Synthesis Of Cannabinoids Research Articles

Enantioselective Total Synthesis of Cannabinoids-A Route for Analogue Development.

A practical synthetic approach to Δ9-tetrahydrocannabinol (1) and cannabidiol (2) that provides scalable access to these natural products and should enable the generation of novel synthetic analogues is reported.

Designing microorganisms for heterologous biosynthesis of cannabinoids.

During the last decade, the use of medical Cannabis has expanded globally and legislation is getting more liberal in many countries, facilitating the research on cannabinoids. The unique interaction of cannabinoids with the human endocannabinoid system makes these compounds an interesting target to be studied as therapeutic agents for the treatment of several medical conditions. However, currently there are important limitations in the study, production and use of cannabinoids as pharmaceutical drugs. Besides the main constituent tetrahydrocannabinolic acid, the structurally related compound cannabidiol is of high interest as drug candidate. From the more than 100 known cannabinoids reported, most can only be extracted in very low amounts and their pharmacological profile has not been determined. Today, cannabinoids are isolated from the strictly regulated Cannabis plant, and the supply of compounds with sufficient quality is a major problem. Biotechnological production could be an attractive alternative mode of production. Herein, we explore the potential use of synthetic biology as an alternative strategy for synthesis of cannabinoids in heterologous hosts. We summarize the current knowledge surrounding cannabinoids biosynthesis and present a comprehensive description of the key steps of the genuine and artificial pathway, systems biotechnology needs and platform optimization.

Endocannabinoid system as a regulator of tumor cell malignancy - biological pathways and clinical significance.

The endocannabinoid system (ECS) comprises cannabinoid receptors (CBs), endogenous cannabinoids, and enzymes responsible for their synthesis, transport, and degradation of (endo)cannabinoids. To date, two CBs, CB1 and CB2, have been characterized; however, orphan G-protein-coupled receptor GPR55 has been suggested to be the third putative CB. Several different types of cancer present abnormal expression of CBs, as well as other components of ECS, and this has been shown to correlate with the clinical outcome. Although most effects of (endo)cannabinoids are mediated through stimulation of classical CBs, they also interact with several molecules, either prosurvival or proapoptotic molecules. It should be noted that the mode of action of exogenous cannabinoids differs significantly from that of endocannabinoid and results from the studies on their activity both in vivo and in vitro could not be easily compared. This review highlights the main signaling pathways involved in the antitumor activity of cannabinoids and the influence of their activation on cancer cell biology. We also discuss changes in the expression pattern of the ECS in various cancer types that have an impact on disease progression and patient survival. A growing amount of experimental data imply possible exploitation of cannabinoids in cancer therapy.

Enrichment and identification of Δ(9)-Tetrahydrocannabinolic acid synthase from Pichia pastoris culture supernatants.

This data article refers to the report Δ9-Tetrahydrocannabinolic acid synthase (THCAS) production in Pichia pastoris enables chemical synthesis of cannabinoids (Lange et. al. 2015) [2]. THCAS was produced on a 2 L lab scale using recombinant P. pastoris KM71 KE1. Enrichment of THCAS as a technically pure enzyme was realized using dialysis and cationic exchange chromatography. nLC-ESI-MS/MS analysis identified THCAS in different fractions obtained by cationic exchange chromatography.

Homeostatic and stimulus-induced coupling of the L-type Ca2+ channel to the ryanodine receptor in the hippocampal neuron in slices

