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Cannabis Phenolics and their Bioactivities

August 2017
Current Medicinal Chemistry 24(10)

DOI:10.2174/0929867324666170810164636

Authors:

Federica Pollastro

Amedeo Avogadro University of Eastern Piedmont

Alberto Minassi

Amedeo Avogadro University of Eastern Piedmont

Background: Although Cannabis sativa L. is one of the most versatile plant species with multipurpose use both as medical, alimentary source and as psychoactive abuse, its biomedical relevance focused the attention on major cannabinoids. Phytochemical characterization of cannabis highlights the presence of various non-cannabinoids constituents including flavonoids, spiroindans, dihyrostilbenes, dihydrophenanthrenes, lignanamides, steroids and alkaloids. This review aims to identify polyphenols present in this plant, their biosynthesis, their bioactivities and their synthesis, when this occurred. Methods: We undertook a systematic research focused on bibliographic databases including all noncannabinoids phenolics in various C. sativa strains from their isolation, structural elucidation, their biological activity to their synthesis. Result: Nevertheless, attention has so far been focused only on cannabinoids (more than one hundred isolated), cannabis is a complex plant able to produce more than 480 chemical entities that represent almost all of the different biogenetic classes. Regarding phenolic compounds, the plant biosynthesises a plethora of unique non-cannabinoids second metabolites, such as prenylated flavonoids, stilbenoids derivatives and lignanammides. Conclusion: Cannabis is a plant with high pharmacological and nutrition values, its potentialities and applications are not only circumscribed to cannabinoids biological activities, but also defined by noncannabinoid compounds. The combination of other cannabinoids together with noncannabinoid components could enhance the beneficial effects of THC and could reduce undesirable side effects.

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Cannabis phenolics and their bioactivities

Journal:

Current Medicinal Chemistry

Manuscript ID

Draft

Manuscript Type:

Thematic Issue Article

Date Submitted by the Author:

n/a

Complete List of Authors:

Pollastro, Federica; Universita degli Studi del Piemonte Orientale Amedeo

Avogadro Dipartimento di Scienze del Farmaco, Department of

Pharmaceutical Sciences

Minassi, Alberto; Universita degli Studi del Piemonte Orientale Amedeo

Avogadro Dipartimento di Scienze del Farmaco, Department of

Pharmaceutical Sciences

Fresu, Luigia; Universita degli Studi del Piemonte Orientale Amedeo

Avogadro Scuola di Medicina, Department of Health Sciences

Keywords:

non-cannabinoids, antioxidant, flavonoids, spiroindans, lignans, cannabis

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Abstract: Although Cannabis sativa L. is one of the most versatile plant species with multipurpose

use both as medical, alimentary source and as psychoactive abuse, its biomedical relevance

focused the attention on major cannabinoids. Phytochemical characterization of cannabis

highlights the presence of various non-cannabinoids constituents including flavonoids,

spiroindans, dihyrostilbenes, dihydrophenanthrenes, lignanamides, steroids and alkaloids.

Cannabis is a plant with high pharmacological and nutrition values, its potentialities and

applications are not only circumscribed to cannabinoids biological activities, but also defined by

non-cannabinoid compounds. This review deals with polyphenols present in this plant, their

biosynthesis, their bioactivities and their synthesis, when this occurred.

Keywords: non-cannabinoids, antioxidant, flavonoids, spiroindans, lignans.

INTRODUCTION: POLYPHENOLS AS MINOR CONSTITUENTS OF Cannabis sativa L.

Cannabis sativa L. (Cannabaceae family) is an herbaceous annual dioecious (rarely monoecious)

plant bearing male and female flowers on separate plants recognizable for their characteristic

spiky leaves. Male and female plant could hardly be distinguished during vegetative growth

although the female plant tends to be stockier and to flower later than the male plant [1]. The

male plant, taller and less robust compared with the female plant, bears axillary or terminal

inflorescences with yellowish green staminate flowers without petals and with sparse prostrate

hairs. The sole function of the staminate (male) flowers is to pollinate the female flowers. The

cannabis female plant has a speudospikes congested and erect to spreading pistillate

inflorescences with green, sometimes purple to red flowers enclosing the dry fruits (achenes). The

unfertilized flower heads and flower bracts of female plant are the primary source of cannabinoids

enclosed in glandular, tiny but visible trichomes.

