16], Parkinson's [17] and diabetes [18]. However, cannabigerol (CBG) However, cannabigerol (CBG) and cannabichromene (CBC) have antibacterial and antifungal effects [19], and can act as antidepressants [20]. In contrast, cannabinol (CBN) has a potential effect on insomnia and sleep disorder [21]. ...
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The traditional Cannabis plant as a medicinal crop has been explored for many thousands of years. The Cannabis industry is rapidly growing; therefore, optimising drying methods and producing high-quality medical products have been a hot topic in recent years. We systemically analysed the current literature and drew a critical summary of the drying methods implemented thus far to preserve the quality of bioactive compounds from medicinal Cannabis. Different drying techniques have been one of the focal points during the post-harvesting operations, as drying preserves these Cannabis products with increased shelf life. We followed or even highlighted the most popular methods used. Drying methods have advanced from traditional hot air and oven drying methods to microwave-assisted hot air drying or freeze-drying. In this review, traditional and modern drying technologies are reviewed. Each technology will have different pros and cons of its own. Moreover, this review outlines the quality of the Cannabis plant component harvested plays a major role in drying efficiency and preserving the chemical constituents. The emergence of medical Cannabis, and cannabinoid research requires optimal post-harvesting processes for different Cannabis strains. We proposed the most suitable method for drying medicinal Cannabis to produce consistent, reliable and potent medicinal Cannabis. In addition, drying temperature, rate of drying, mode and storage conditions after drying influenced the Cannabis component retention and quality
... Cannabinoids, the terpenophenolic compounds with 21 or 22 carbons (Sirikantaramas et al. 2005), mainly found in the glandular trichomes of cannabis, an annual, dioecious plant from central Asia, are widely used to alleviate or treat symptoms of disease (Bridgeman and Abazia 2017). Therapeutic effects of cannabinoids such as relief from cancer-associated pain (Blake et al. 2017), neuropathic pain, fibromyalgia, rheumatoid arthritis and mixed chronic pain (Bridgeman and Abazia 2017), loss of appetite (Mechoulam and Ben-Shabat 1999), inflammation (Formukong et al. 1988), infection (Eisohly et al. 1982), depression, anxiety, sleep disorders (Grotenhermen and Russo 2002;Musty 2004), and nausea and vomiting caused by cytostatic therapy (Grotenhermen and Müller-Vahl 2012) have been observed. So far, over 120 cannabinoids have been isolated from cannabis (Morales et al. 2017). ...
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Key message Three novel transcription factors were successfully identified and shown to interact with the trichome-specific THCAS promoter regulatory region. Abstract Cannabinoids are important secondary metabolites present in Cannabis sativa L. (cannabis). One cannabinoid that has received considerable attention, 9-tetrahydrocannabinol (THC), is derived from Delta-9-Tetrahydrocannabinolic acid (THCA) and responsible for the mood-altering and pain-relieving effects of cannabis. A detailed understanding of transcriptional control of THCA synthase (THCAS) is currently lacking. The primary site of cannabinoid biosynthesis is the glandular trichomes that form on female flowers. Transcription factors (TFs) have been shown to play an important role in secondary-metabolite biosynthesis and glandular trichome formation in Artemisia annua, Solanum lycopersicum and Humulus lupulus. However, analogous information is not available for cannabis. Here, we characterize a 548 bp fragment of the THCAS promoter and regulatory region that drives trichome-specific expression. Using this promoter fragment in a yeast-one-hybrid screen, we identified 3 novel TFs (CsAP2L1, CsWRKY1 and CsMYB1) and provided evidence that these 3 TFs regulate the THCAS promoter in planta. The O-Box element within the proximal region of the THCAS promoter is necessary for CsAP2L1-induced transcriptional activation of THCAS promoter. Similar to THCAS, the genes for all three TFs have trichome-specific expression, and subcellular localization of the TFs indicates that all three proteins are in the nucleus. CsAP2L1 and THCAS exhibit a similar temporal, spatial and strain-specific gene expression profiles, while those expression patterns of CsWRKY1 and CsMYB1 are opposite from THCAS. Our results identify CsAP2L1 playing a positive role in the regulation of THCAS expression, while CsWRKY1 and CsMYB1 may serve as negative regulators of THCAS expression.
