Synthetic approaches to cis-THC, a promising scaffold in medicinal chemistry

Introduction

Plants of the genus Cannabis have been used by different cultures for millennia (Russo, 2014). Throughout history this plant has been used in religious acts, for recreational purposes, therapeutic uses for the treatment of pain and different disorders and even as a source of fibers for making cloth and cordage (Appendino, 2020). Its history has been as extensive as controversial, generally influenced by social belief around marijuana consumption as well as by all the legal restrictions imposed by different governments on the research and use of this plant and its phytocannabinoid components (Mechoulam, 1986). Investigations during the last century can be divided into three stages: a chemical one, the biochemical era and the current one focused on the commercialization and legal status. The chemical stage mainly dealt with the identification and characterization of the active components of the plant, having a milestone in 1964 with the isolation, structural elucidation and identification of (−)-Δ⁹-trans-tetrahydrocannabinol [(−)-Δ⁹-trans-THC, 6a, Figure 1] as the main psychoactive component of the plant by the group of Mechoulam (Gaoni and Mechoulam, 1964; Mechoulam and Hanuš, 2000). The biochemical era began with the identification of the first cannabinoid receptors leading later to the establishment of what today is known as the endocannabinoid system (ECS), which comprises the cannabinoid receptors, endogenous lipid mediators (endocannabinoids) and the corresponding metabolic enzymes (Mechoulam et al., 2014). The relevance that this system has been shown to possess, particularly on key physiological functions and dysfunctions, has promoted increased interest, a boost in research on cannabinoids and most importantly reduced restrictions opening the way for a commercial era involving the approval of medical treatments based on cannabinoids (Vemuri and Makriyannis, 2015). In this context, a plethora of pharmaceutical products and cosmetics appeared containing cannabidiol (CBD, 2) or Δ⁹-THC (6a). Since 1985, FDA has already approved four treatments based on cannabinoids: Marinol^® and Syndros^®, based on synthetic 6a as active ingredient, are indicated for the treatment of nausea associated with chemotherapy and anorexia in AIDS patients; Epidiolex^®, which contains 2 as active principle, being the first FDA approved treatment to contain a purified extract of the plant and used for the treatment of seizures associated with two severe forms of epilepsy in patients over 2 years of age; and Cesamet^®, based on drug nabilone, a synthetic analogue of 6a, is used to treat nausea and chemotherapy-induced vomit (Khalsa et al., 2022).

FIGURE 1

FIGURE 1. Structures of main classes of cannabinoids.

Phytocannabinoids are biologically active meroterpenoids of mixed polyketide and terpenoid biosynthetic origin (Degenhardt et al., 2017; Jamieson et al., 2021; Tahir et al., 2021; Purdy et al., 2022). Structurally isoprenylated resorcinols, main classes of cannabinoids include cannabigerol (1a, CBG), cannabidiol (2, CBD), cannabichromene (3, CBC), cannabinol (4, CBN), Δ⁸-tetrahydrocannabinol (5, Δ⁸-THC) and Δ⁹-tetrahydrocannabinols (6, THCs) (Figure 1). To date, more than a hundred cannabinoids have been found to be produced by Cannabis sativa L. (Hanuš et al., 2016). Diversification in structure comprises oxidized and cyclized derivatives, analogues with variations in the length of the resorcinyl alkyl chain, and carboxylated versions called acidic cannabinoids which are metabolic precursors in their biosynthesis (e.g., cannabigerolic acid CBGA, 1b).