Cannabis was one of the first plants domesticated by man and, starting from the native Central

Asia; humans have spread its cultivation worldwide over the past 10,000 years. It has been an

important alimentary and fibre source as medicinal and ritual/psychoactive agent since ancient

time date back to 3000 B. C. [2]. Due to the considerably efforts in breeding and selection,

cannabis now could be divided into different cultivar and Group based on economically important

characteristic depending on the use emphasized: drug Group, CBD-drug Group, mixed THC-CBD-

drug Group, fibre-hemp Group, seed-oil Group etc... [3]. Anyway, such “cultomic” and not

taxonomic nomenclature could be simplified into two generic phenotypes: drug and non-drug

varieties [4] which main difference is the content of the psychoactive molecule Δ

tetrahydrocannabinol 1 simply referred as THC. The drug type, best known as marijuana or

hashish, contain THC 1 in concentration between 1 and 20% [5]. The nondrug type, commonly

referred as industrial hemp, has no psychoactive activities because, according to the European

Industrial Hemp Association, 0.2% THC 1 content should not exceed in dry matter of the upper

one-third of the crop [5]. The fibre-phenotype, economically important in China, Europe, Canada

and many other territories, is extensively cultivated for textiles and edible seed-oil, while the

psychotropic phenotype has illicit cultivation for recreational purpose or as chemical and

biomedical research interests [6]. Drug types, however, are typically acclimatized to semi-tropical

zones.

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Cannabis is a complex plant able to produce more than 480 chemical entities that represent

almost all of the different biogenetic classes [7]. Nevertheless, attention has so far been focused

only on cannabinoids (more than one hundred isolated), and essentially on THC 1, on its natural

occurring degradation product cannabinol (CBN) 2, and on three major non-psychoactive

cannabinoids: cannabidiol (CBD) 3, cannabichromene (CBC) 4 and cannabigerol (CBG) 5 (Fig. 1).

The efforts resulting in the study of THC 1 and in the isolation of other cannabinoids, led to the

discovery of other secondary metabolites occurring in the plant. These natural compounds are

represented by terpenoids, more than 140 and responsible of the typical cannabis scent;

carbohydrates which common sugars are the predominant constituent of this class; saturated and

unsaturated fatty acids and their esters (oxylipins); quaternary bases (choline and trigonelline),

amides and amines, phytosterols and non-cannabinoids phenolic compounds. Between non-

cannabinoids phenols, structurally unique compounds exist as lignans, spiro-indan-type,

dihydrostilbene-type, dihydrophenantrene derivatives, stilbenoids, cannabispirans and a rare

quinoid (denbinobin 28). In addition, more than 20 flavonoids have been identified in cannabis,

belonging mainly to two classes, flavones and flavonols, and three prenylated aglycone flavanones

named cannflavin A, B and C [3, 8] have been isolated.

FLAVONOIDS

Flavonoids belong to one of the largest group of natural compound encompassing more than

10,000 different structures. They are ubiquitous in higher plants and their great diversity and

diversification render them useful for taxonomical studies. Although these second metabolites are

distributed in different extracellular and sub-cellular compartments of the plant (membranes,

chloroplasts, vacuoles and nucleus) [9, 10], their biochemistry and physiology is not completely

elucidated and it is still a matter of debate. Flavonoids are not only pigments displaying marvellous

and intense colours to flower petals, but they are associated to UV-screening functions playing a

key-role in preventing the generation of reactive oxygen species (ROS) by a mechanism not

completely discovered yet [11]. Moreover, they may control cell growth and differentiation with

the selective activation of light-sensitive genes, or genes involved in grown regulation expected to

be particularly sensitive to environmental cues representing the competitive strength of the

species. Despite their strong light absorption, there is no evidence of flavonoids involvement in

primary photosynthetic process [12].

Flavonoids are recognized for their health promoting in both human and animal nutrition [13, 14]

due to their wide range of biomedical and pharmacological properties, such as activation or

inhibition of specific enzymes including lipoxygenase and cyclooxygenase [15, 16], the

detoxification of carcinogens and chemoprevention [17, 18].

The basis of flavonoids structural great variability in higher plants make it possible to divide these

aromatic compounds in six subgroups named chalcones, flavones, flavonols, flavandiols,

anthocyanins and proanthocyanidins [19]. Differences could be found in the ring structure,

oxidation and reduction of aglycone, its hydroxylation and different position of hydroxyl group and

their diversification.

FLAVONOIDS IN CANNABIS

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The examination of cannabis flavonoids composition can not ignore the striking evidence that

cannabis is a plant with a great individual biosynthetic capacity [20]. Twenty-six flavonoids have

been isolated and detected in cannabis plants representing seven chemical structures: vitexin 6,

isovitexin 7, apigenin 8, luteolin 9, kaempferol 10, orientin 11 and quercetin 12, developed as

methylated and prenylated aglicones or as O-glycosides or C-glycosides conjugated [4, 21, 22, 7,

23, 20, 24]. Particular attention deserves to the aglycone flavonoids uniquely belonging to

cannabis [25]: two C-6 prenylated and C-6 geranylated flavones with close resemblances to

chrysoeriol and diosmetin first isolated by Crombie and Jamieson in the 1980 [26] from a Thailand-

strain cannabis and named canniflavone-1 and canniflavone-2. Actually, canniflavones are better

known as cannflavin A (13 geranyl-flavone) and cannflavin B (14 prenyl-flavone) [27]. A last

geranyl-flavone, cannflavin C 15, with geranyl group at C-8 instead of C-6, was detected and

characterized in the 2008 from a Mexican-high potency C. sativa [28] (Fig. 2).