Activity-dependent increase in cytosolic calcium ([Ca2+]i) is a prerequisite for many neuronal functions. We previously reported a strong direct depolarization, independent of glutamate receptors, effectively caused a release of Ca2+ from ryanodine-sensitive stores and induced the synthesis of endogenous cannabinoids (eCBs) and eCB-mediated responses. However, the cellular mechanism that initiated the depolarization-induced Ca2+-release is not completely understood. In the present study, we optically recorded [Ca2+]i from CA1 pyramidal neurons in the hippocampal slice and directly monitored miniature Ca2+ activities and depolarization-induced Ca2+ signals in order to determine the source(s) and properties of [Ca2+]i-dynamics that could lead to a release of Ca2+ from the ryanodine receptor. In the absence of depolarizing stimuli, spontaneously occurring miniature Ca2+ events were detected from a group of hippocampal neurons. This miniature Ca2+ event persisted in the nominal Ca2+-containing artificial cerebrospinal fluid (ACSF), and increased in frequency in response to the bath-application of caffeine and KCl. In contrast, nimodipine, the antagonist of the L-type Ca2+ channel (LTCC), a high concentration of ryanodine, the antagonist of the ryanodine receptor (RyR), and thapsigargin (TG) reduced the occurrence of the miniature Ca2+ events. When a brief puff-application of KCl was given locally to the soma of individual neurons in the presence of glutamate receptor antagonists, these neurons generated a transient increase in the [Ca2+]i in the dendrosomal region. This [Ca2+]i-transient was sensitive to nimodipine, TG, and ryanodine suggesting that the [Ca2+]i-transient was caused primarily by the LTCC-mediated Ca2+-influx and a release of Ca2+ from RyR. We observed little contribution from N- or P/Q-type Ca2+ channels. The coupling between LTCC and RyR was direct and independent of synaptic activities. Immunohistochemical study revealed a cellular localization of LTCC and RyR in a juxtaposed configuration in the proximal dendrites and soma. We conclude in the hippocampal CA1 neuron that: (1) homeostatic fluctuation of the resting membrane potential may be sufficient to initiate functional coupling between LTCC and RyR; (2) the juxtaposed localization of LTCC and RyR has anatomical advantage of synchronizing a Ca2+-release from RyR upon the opening of LTCC; and (3) the synchronized Ca2+-release from RyR occurs immediately after the activation of LTCC and determines the peak amplitude of depolarization-induced global increase in dendrosomal [Ca2+]i.

Synthesis of Cannabinoids

Synthesis of Cannabinoids

Behavioral effects of inhibition of cannabinoid metabolism: The amidase inhibitor AM374 enhances the suppression of lever pressing produced by exogenously administered anandamide

Biochemical investigations have identified putative enzymatic pathways for the synthesis and metabolism of endogenous cannabinoids. Anandamide amidase is an enzyme that metabolizes anandamide into arachadonic acid and ethanolamine. Using in vitro methods, various inhibitors of amidase have been identified. The present studies were undertaken to determine if the amidase inhibitor AM 374 could enhance the effects of intraperitoneal (IP) injections of anandamide. Three studies were conducted to investigate the effects of various drug treatments on fixed ratio 5 operant lever pressing for food reinforcement. In the first study, the effects of different doses of anandamide were assessed, and it was demonstrated that 5.0 and 10.0 mg/kg anandamide IP significantly suppressed lever pressing, while 2.5 mg/kg produced very little effect. The second study tested the effects of intraventricular (ICV) injections of AM 374, and it was observed that doses up to 10.0, 20.0 and 40 μg AM 374 had no significant effect upon lever pressing. The third study investigated the combined effect of AM374 with a low dose of anandamide. Rats received two drug injections: one ICV and one IP. Four different drug treatments were assessed: 1) ICV vehicle + IP vehicle, 2) ICV vehicle + 2.5 mg/kg anandamide IP, 3) ICV 20.0 μg AM 374 + IP vehicle, and 4) ICV 20 μg AM 374 + 2.5 mg/kg anandamide IP. Combined administration of AM 374 plus anandamide led to a significant decrease in lever pressing compared to either AM374 or anandamide administered alone. Observations of the animals treated with the combination of AM374 plus anandamide indicated that the drug combination resulted in motor slowing, which is consistent with the notion that stimulation of cannabinoid receptors produced a motor deficit that interfered with lever pressing. Although AM374 produced no effect on its own, this amidase inhibitor did enhance the behavioral effect of a low dose of anandamide. These results are consistent with the notion that AM 374 inhibited the enzymatic breakdown of exogenously injected anandamide. This type of procedure can be used to assess a variety of different compounds for their ability to inhibit cannabinoid metabolism.

Thioamide derivatives of cannabinoids. A study of the influence of the thioamide function on regiochemistry in the synthesis of thioamide cannabinoids from 2,4-dihydroxybenzothioamides

Several thiocarbamoyl derivatives of cannabinoids were obtained in the collidine-catalysed condensation of 2,4-dihydroxybenzothioamides with citral and citronellal. The thioamide function was found to change the regioselective preferences of the reaction as compared with the known cannabinoid syntheses from hydroxyacetophenones. The experimental results and theoretical (FMO theory) considerations made it possible to advance the reaction mechanism. Convenient methods were developed for the synthesis of the starting 2,4-dihydroxybenzothioamides from resorcinol and isothiocyanates in the presence of the boron trifluoride/acetic acid 1:2 complex or aluminum chloride in nitromethane.