Although literature review reveals that most research studies have focused on only two major components of the plant [namely, CBD (2) and (−)-trans-Δ⁹-tetrahydrocannabinol (Δ⁹-trans-THC, 6a)] (Sampson, 2021), over the last two decades there has been an increase in interest in the occurrence, synthesis, and medicinal potential of minor components of the plant, known as “minor cannabinoids” or “rare cannabinoids”, probably as a result of reduced restrictions and approvals of cannabinoid-based therapeutic treatments (Walsh et al., 2021; Caprioglio et al., 2022; Maioli et al., 2022; Nguyen et al., 2022). Δ⁹-trans-THC, (6a) the main psychoactive constituent of Cannabis sativa, features a tetrahydrobenzo[c]chromene motif bearing two stereogenic centers at positions 6a and 10a and thus four stereoisomers can be conceived. Nevertheless, only one of these four compounds is produced in the plant via non-enzymatic decarboxylation of (−)-Δ⁹-trans-tetrahydrocannabinolic acid [(−)-Δ⁹-trans THCA, 8], formed in turn by enzyme tetrahydrocannabinolic acid synthase (THCA synthase) from cannabigerolic acid (1b) (Scheme 1). THCA synthase, with the aid of a doubly-covalent attached FAD cofactor (binding residues shown in grey), catalyzes the stereoselective oxidative cyclization of cannabigerolic acid (1b) through oxidized ortho-quinone intermediate 7, which undergoes an intramolecular hetero Diels–Alder reaction to deliver (−)-Δ⁹-trans-tetrahydrocannabinolic acid 8. While this particular cannabinoid has been assumed as the only relevant isomer since its identification in 1964, the cis-stereoisomers of 6a [(+)- and (−)-Δ⁹-cis-THC, 6b] have been both obtained via synthesis as well as identified in C. Sativa as minor constituents. The present review discloses the natural occurrence and bioactivity of these minor phytocannabinoids as well as all synthetic approaches that have been established to selectively prepare this medicinally promising enantiomeric pair of natural products.

SCHEME 1

SCHEME 1. Biosynthesis of (−)-Δ⁹-trans-THC (6a) as its acid version (THCA).

Synthetic strategies toward Δ⁹-cis-THC

Shortly after the characterization and identification of (−)-Δ⁹-trans-THC as the main psychoactive component of Cannabis, cis-THC as a racemic mixture was first obtained by Taylor and co-workers in 1966 (Scheme 2) (Taylor et al., 1966). The group established a one-pot synthetic strategy based on the acid promoted condensation between olivetol (9) and citral (10), giving access to Δ⁸-trans-THC (which at the time had been identified in the plant as another psychoactive constituent) as well as Δ⁸-cis-THC and Δ⁹-cis-THC. In particular, treatment of the substrates with BF₃.Et₂O in benzene at 5°C–10°C led to the isolation of Δ⁸-cis-THC, Δ⁸-trans-THC and derivative Δ⁸-trans-11, in 20%, 20% and 10%–20% yields, respectively. On the other hand, when the condensation was carried out under milder acid conditions (HCl 0.0005 N) Δ⁹-cis-THC and Δ⁹-trans-THC were instead obtained as a mixture hard to separate (12% pure Δ⁹-cis-THC fraction, ca 25% mixture fraction). During this study, acid treatment was also shown to isomerize Δ⁹-THC isomers to the corresponding Δ⁸-THC products, as well as thermal treatment for the case of Δ⁹-trans-THC when using vapor phase partition chromatography (280°C) and based on these observations the group proposed that the effects of smoking Cannabis may be due to isomer Δ⁸-THC instead of Δ⁹-THC (Taylor et al., 1966). The same year, after this report, Gaoni and Mechoulam reevaluated these results and claimed that Δ⁹-cis-THC does not undergo acid-promoted isomerization toward Δ⁸-cis-THC and that the structure of the originally proposed product of this transformation (Δ⁸-cis-THC) should be reassigned to iso-THC (Δ⁴⁽⁸⁾-12) (Gaoni and Mechoulam, 1966). The researchers also indicated that Δ⁹-trans-THC does not undergo thermal isomerization to Δ⁸-trans-THC and that the isomerization found by Taylor and co-workers on vapor phase chromatography may have been promoted by the nature of the column support used. Mechoulam later demonstrated that both Δ⁹-cis-THC and Δ⁸-trans-THC were inert to oxidation conditions that converted Δ⁹-trans-THC to cannabinol (Mechoulam et al., 1968). This condensation of olivetol (9) and citral (10) using HCl in EtOH was reinvestigated by Crombie and Ponsford later under reflux conditions for 5 h to afford, after Florisil chromatography, a mixture of Δ⁹-cis-THC and Δ⁹-trans-THC in 19% yield (ca 5:1 by NMR analysis) (Crombie and Ponsford, 1971). Mechoulam and co-workers also repeated the BF₃.Et₂O promoted direct condensation and found that when the acid was used in low loading (1%) in CH₂Cl₂ for 1 h at room temperature, Δ⁹-trans-THC was obtained in 20% yield and isomer Δ⁹-cis-THC in 5% yield (Mechoulam et al., 1972).