... Compounds 15 and 16 were previously synthesized by means of Electrophilic Aromatic Substitutions reactions, catalyzed by mineral acids, such as orcinol reaction with geraniol in aqueous formic acid solutions [38], condensation reaction of geraniol and orcinol in methylene chloride in the presence of p-toluenesulfonic acid [39]. However, the yields obtained with these methodologies were low (2e18% yield). ...
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Sixteen synthetic linear derivatives geranylphenols, were obtained from phloroglucinol and orcinol, and cytotoxic activity was evaluated in vitro against cancer cell lines (HT-29, PC-3, MDA-MB231, DU-145) and one non-tumor cell line, human dermal fibroblast (HDF). IC50 values were determined at concentrations of 0–100 μM of each compound for 72 h. Compounds 12, 13, 17, 21, 22 and 25, showed cytotoxic activity. To elucidate whether these compounds reduce cell viability by inducing apoptosis, cell lines MCF-7, PC-3 and DHF were treated with each active compound 12, 13, 17, 21, 22 and 25 and were examined after Hoechst 33342 staining. The compounds 12, 13 and 17 induced apoptosis in various cancer cell lines, as shown by nuclear condensation and/or fragmentation. In addition, it was found that compounds 12 and 13, induced changes in mitochondrial membrane permeability in those cancer cell lines. Such induction was associated with the depletion of mitochondrial membrane potential. These activities led to the cleavage of caspases inducing the cell death process.
... The physical and spectroscopic properties of compounds 1 and 2 were consistent with those previously reported. 11,29,31 The structural determination of new compounds 3−6 is described in detail in the Materials and Methods. ...
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Herein we explore the potential use of two micelle-forming block copolymers, i.e. Pluronic F-127 and poly(ethylene oxide)-b-poly(caprolactone), for application of fungicide agents. The polymer effect on the in vitro fungicide activity of a series of geranyl orcinol derivatives against Botrytis cinerea has been assessed. The results show that for all test compounds the incorporation into micelles, formed by Pluronic F-127, produce a great enhancement of the inhibitory effect on growth of B. cinerea. For some compounds, at the lowest tested concentration (50 ppm), the percentage of inhibition increases significantly (from 0-10 % to 80-90%) when the application is made by using a polymer solution instead of an ethanol/water mixture. The synthesis and structural determination of a series of eight geranylphenols/diacetates, which were used as fungicide agents, is also discussed. These results suggest that polymer micelles are promising systems for application of crop-protecting agents.
... CBC is the third most studied phytocannabinoid after THC and CBD. It possesses high levels of anti-inflammatory, [27] antibacterial, and antifungal [28] properties in addition to analgesia and sedation [29] . It is also a potent inhibitor of anandamide uptake [14] . ...
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Millions of Americans use cannabis for medical purposes including but not limited to pain, nausea, mood changes and appetite stimulation. The use of cannabinoid in the palliative care setting is a relatively new trend. Given the fact that a patient receiving palliative care is not necessarily approaching death, the increasing need for palliative care as the American population ages, this literature review was compiled in order to examine the potential efficacy of cannabis in treating the mental health comorbidities of palliative care patients. We attempted to create the most comprehensive report on cannabinoid use in palliative psychiatry. It summarizes the most recently published science on cannabinoid use in palliative care patients and its impact on mood and anxiety symptoms. The mechanism of action of cannabinoids on their associated receptors was elucidated, as were the pharmacological roles that specific molecules in cannabinoids, like cannabidiolic acid and terpenes, play in cannabinoids’ overall efficacy. The legal impediments to widespread cannabis use were also explored. While the potential efficacy of cannabinoids has proven to be mixed, more research is necessary to ensure that a potentially vital resource in treating palliative care patients does not go underutilized.