Resolution of chiral cannabinoids on amylose tris(3,5-dimethylphenylcarbamate) chiral stationary phase: Effects of structural features and mobile phase additives

The separation of six pairs of chiral cannabinoids was achieved using a dimethylphenylcarbamate derivative of amylose, immobilized on silica gel (ChiralPak AD, Daicel), using 2-propanol and ethanol as the modifiers of n-hexane in the mobile phase. Good separation was achieved for most of the solutes in both solvent systems under various conditions. The chromatographic parameters of various cannabinoids in the two solvent systems were determined. The pairs differ from each other in small structural features such as the degree of saturation, position of a double bond and closure of a pyran ring. Therefore, a comparative study could give some clues regarding the mechanism of discrimination between the enantiomeric pairs on the chiral stationary phase. Preliminary measurements of limit of determination showed that it was possible to assess 99.9% enantiomeric purity of the cannabinoids, owing to the high efficiency of the separation. Enantiomers of two monoterpenes, used as intermediates or as starting materials in the chiral synthesis of cannabinoids, were also separated, hence the described procedure is capable of assessing whether the chiral centres in the molecules were sustained throughout the synthetic procedures.

Use of Alkenylresorcinols from Ononis speciosa as Synthetic Precursors of Compounds with Potential Biological Activity

Selective ozonization of the alkenylresorcinols isolated from Ononis speciosa was studied. The derivatives thus obtained were used as precursors in the synthesis of cannabinoids and macrocyclic lactones.

Dichlorophenylborane a new reagent for the preparation of 2-phenyl-4H-1,3,2-benzodioxaborins

A novel approach in the preparation of 2-phenyl-4H-1,3,2-benzodioxaborin using dichlorophylborane was developed. The method was applied to the synthesis of cannabinoids via an orthoquinone-methide intermediate generation from the benzodioxaborins.

ChemInform Abstract: Synthesis of Both Enantiomers of Nabilone (I) from a Common Intermediate. Enantiodivergent Synthesis of Cannabinoids.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of both enantiomers of nabilone from a common intermediate. Enantiodivergent synthesis of cannabinoids

Both enantiomers of the synthetic cannabinoid nabilone (4) have been synthesized from a common intermediate, enone 7. Enone 7 was prepared by reaction of [2,6-dimethoxy-4-(1,1-dimethylheptyl) phenyl] lithium with (+)-apoverbenone (2), followed by PDC oxidation

A New Synthesis of 1-n-Alkyl-3,5-dimethoxybenzenes (Olivetol Dimethyl Ether and Homologs)

An efficient method is reported for the synthesis of 1-n-alkyl-3,5-dimethoxybenzenes, useful intermediates in the synthesis of cannabinoids, from the readily available and cheap 3,4,5-trimethoxybenzoic acid. The key step is the electron-transfer induced highly regioselective demethoxylation of 1-n-alkyl-3,4,5-trimethoxybenzenes.

Acid-catalysed terpenylations of olivetol in the synthesis of cannabinoids

Examination of the toluene-p-sulphonic acid-catalysed reaction of (1S,2S,3R,6R)-(+)-trans-car-2-ene epoxide with olivetol shows that, inconsistently with the accepted mechanism, (3R,4R)-(–)-o- and -p-cannabidiols are produced as well as (3R,4R)-(–)-Δ1-and Δ6-tetrahydrocannabinols. Evidence is now presented that, as in Petrzilka's reaction employing chiral p-mentha-2,8-dien-1-ols, the reacting species is the delocalised (4R)-p-mentha-2,8-dien-1-yl cation (9).Similar terpenylation using (1S,3S,4R,6R)-(+)-trans-car-3-ene epoxide shows that besides the reported (–)-Δ6-THC, o- and p-cannabidiols, Δ1-THC and Δ4,8-iso-THC can also be produced. The nature of the products, the chirality, and the characteristics of the reaction implicate again the delocalised cation (9). Its formation via Kropp-type rearrangement is excluded and a pathway leading to (4R)-p-mentha-2,6,8-triene, which on protonation gives (9), is proposed. Protonated on C-8, the triene can be trapped and isolated as (4R)-p-mentha-2,6-dien-8-ol. The latter, made in (±)-form from citral, proved to be an excellent terpenylating agent for producing cannabinoids.Terpenylation of olivetol by the pinanes (1S,4S,5S)-(–)-cis-verbenol and (1R,5S,7R)-(+)-cis-chrysanthenol is compared. A major drawback of the latter is partial racemisation which occurs in the verbenone–chrysanthenone isomerisation during its photochemical preparation. Whilst Δ1-THC cannot be directly obtained from verbenol, its tertiary allylic cation permits a much higher yielding terpenylation than the secondary cation from chrysanthenol.