SCHEME 2

SCHEME 2. First synthesis of (±)-Δ⁹-cis-THC via condensation between olivetol (9) and citral (10) (1966).

In 1967, Fahrenholtz and co-workers reported a novel synthetic approach towards many cannabinoids including Δ⁹-cis-THC, at the time considered an unnatural isomer of THC (Scheme 3) (Fahrenholtz et al., 1967). The synthetic strategy began with a von Pechmann condensation between olivetol (9) and diethyl 2-acetylglutarate (13) to afford a coumarin intermediate (14). Intramolecular condensation was then achieved using NaH in DMSO which led to a ketone intermediate (15) which was then protected as a cyclic ketal. Hydrogenation with Raney Ni under vigorous conditions afforded cis-lactone 16, which was treated with MeMgI followed by hydrolysis to afford a ketone intermediate that upon a new sequence of MeMgI treatment followed by hydrolysis yielded alcohol 17. Acid-catalyzed dehydration of this intermediate produced cis-THC in good yield.

SCHEME 3

SCHEME 3. Synthesis of Δ⁹-cis-THC by Fahrenholtz and co-workers (1967).

In 1969, Razdan and Zitko reported that through treatment with p-toluenesulfonic acid (TsOH) in refluxing benzene, Δ⁹-cis-THC interconverted with cannabicitran (18) and iso-THC’s (12) leading to an equilibrium that favors the iso-THC´s (Scheme 4) (Razdan and Zitko, 1969). The acetylation of Δ⁹-cis-THC was shown to block this process. Cannabicitran (18) is established as an intermediate between Δ⁹-cis-THC and the iso-THC’s (12), a process that cannot take place with the trans-THC’s since a polycyclic system as cannabicitran cannot be formed with a trans-ring fusion. The group also found that BBr₃ isomerizes Δ⁹-cis-THC to Δ⁸-trans-THC in 60% yield. The first proposed mechanism involves ionization of the ether linkage followed by epimerization at C-4 via elimination. Almost a decade after this report the group continued to investigate this isomerization making advances on the mechanistic interpretation (Uliss et al., 1978).

SCHEME 4

SCHEME 4. Isomerization of Δ⁹-cis-THC found by Razdan and Zitko (1969).

Also in 1969, Yagen and Mechoulam reported that on BF₃.Et₂O (5% in dichloromethane) treatment, cannabichromene (CBC, 3) gives rise to a low yield of Δ⁹-cis-THC (5%) among other isomers. A mechanism based on the intermediacy of cationic species was proposed to account for the transformation (Scheme 5) (Yagen and Mechoulam, 1969).

SCHEME 5

SCHEME 5. Acid-promoted isomerization of cannabichromene (3) by Yagen and Mechoulam (1969).

In 1970, Razdan and co-workers reported an asymmetric strategy towards THC-derivatives based on the use of a carene derivative (Scheme 6) (Razdan and Handrick, 1970). During their studies, they found that condensation between (+)-trans-2-carene oxide (20) and olivetol (9) promoted by 1% BF₃.Et₂O in dichloromethane at room temperature or p-toluenesulfonic acid in benzene (with a molar ratio of substrates 1.6:1) led to a mixture in which major products were (+)-Δ⁹-cis-THC and (−)-Δ⁹-trans-THC (28%).

SCHEME 6

SCHEME 6. Asymmetric synthesis of (+)-Δ⁹-cis-THC reported by Razdan and Handrick (1970).