... CBD is investigated for its application in treatment of Alzheimer's disease, Parkinson's disease and epilepsy, as well as for its antitumor properties and neuroprotective efficacy (Pisanti et al., 2017). CBC is investigated for its anti-inflammatory, anti-fungal, antibiotic and analgesic effects (Elsohly et al., 1982;Maione et al., 2011;Romano et al., 2013). ...
Article
Cannabinoids are secondary natural products from the plant Cannabis sativa L. Therapeutic indications of cannabinoids currently comprise a significant area of medicinal research. We have expressed the Δ9-tetrahydrocannabinolic acid synthase (THCAS) and cannabidiolic acid synthase (CBDAS) recombinantly in Komagataella phaffii and could detect eight different products with a cannabinoid scaffold after conversion of the precursor cannabigerolic acid (CBGA). Besides five products remaining to be identified, both enzymes were forming three major cannabinoids of C. sativa - Δ9-tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) and cannabichromenic acid (CBCA). In pursuit of improved enzyme properties for a biotechnological cannabinoid production, we performed site-directed mutagenesis to investigate the glycosylation pattern, the C-terminal berberine-bridge-enzyme (BBE) domain, the active site and the product specificity of both enzymes. The THCAS variant T_N89Q + N499Q (lacking two glycosylation sites) exerted about two-fold increased activity compared to wild-type enzyme. Variant T_H494C + R532C (additional disulfide bridge) exerted about 1.7-fold increased activity compared to wild-type enzyme and a shifted temperature optimum from 52 °C to 57 °C. We generated two CBDAS variants, C_S116 A and C_A414 V, with 2.8 and 3.3-fold increased catalytic activities for CBDA production. C_A414 V additionally showed a broadened pH spectrum and a 19-fold increased catalytic activity for THCA production. These studies lay the groundwork for further research as well as biotechnological cannabinoid production.
... Pinene-type monoterpene hydrocarbons (a-pinene and b-pinene), borneol (oxygenated monoterpene) and camphor are considered the main compounds in sage oil responsible to antifungal and antibacterial activity (Alvarez-Castellanos, Bishop, & Pascual-Villalobos, 2001;Dorman & Deans, 2000;Tabanca, Kirimer, Demirci, Demirci, & Baser, 2001). Terpinolene and alpha-pinene in hemp oil are well known to have antibacterial activity against various pathogens (Farooq et al., 2002;El-Sohly, Turner, Clarck, & Elsohly, 1982). Different quantitative composition, resulting from the variety of plants, the parts of the plant subject of extraction (inflorescences, seeds and leaves), the extraction method and the storage parameters can explain the difference in efficiency of the oils derived from the same species against microorganisms. ...
Article
The aim of the study is to prepare and characterize gelatin films incorporating hemp and sage oil, to obtain an edible film which combines both food preservation and nutritional properties. Gelatin film-forming solutions were investigated in terms of wettability in relation to different foodstuff and their antimicrobial properties against Escherichia coli, Staphylococcus aureus, Listeria innocua, Saccharomyces cerevisiae and Penicillium expansum. The gelatin films were evaluated for their water vapor permeability, solubility in food simulants, moisture content, thickness and light barrier property. The steeper decrease in contact angles, surface tension and spreading coefficients was displayed by the sage oil-gelatin film solution and the mildest by the hemp oil-gelatin film solution. The most suitable foodstuffs to be coated in sage/hemp oil-gelatin films seem to be Golden Apple, pork meat and processed cheese, whereas the least suitable appear to be garlic, red bell pepper and cauliflower. Hemp oil has moderate antimicrobial action, while the sage oil displays a strong inhibition. Additive effect is expressed in case of all gelatin film solutions containing sage and hemp oils combinations. The sage oil-gelatin film displays the lowest water vapor permeability and moisture content, while the hemp oil-gelatin film results in the lowest thickness and highest light barrier property. Hemp oil-gelatin film is more soluble than the sage oil-gelatin film. Varying degrees in the investigated parameters can be noticed in cases of oils mixtures-gelatin films depending by the dominant oil.