Synthesis of bibenzyl cannabinoids, hybrids of two biogenetic series found in Cannabis sativa

Syntheses of a series of compounds which merge a m-dihydroxybibenzyl with a terpenoid structure, giving a series of hybrid cannabinoids in which products of two major biogenetic routes of Cannabis are united, are described. The compounds made are the bibenzyl/o- and p-cannabigerols (19) and (18)/o- and p-cannabidiols (21) and (20),/Δ1-THC (22),/Δ6-THC (23),/o- and p-cannabichromenes (25) and (24),/o- and p-cannabicyclols (28) and (27) and/cannabicitran (26). Chromatographic and spectral data are listed in order to facilitate search for such ‘crossed’ types since only the bibenzyl cannabigerols and a chromene have as yet been found in natural sources.The bibenzyl/p-cannabigerol (18) has been reported in Helichrysum umbraculigerum(Compositae) and the liverwort Radula variabilis. Our synthetic work confirms the former observation, but the liverwort compound appears to be its o-isomer.

Synthesis of cannabinoids carrying ω-carboxy substituents: the cannabidiols, cannabinol and Δ1- and Δ6-tetrahydrocannabinols of this series

A convenient synthesis of methyl 5-(3,5-dihydroxyphenyl)pentanoate adaptable for isotopic side-chain labelling is reported. Using acid-catalysed terpenylations involving (1S,4R)-(+)-trans-p-menthadienol, conditions for making (3R,4R)-o-and p-cannabidiols, (3R,4R)-Δ1-THC's, (3R,4R)-Δ6-THC's and cannabinol in ω-carboxylated or methoxycarbonylated formats are described. Multigram amounts of the thermodynamically labile (3R,4R)-Δ1-THC-ω-ester, readily convertible to the ω-acid, were made: the acid is a mammalian and microbial metabolite of Δ1-THC and is of interest for membrane studies as well as for spin-labelling and radioimmunoassay purposes. A convenient synthesis of (2E,4E)-5-(3,5-dihydroxyphenyl)penta-2,4-dienoate allows its conversion into the crystalline Δ6-THC analogue having a conjugated dienoic esterside chain. Chromatographic information is tabulated for esters of the ω-carboxy cannabinoid series along with data for esters of the naturally occurring Ar-carboxylated cannabinoid series made synthetically in earlier work.

A novel approach to the synthesis of the cannabinoids

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA novel approach to the synthesis of the cannabinoidsWayne E. Childers Jr. and Harold W. PinnickCite this: J. Org. Chem. 1984, 49, 26, 5276–5277Publication Date (Print):December 1, 1984Publication History Published online1 May 2002Published inissue 1 December 1984https://doi.org/10.1021/jo00200a061RIGHTS & PERMISSIONSArticle Views719Altmetric-Citations31LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (271 KB) Get e-Alerts Get e-Alerts

Studies on the Cannabinoid Field: Synthesis of New Cannabinoids from 4-Hydroxycoumarin and 4-Hydroxythiocoumarin by Pyridine-catalysed Condensation of Citral and Citronellal

Abstract The reaction of 4-hydroxycoumarin and 4-hydroxythiocoumarin with citral in basic as well as acidic conditions led to the formation of tetrahydrocannabiol derivatives. With citronellal, the above hydroxycoumarins afforded the corresponding hexahydrocannabiol derivatives in moderate yields. The structures and the stereochemistry of the compounds obtained are established on the basis of spectral-analytical evidence.

Synthesis of cannabinoids by pyridine-catalysed citral–olivetol condensation: synthesis and structure of cannabicyclol, cannabichromen, (hashish extractives), citrylidene-cannabis, and related compounds

Citral condenses with olivetol in the presence of pyridine (1 mol) to give citrylidene-cannabis(III)(26%), cannabi-chromen (IV)(15%), its isomer (V)(3%) the bischromen (II)(6%), cannabicyclol (IX)(1%), its isomer (XV)(3%), and the bis-compound (XVI)(1·3%). Cannabichromen when heated with pyridine gives citrylidene-cannabis and cannabicyclol: the latter is also formed from cannabichromen under acid catalysis, and photochemically, in preparatively acceptable yields. Reasons for revising to (IX) the earlier structural proposal (VII) for cannabicyclo, are presented. Cannabichromen and cannabicycol are extractives of Cannabis(hashish).