Taylor’s direct condensation between olivetol (9) and citral (10) was reinvestigated by Razdan and co-workers in 1975 using HCl (0.5 N) in EtOH/benzene for structure-activity relationship studies during their program on THC analogues (Uliss et al., 1975b). The reaction led to the formation of Δ⁹-cis-THC in 10% yield and regioisomer Δ⁹-cis-21 in 20% yield (Scheme 7). The same year the group reported a synthetic strategy to prepare Δ⁸-cis-THC, an isomer that had not been previously prepared in the THC series (Uliss et al., 1975a). The asymmetric version of this strategy was then realized accomplishing the preparation of (+)-Δ⁹-cis-THC and (+)-Δ⁸-cis-THC in 0.7% and 0.06% yields, respectively (Uliss et al., 1977).

SCHEME 7

SCHEME 7. Reinvestigation of Taylor’s condensation approach by the group of Uliss et al. (1975a).

Based on a Diels–Alder approach previously developed by Taylor and Strojny (1960), the group of Razdan reported in 1977 an entry to Δ⁹-cis-THC via prior preparation of cis-CBD (Scheme 8) (Handrick et al., 1977). Tandem Diels–Alder reaction/decarboxylation between isoprene (23) and 3-carboxy-5-hydroxy-7-pentylcoumarin (22) led to lactone 24, bearing a cis-ring fusion, which under acid treatment becomes an equilibrated 1:1 mixture of Δ⁸- and Δ⁹-olefins. To this mixture, addition of MeMgI leads to a mixture of triols, which upon bis-acetylation and dehydration using thionyl chloride affords Δ⁸- and Δ⁹-cis-CBD diacetates (25), separable by HPLC. Basic hydrolysis of Δ⁹-25 provided an entry to Δ⁹-cis-CBD which upon acid treatment (TsOH) underwent cyclization toward a mixture of Δ⁹-cis-THC, Δ⁸-cis-THC and iso-THC’s in ratio 40:17:43. Remarkably, a recent patent described the use of triisobutylaluminium as efficient Lewis acid for this same cyclization, actually performed on each enantiomer of Δ⁹-cis-CBD, towards the corresponding Δ⁹-cis-THC cyclized product (85% yield) (Abdur-Rashid et al., 2020).

SCHEME 8

SCHEME 8. Synthesis of Δ⁹-cis-THC from cis-CBD (1977).

In 1979 Luteijn and Spronck reported an alternative synthesis of (±)-Δ⁹-cis-THC based on the reaction between olivetol bis(tetrahydropyranyl ether)homocuprate (26) and dehydrolinalool acetate (27) (Scheme 9, overall yield 20%) (Luteijn and Spronck, 1979). The reaction would work via initial S_N2’ reaction leading to an allene intermediate (28) which upon acid treatment undergoes hydrolysis of the tetrahydropyranyl groups (THP) followed by bicyclization.

SCHEME 9

SCHEME 9. Synthesis of (±)-Δ⁹-cis-THC reported by Luteijn and Spronck (1979).

In 1984, Rickards’ group showed that the use of olivetol di (methoxymethyl)ether as coupling partner of citral (10) enables an efficient route to (±)-Δ⁹-cis-THC (Scheme 10) (Moore et al., 1984). The reaction begins with the alkylation of citral (10) with a protected olivetol substrate lithiated at C-2 which yielded the corresponding alcohol product 29 in 79% yield. Reaction of this intermediate with TMSCl in the presence of tetraethylammonium bromide at 0°C, followed by aqueous work-up, led to the formation of (±)-Δ⁹-cis-THC in 65% yield. The mild conditions are believed to favor the formation of an ortho-quinone methyde-type intermediate that undergoes the required intramolecular hetero-Diels Alder reaction towards the product avoiding cationic intermediates. Later, in 2001, Malkov and Kočovský reported that the condensation between olivetol (9) and citral (10) catalyzed by a Mo(IV) catalyst [(acac)₂MoCl₂] affords a mixture of (±)-Δ⁹-cis-THC and (±)-Δ⁹-trans-THC in 20% yield and 1:2.2 cis-trans ratio (Malkov and Kočovský, 2001).

SCHEME 10

SCHEME 10. Synthesis of Δ⁹-cis-THC reported by the group of Moore et al. (1984).