... Pinene-type monoterpene hydrocarbons (a-pinene and b-pinene), borneol (oxygenated monoterpene) and camphor are considered the main compounds in sage oil responsible to antifungal and antibacterial activity (Alvarez-Castellanos, Bishop, & Pascual-Villalobos, 2001;Dorman & Deans, 2000;Tabanca, Kirimer, Demirci, Demirci, & Baser, 2001). Terpinolene and alpha-pinene in hemp oil are well known to have antibacterial activity against various pathogens (Farooq et al., 2002;El-Sohly, Turner, Clarck, & Elsohly, 1982). Different quantitative composition, resulting from the variety of plants, the parts of the plant subject of extraction (inflorescences, seeds and leaves), the extraction method and the storage parameters can explain the difference in efficiency of the oils derived from the same species against microorganisms. ...
... Besides the fact, that CBC is a potent inhibitor of anandamide uptake, an endogenous ligand of CB receptors, it has similar properties as CBD, such as anti-inflammatory, sedative, analgesic, anti-bacterial and antifungal properties [105,106,115,116]. ...
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This review paper gives an overview of Cannabis Sativa, also known as hemp, which has been cultivated and used century's B.C. due to its medical, hallucinogenic and agricultural properties. Cannabis has been described in 1938 as the billion-dollar plant but has lost its value in the U.S. due to regulatory and legislative issues. Hemp has seen as new push In the U.S. with the introduction of the 2018 Farm Bill which allows on a federal level to grow hemp, pending on individual state regulations. Currently, industrial hemp production is allowed in at least 38 U.S. States under strict regulations. Today hemp is used in counties that do not have as strict regulations as the U.S. in a variety of applications such as beauty products, carpets, cooking oil, personal care products and textiles. Hemp can be considered as an alternative feedstock due to its low lignin and high cellulose level for biofuel application as an alternative to replace petroleum-based fuels and gases. In the U.S. hemp research in these areas has stalled due to the complexity of the law. Beside industrial application such as ropes, textiles, shoes, etc., hemp today is used in pharmaceutical and medical applications, by extracting Δ9-tetrahydrocannabinol and cannabinoids from the leaves and fluorescence of the hemp plant that contain no more than of up to 0.3% of these compounds. The use of hemp plants with higher levels are strictly forbidden in most countries. Several extraction processes of cannabinoids from hemp are used They all use a solvent for extraction but differ in terms of efficiency, usage range and other factors influencing the extraction. Nonetheless, overconsumption of cannabis products can be associated with several side effects, that can cause serious physiological and psychological damage in the human body may cause serious damage.
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Cannabinoids have considerable interest in the pharmaceutical industry. However, the production of medicines from hemp (Cannabis sativa L.) in most countries is restricted by law. Large-scale, field cultivation of hemp is difficult to control. Cannabinoid content in plants is variable and depends on multiple factors. Therefore, alternative methods of production have been investigated. The development of micropropagation techniques is a necessary step for genetic modification. Promising results have been obtained for certain narcotic genotypes. However, micropropagation of fibre types requires further research. Hemp can be genetically modified which may contribute to the breeding of new varieties in the future. Cell suspension cultures and hairy root cultures of hemp have been used to produce cannabinoids but obtaining cannabinoids from callus and cell suspension cultures has proved impossible. Adventitious roots can, however, deliver small amounts of these metabolites but production ceases over time and is too low for industrial applications.
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Cannabinoids are the primary bioactive constituents of Cannabis sativa and Cannabis indica plants. In this work, gas chromatography in conjunction with triple quadrupole mass spectrometry in multiple reaction monitoring mode was explored for determination of cannabinoids from a surrogate hops matrix. Gas chromatography with mass spectrometry is a reasonable choice for the analysis of these compounds; however, such methods are susceptible to false positives for Δ9-tetrahydrocannabinol, due to decarboxylation of Δ9-tetrahydrocannabinolic acid, its acid precursor, in the hot injection port. To avoid this transformation, the carboxyl group of Δ9-tetrahydrocannabinolic acid was protected through a silylation reaction. Multiple reaction monitoring transitions for both unmodified and silylated cannabinoids were developed and the fragmentation pathways of the different species were assigned. Precision and accuracy were evaluated for cannabinoids spiked into hops at different levels. The developed methods provided good linearity (R² > 0.99) for all the cannabinoids with a linear range from 0.15 to 20 mg/L, and with limits of detection in the orders of low- to mid-picogram on column. The recoveries for the cannabinoids were generally between 75 and 120%. Precisions (< 6% coefficient of variation) were within acceptable ranges.
Chapter
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By using the Inverted Chirality Columns Approach (ICCA) we have developed an enantioselective UHPSFC method to determine the enantiomeric excess (e.e.) for (–)-Δ ⁹ -THC in medicinal marijuana (Bedrocan ® ). The e.e. was...
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Total synthesis of biologically interesting (?)-cannabichromene, (?)-cannabichromenic acid, and (?)-daurichromenic acid is described. The key step in the synthetic strategy involves the formation of benzopyrans by ethylenediamine diacetate-catalyzed reactions of resorcinols with \alpha,\beta-unsaturated aldehydes.
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Marijuana (Cannabis sativa) has long been known to contain antibacterial cannabinoids, whose potential to address antibiotic resistance has not yet been investigated. All five major cannabinoids (cannabidiol (1b), cannabichromene (2), cannabigerol (3b), Delta (9)-tetrahydrocannabinol (4b), and cannabinol (5)) showed potent activity against a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains of current clinical relevance. Activity was remarkably tolerant to the nature of the prenyl moiety, to its relative position compared to the n-pentyl moiety (abnormal cannabinoids), and to carboxylation of the resorcinyl moiety (pre-cannabinoids). Conversely, methylation and acetylation of the phenolic hydroxyls, esterification of the carboxylic group of pre-cannabinoids, and introduction of a second prenyl moiety were all detrimental for antibacterial activity. Taken together, these observations suggest that the prenyl moiety of cannabinoids serves mainly as a modulator of lipid affinity for the olivetol core, a per se poorly active antibacterial pharmacophore, while their high potency definitely suggests a specific, but yet elusive, mechanism of activity.
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A concise synthesis of yaequinolones J1 and J2 is reported. The route is based on the aryne insertion into the σ-C-N bond of an unsymmetric imide followed by a diastereoselective aldol cyclization of the resulting N-acylated aminobenzophenone. The chromene motif is generated in the first step by an organocatalytic tandem Knoevenagel electrocyclization of citral and 2-bromoresorcinol. The approach adheres to the ideality principle, using almost exclusively strategic bond-forming reactions.
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Cannabis is well-known for its numerous therapeutic activities, as demonstrated in pre-clinical and clinical studies primarily due to its bioactive compounds. The Cannabis industry is rapidly growing; therefore, product development and extraction methods have become crucial aspects of Cannabis research. The evaluation of the current extraction methods implemented in the Cannabis industry and scientific literature to produce consistent, reliable, and potent medicinal Cannabis extracts is prudent. Furthermore, these processes must be subjected to higher levels of scientific stringency, as Cannabis has been increasingly used for various ailments, and the Cannabis industry is receiving acceptance in different countries. We comprehensively analysed the current literature and drew a critical summary of the extraction methods implemented thus far to recover bioactive compounds from medicinal Cannabis. Moreover, this review outlines the major bioactive compounds in Cannabis, discusses critical factors affecting extraction yields, and proposes future considerations for the effective extraction of bioactive compounds from Cannabis. Overall, research on medicinal marijuana is limited, with most reports on the industrial hemp variety of Cannabis or pure isolates. We also propose the development of sustainable Cannabis extraction methods through the implementation of mathematical prediction models in future studies.