A major breakthrough in the total synthesis of THC natural products was achieved in 2014, when the group of Carreira established an efficient catalytic asymmetric synthetic strategy to access any stereoisomer of Δ⁹-THC (Scheme 11) (Schafroth et al., 2014). This uniform stereodivergent assembly of all stereoisomers of Δ⁹-THC was achieved via dual stereodivergent catalysis, applying identical synthetic sequences, under identical reaction conditions and using the same set of substrates though five synthetic steps. The asymmetric approach involves simultaneously using two chiral catalysts, each of which exerts full and independent control over the configuration of one of the stereocenters and the concept was implemented in the α-allylation of 5-methylhex-5-enal (31) catalyzed by a chiral Ir/(P,olefin) complex and a chiral amine. In the presence of 3 mol% of [{Ir(cod)Cl)}₂], 12 mol% of (R)-L or (S)-L, and 15 mol% of Jørgensen amine (R)-A or (S)-A, all possible stereoisomers of γ,δ-unsaturated aldehyde product 32 were obtained in good yields (55%–62%) and excellent selectivity (dr 15:1, er > 99:1) via activation of both allylic alcohol (30) and aldehyde (31). Reactions could be performed in Gram scale with similar selectivity and yields. From the aldehyde 32 intermediates, ring-closing metathesis using Grubbs second-generation catalyst first secured cyclohexenecarbaldehydes 33 in 85%–92% yield. Pinnick oxidation of the aldehydes to the corresponding carboxylic acids, followed by treatment with trimethylsilyldiazomethane gave the corresponding methyl esters (60%–66% yield over two steps). The formation of a tertiary alcohol and double methyl ether deprotection was achieved with excess MeMgI at 0°C–160°C at reduced pressure (150 mm Hg). After aqueous work-up and extraction, the organic phase was treated with Lewis acid ZnBr₂, which promoted aryl ether formation and thus the formation of each stereoisomer of Δ⁹-THC.

SCHEME 11

SCHEME 11. Catalytic asymmetric synthesis of all Δ⁹-THC stereoisomers (2014).

More recently, another asymmetric and straightforward approach towards (−)-Δ⁹-cis-THC, also applicable to many analogues, was reported by Dorsch and Schneider. The group reinvestigated the bicyclization reaction studied by Rickards and found that chiral imidodiphosphorimidates (IDPis, e.g., 34), as sterically confined Brønsted acid catalysts, allow the cyclization to proceed with high yield and selectivities (Scheme 12) (Dorsch and Schneider, 2023). In particular, cyclization of 29 led to derivative 35 which after MOM-removal using AcCl afforded (−)-Δ⁹-cis-THC (71% yield from 29). Some control experiments supported a cationic stepwise mechanism for the organocatalyzed cyclization involving initial carbocycle formation via a Prins-type reaction.

SCHEME 12

SCHEME 12. Asymmetric synthesis of (−)-Δ⁹-cis-THC by Dorsch and Schneider (2023).

It should be noted that some of the presented strategies, such as Rickards’ synthetic sequence, have also been used for the preparation of other natural products bearing the cis-fused tetrahydro-6H-benzo[c]chromene system of Δ⁹-cis-THC. These natural products can be found in species other than Cannabis sativa and include, for instance, perrottetinene from different Radula liverwort species (Toyota et al., 1994; Cullmann and Becker, 1999; Park and Lee, 2010), which medicinal potential has attracted considerable attention (Chicca et al., 2018); and epiconicol found in many marine ascidians, which displays considerable antiproliferative activity against different cancer cell lines (Carroll et al., 1993; Garrido et al., 2002; Simon-Levert et al., 2005; Ren et al., 2020). Also, other synthetic strategies have been explored and developed to gain access to this same cis-fused structural motif but have not been yet applied to cis-THC in particular. A radical cyclization approach was explored by Parker and co-workers to gain access to natural product bisabosqual A (am Ende et al., 2013; am Ende and Parker, 2019). Substituted 1-aryl-1,3-butadienes have been evaluated in Diels–Alder strategies toward cis-fused tetrahydrobenzo[c]chromenes including epiconicol and some members of palodesangrens family of natural products (Minuti et al., 2015; Tangdenpaisal et al., 2019; Tangdenpaisal et al., 2022). A domino electrocyclic ring-opening/hetero Diels–Alder reaction of 2-prenylated 2H-pyrans, originally developed by Chizhova and Anufriev (Chizhova and Anufriev, 2000), has been employed for the synthesis of reduced versions of cannabinoids (Garcia et al., 2009), natural products benzosimuline (Riveira et al., 2016), 7-demethylnaphterpin (Murray et al., 2018), as well as others (Coleman et al., 2019; Murray et al., 2019). Interestingly, a related strategy was developed by Appendino and co-workers using iodine as promoter but to afford aromatized versions of the corresponding tetrahydro-6H-benzo[c]chromene derivatives (Caprioglio et al., 2019). Based on all the available data, a direct oxidative cyclization method (resembling THCA synthase activity) that converts geranylresorcinols (such as CBG) into cis-THC derivatives selectively is also lacking. The only examples involve oxidative cyclization toward chromenes promoted by oxidants such as DDQ, MnO₂ or through Pd-catalyzed procedures (Miyase et al., 1980; Lok et al., 1983; Verotta et al., 2004; Ma et al., 2020). Studies on all the established synthetic strategies in the future will prove whether they can efficiently provide access to cis-THC and analogues in order to advance biological studies on these precious molecules.

Natural occurrence and biological activity of cis-THC isomers

In 1977, Smith and Kempfert reported for the first time the isolation of Δ⁹-cis-THC from a natural source (Smith and Kempfert, 1977). Natural Δ⁹-cis-THC was found as a contaminant during routine analysis of samples of marijuana. An amount of 460 g of dried plant material afforded ca 1 mg of the compound which absolute stereochemistry was assigned as (6aS,10aR) based on circular dichroism studies. The researchers found that this natural product was prominent in samples that had high content of CBD. In general, samples that had CBD:THC ratios of ca 16:1 were found to exhibit trans:cis ratios of THC of about 1:1 to 2:1 (phenotype considered as non-narcotic hemp). Phenotypes having ratios less than 1 showed trans-THC:cis-THC ratios greater than 10:1. The total concentration of Δ⁹-cis-THC in plants having a phenotype ratio greater than ca 2 was relatively constant at ca 0.04% of the dry plant weight. On the other hand, plants having low amounts or lacking CBD did not exhibit detectable amounts of Δ⁹-cis-THC. Remarkably, this natural product as well as other cis-homologues (different alkyl branched chains) and carboxylated versions were identified more recently in C. sativa L. varieties (Basas-Jaumandreu and de las Heras, 2020). In particular, Δ⁹-cis-THCA (Δ⁹-cis-tetrahydrocannabinolic acid, Δ⁹-cis-8), found in samples that had not been heated before analysis, would be the biosynthetic precursor of Δ⁹-cis-THC which would then be formed via non-enzymatic decarboxylation (Tolomeo et al., 2022). As for Δ⁹-cis-THC, the corresponding carboxylated cannabinoid Δ⁹-cis-THCA was present in concentrations comparable to or slightly lower than those of the well-known trans isomer in CBD-rich or CBG-rich varieties of the plant.

Mechoulam and co-workers were the first to report in1971 on the biological activity of Δ⁹-cis-THC. The group found that (±)-Δ⁹-cis-THC was inactive in behavioral tests in adult Rhesus monkeys at doses of 1.5 mg/kg (Edery et al., 1971). Later, in 1975, Razdan’s group described racemic Δ⁹-cis-THC as a mild depressor and reported that it was 20-fold less potent than natural (−)-Δ⁹-trans-THC in the “popcorn assay”, a rarely used mouse model of cannabinoid activity based on the association of ataxia and hyperexcitability to touch (Uliss et al., 1975a). Additionally, in 1984 Razdan and Martin showed that (+)-Δ⁹-cis-THC, together with (+)-Δ⁹-trans-THC, were quite less active in behavioral tests in dogs compared to (−)-Δ⁹-trans-THC (Martin et al., 1981).