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Introduction: Cannabigerol (CBG), and its precursor before decarboxylation, cannabigerolic acid is sometimes labeled the "mother of all cannabinoids." The purpose of the present study was to investigate reasons for use and self-reported therapeutic effects in CBG-predominant cannabis users. Usage patterns and adverse effects, including withdrawal symptoms were also explored. Methods: Cannabidiol-predominant cannabis users were recruited online to complete an online survey assessing CBG use patterns, conditions treated with CBG-predominant cannabis (containing >50% CBG), perceived efficacy, associated adverse events, and withdrawal symptoms. One hundred twenty-seven eligible participants (U.S. residents ages 21+ who reported using CBG-predominant cannabis in the past 6 months) completed the survey. Results: Most of the samples (n=65; 51.2%) reported use of CBG-predominant products solely for medical purposes (n=46; 36.2% reported use for medical and recreational purposes; n=8; 6.3% reported recreational use only, and n=8 were missing). The most common conditions the complete sample reported using CBG to treat were anxiety (51.2%), chronic pain (40.9%), depression (33.1%), and insomnia/disturbed sleep (30.7%). Efficacy was highly rated, with the majority reporting their conditions were "very much improved" or "much improved" by CBG. Furthermore, 73.9% claimed superiority of CBG-predominant cannabis over conventional medicines for chronic pain, 80% for depression, 73% for insomnia, and 78.3% for anxiety. Forty-four percent of CBG-predominant cannabis users reported no adverse events, with 16.5% noting dry mouth, 15% sleepiness, 11.8% increased appetite, and 8.7% dry eyes. Around 84.3% reported no withdrawal symptoms, with sleep difficulties representing the most frequently endorsed withdrawal symptom (endorsed by two respondents). Conclusions: This is the first patient survey of CBG-predominant cannabis use to date, and the first to document self-reported efficacy of CBG-predominant products, particularly for anxiety, chronic pain, depression, and insomnia. Most respondents reported greater efficacy of CBG-predominant cannabis over conventional pharmacotherapy, with a benign adverse event profile and negligible withdrawal symptoms. This study establishes that humans are employing CBG and suggests that CBG-predominant cannabis-based medicines should be studied in randomized controlled trials.
Chapter
Cannabis refers to a genus of flowering plants and includes three major species Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Phytocannabinoids (plant-based cannabinoids) include cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC). Endocannabinoids are endogenous chemicals which act on the cannabinoid receptors (CBR). Synthetic medications such as nabilone, dronabinol, and rimonabant are also commercially available. The phytocannabinoids are chemicals extracted from the cannabis plant either interacting directly with cannabinoid receptors or sharing chemical similarity with endocannabinoids or both. While Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most studied phytocannabinoids, other phytocannabinoids that require special mention include cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), and tetrahydrocannabivarin (THCV). These minor cannabinoids have demonstrated anticonvulsant, anti-inflammatory, antibacterial, and antidepressant properties apart from showing promise in pain relief and muscle relaxation. Evidence of anticancer and cytotoxic properties on human epithelioid carcinoma and breast cancer in basic research models highlights the need for further research in this arena, to validate their use.
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The development of multidrug‐resistant bacteria has revealed the need for new antimicrobial compounds. Cannabis sativa preparations have a long history of medical applications, including the treatment of infectious diseases. This review collects the information about the activity of C. sativa extracts and its main components (cannabinoids and terpenes) against pathogenic bacteria and fungus, to assess its potential using as antimicrobial agents. Cannabis sativa preparations have a long history of medical applications, including the treatment of infectious diseases. This review collects the information about the activity of C. sativa extracts and its main components (cannabinoids and terpenes) against pathogenic bacteria and fungus. All the data presented in this work suggests that cannabinoids and related compounds demonstrated antibacterial activity against clinically important bacteria in the search of new tools as potential antimicrobial agents.
Chapter
Cannabis sativa spp. is an exceptional multicomponent natural resource used as nutritional supplements, textiles, building materials, body care products, food, and medicines, to name a few. It has been cultivated for millennia to exploit the plant’s toolbox of useful natural compounds it offers. This chapter explores the chemical constituents responsible for the plant’s therapeutic properties and examines efficacious compounds as nutraceuticals. A qualitative and quantitative look at these components highlights important trends for both fiber-type hemp and medical C. sativa. Key aspects of C. sativa taxonomy, biology, and biochemistry are addressed. Specifically, the convergent biosynthetic pathways used by the plant to produce cannabinoids and terpenes are outlined. The biologically active components are described at a molecular level and the in vitro and in vivo data are compiled to offer quantitative insight into the mechanism of action, as well as their potential for use as nutraceuticals.