In 2021, the groups of Appendino, Carreira and Gertsch published a thorough study on Δ⁹-cis-THC addressing its natural occurrence, chirality and pharmacological activity (Schafroth et al., 2021). Consistent with the report by Smith and Kempfert, the authors found that in hemp non-narcotic varieties of the plant featuring low content of (−)-Δ⁹-trans-THC the concentration of Δ⁹-cis-THC was in the same order of the psychoactive component whereas the concentration of Δ⁹-cis-THC was below the limits of detection in a sample of medicinal Cannabis chemotype with high content of (−)-Δ⁹-trans-THC. In this same medicinal Cannabis sample Δ⁹-THC was found with very high enantiomeric purity (ee > 99%) and exclusively as the trans diastereoisomer. On the contrary, in 34 samples of Cannabis varieties in which CBD or CBG was the most prominent phytocannabinoid, Δ⁹-THC was found with lower diastereomeric purity. The authors showed that natural Δ⁹-cis-THC is scalemic (approx. 80–90% enantiomeric purity), the major enantiomer being 6aS, 10aR [(−)]. Regarding binding affinity to cannabinoid receptors CB₁ and CB₂, (−)-Δ⁹-cis-THC exhibited binding affinities ten times lower than the ones found for the natural trans isomer, whereas (+)-Δ⁹-cis-THC was found to be inactive. The researchers found that (−)-Δ⁹-cis-THC mildly inhibits endocannabinoid hydrolytic enzymes similarly to (−)-Δ⁹-trans-THC. In general, IC₅₀ values of these natural tetrahydrocannabinols on endocannabinoid degrading enzymes were higher than the in vivo achieved concentrations after Cannabis consumption. Possible effects of isomer (−)-Δ⁹-cis-THC were evaluated in vivo and compared with the effects of (−)-Δ⁹-trans-THC on a series of four tests typically associated with the activation of receptor CB₁ in mice (hypothermia, catalepsy, hypomobility and analgesia). The experiments showed that (−)-Δ⁹-cis-THC could provoke the complete tetrad in mice with a dose of 50 mg/kg, whereas Δ⁹-trans-THC exhibited similar potency at lower doses between 6 and 10 mg/kg, according to the different potencies measured in vitro for the activation of receptor CB₁. The group proposed that if lower doses of Δ⁹-trans-THC cause therapeutic beneficial effects with little secondary effects, then less potent (−)-Δ⁹-cis-THC could retain the therapeutic potential of Δ⁹-trans-THC without undesired effects. The group also raised the debate on the legal status of all isomers of THC which are currently not distinguished nor discriminated to determine the classification of marijuana samples as narcotics and non-narcotic variants (La Maida et al., 2022).

On the other hand, the same year, first patents appeared on the potential therapeutic use of each enantiomer of Δ⁹-cis-THC based on animal models of disease (Guy et al., 2021; Guy et al., 2021). Taking into account the natural products featuring the cis-fused system that have been shown to display antiproliferative properties against a diverse set of cancer cell lines, future studies should address whether Δ⁹-cis-THC enantiomers exhibit anticancer potential.

Concluding remarks

Cis-THC, as well as other natural products bearing the cis-fused tetrahydrobenzo[c]chromene motif, demonstrated an interesting biological activity profile. A review such as this is hoped to enhance both synthetic chemists and medicinal chemists in their pursuit of discovering the biological potential of natural products including Δ⁹-cis-THC and related systems, leading to more simple, straightforward, and selective synthetic processes as well as greater application possibilities.

Author contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Funding

Support from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, PUE-2016, PIP 2021-2023-1045), Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT, PICT-2021-353, PICT-2018-4150), and Universidad Nacional de Rosario (BIO 580, UNR-80020180300024UR, 80020210200028UR) is acknowledged. Work in Novara (DC) was supported by MIUR (PRIN 2017, Project 2017WN73 PL, Bioactivity-directed exploration of the phytocannabinoid chemical space).

Acknowledgments

LG thanks CONICET for fellowship.

Conflict of interest

The authors MR and DC declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

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