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The total synthesis of nyingchinoids A and B has been achieved via successive rearrangements of a 1,2‐dioxane intermediate that was assembled using a visible light photoredox catalysed aerobic [2+2+2] cycloaddition. Nyingchinoid D was synthesised by a competing [2+2] cycloaddition. Based on NMR data and biosynthetic speculation, we proposed a structure revision of the related natural product rasumatranin D, which was confirmed through total synthesis. Under photoredox conditions, we observed the conversion of a cyclobutane into a 1,2‐dioxane via retro‐[2+2] cycloaddition followed by aerobic [2+2+2] cycloaddition.
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The synthesis of three phenolic natural products has been accomplished with unprecedented efficiency using a new alumina-promoted regioselective aromatic allylation reaction. Cannabigerol and grifolin were prepared in one step from the inexpensive 5-alkyl-resorcinols olivetol and orcinol. Piperogalin was synthesized, for the first time, via two sequential allylations of orcinol with geraniol and prenol.
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Cannabis research has historically focused on the most prevalent cannabinoids. However, extracts with a broad spectrum of secondary metabolites may have increased efficacy and decreased adverse effects compared to cannabinoids in isolation. Cannabis’s complexity contributes to the length and breadth of its historical usage, including the individual application of the leaves, stem barks, and roots, for which modern research has not fully developed its therapeutic potential. This study is the first attempt to profile secondary metabolites groups in individual plant parts comprehensively. We profiled 14 cannabinoids, 47 terpenoids (29 monoterpenoids, 15 sesquiterpenoids, and 3 triterpenoids), 3 sterols, and 7 flavonoids in cannabis flowers, leaves, stem barks, and roots in three chemovars available. Cannabis inflorescence was characterized by cannabinoids (15.77–20.37%), terpenoids (1.28–2.14%), and flavonoids (0.07–0.14%); the leaf by cannabinoids (1.10–2.10%), terpenoids (0.13–0.28%), and flavonoids (0.34–0.44%); stem barks by sterols (0.07–0.08%) and triterpenoids (0.05–0.15%); roots by sterols (0.06–0.09%) and triterpenoids (0.13–0.24%). This comprehensive profile of bioactive compounds can form a baseline of reference values useful for research and clinical studies to understand the “entourage effect” of cannabis as a whole, and also to rediscover therapeutic potential for each part of cannabis from their traditional use by applying modern scientific methodologies.
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The effects of cannabichromene (CBC), delta 9-tetrahydrocannabinol (delta 9-THC) and their combination (all doses 50 mg/kg orally) were determined after being administered to female mice for 7 days beginning on the 20th day of gestation. The THC treatment reduced postnatal viability, impaired male reproductive behavior at maturity and significantly reduced seminal vesicle weights. No changes from control values occurred after CBC or CBC + THC. Thus, CBC alone at this dosage did not act like THC; moreover, it antagonized the effects of THC when the two were given in combination.
1.1. LD50's in mice after single intraperitoneal (i.p.) doses of cannabichromene (CBC) and Δ9-tetrahydrocannabinol (Δ9-THC) were 113.4 and 276.3 mg/kg, respectively. A small dose (25 mg/kg) of CBC given concurrently with Δ9-THC lowered the LD50 of Δ9-THC to 152.0 mg/kg.2.2. CBC, like Δ9-THC, caused hypothermia in mice; it reduced the effect of Δ9-THC at early times and increased it at later times after the two were injected simultaneously i.p.3.3. CBC and Δ9-THC, in 25 mg/kg i.p. doses, each prolonged hexobarbital hypnosis equally in mice, but had no additive effect in combination.
1.1. One intraperitoneal dose of the cannabinoid, cannabichromene (CBC), increased the duration of loss of righting reflex in mice after hexobarbital, barbital or zoxazolamine.2.2. After 7 daily doses of CBC, prolongation of response to the 3 drugs no longer occurred; duration for hexobarbital and zoxazolamine was less than for vehicle controls.3.3. The data reflect a CNS depressant action of CBC, the development of tolerance to this action, and a possible induction of drug metabolism.
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