Distribution of flavonoids is characterized by high variability between cannabis species with

important diversity from plant to plant and from plant tissue to another. Flores-Sanchez and

Verpoorte [29] provide an exhaustive elucidation about flavonoids distribution in cannabis plant

and tissues. For example, orientin 11 contents is higher in leaves than in seedlings and fruits,

without significant differences between genders and cannabis varieties; Vitexin 6 has the higher

levels in seedlings, instead isovitexin 7 and quercetin 12 have the lowest contents in fruits; the

highest quercetin 12 amounts are revealed in male flowers with a surprisingly difference between

fibre-type male flowers and drug-type male flowers. Luteolin 9 has the higher contents in male

flowers than in leaves, and kaempferol 10 is more concentrated in female flowers than in fruits.

Apigenin 8 contents are significantly different between flower genders. Therefore, Cannabis

flavonoids have been isolated and detected in several part of mature organism: flowers, leaves,

twigs and pollen [22, 23, 24]. Although evidences demonstrate flavonoids presence and secretion

in trichomes or by a secretory epithelium in some genera and families plant (genera Populus and

Aesculus, Betulaceae family), none of these natural compounds have been isolated from cannabis

glandular trichomes [4] and there is no prove of their detection in roots. Seeds also lack

prenylflavonoid compounds, but sprouting induces the production of cannflavin A 13 and B in

buds without any traces of cannabinoids biosynthesis [30]. Otherwise cannabinoids, accumulation

of flavonoids decreases during the growth of the plant [29].

FLAVONOIDS BIOSYNTHESIS IN Cannabis sativa

Although flavonoid biochemistry and biosynthesis has been fully studied in a conspicuous number

of plants, flavonoid biosynthesis pathways in cannabis are still missing [12, 31]. Flores-Sanchez and

Verpoorte [4] provided the general pathway for flavone and flavonol biosynthesis as it is expected

to occur in cannabis (Fig. 3).

The precursors are phenylalanine, which derive from shikimate pathway, and malonyl-CoA

(malonyl-Coenzyme A), synthetized by carboxylation of acetil-CoA, intermediate in the Krebs

tricarboxylic acid circle. The first step consists in the conversion of phenylalanine in p-cinnamic

acid by a phenylalanine ammonia lyase (step a), EC 4.3.1.5; the obtained p-cinnamic acid is at first

hydroxylated by the cynnamate 4-hydroxylase, EC1.14.13.11, to p-coumaric acid (step b) and then

a 4-coumarate: CoA-ligase, EC6.2.1.12, adds a CoA thiol ester (step c). One molecule of the

resulting p-coumaroyl-CoA is condensed with three molecules of the second precursor malonyl-

CoA by a chalcone synthase, EC 2.3.1.74 yielding naringenin chalcone (step d) that is finally

isomerized to the flavanone naringenin by a chalcone isomerase (step e), EC 5.5.1.6. Naringenin

represents the common starting point for the biosynthesis of flavones and flavonols.

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Hydroxysubstitution to ring C at position 3 by a flavanone 3-hydroxylase, EC 1.14.11.9 (step f)

delivers to dihydrokaempferol 10, a hydroxylation occurs in ring B at position 3’ by a flavonoid 3’-

hydrolase, EC 1.14.13.21 leading to dihydroquercetin (step g). Subsequently in the ring C at

position 2 and 3 a double bond is formed by a flavonol synthase, EC 1.14.11.- (step h) obtaining

kaempferol 10 and quercetin 12, or by a flavone synthase (step i) obtaining apigenin 8 from

naringenin (step i). Finally, glycosidation by UDP-glycosyltransferase, EC 2.4.1.-, convert apigenin 8

in isovitexin 7 and vitexin 6 and luteolin 9 in orientin 11 (step l). Modification reactions as

methylation by a SAM-methyltransferase (S-adenosyl methionine-methyltransferase), EC 2.1.1-,

(step m) and prenylation by prenyltrasnferase are added to aglycones.

Moreover, alternative biosynthetic routes for luteolin 9 and cannflavin A 13 and B 14 are

proposed. The biosynthesis starts from feruloyl-CoA and caffeoyl-CoA with malonyl-CoA, proceeds

with the conversion of these substrates to homoeriodyctol or eriodyctol chalcone by

homoeryodictol/eriodyctol synthase (step n) [32] and finally leads to the production of the

methylated flavanones homoeryodictol without the action of the flavonoind 3’hydrolase and S-

adenosyl methyltransferase (SAM-methyltransferase).

From an enzymatic point of view, glycosidation of aglycones has been detected in cannabis cell

cultures [33] and chalcone synthase activity from flower protein extracts [34]. Flavonoids C-

prenylation is common on ring A at position 6/8 and, generally, the most recurrent type of

prenylation is represented by 3,3-dimethylallyl chain although 1,1-dimethylallyl, geranyl,

lavandulyl, farnesyl derivatives have been detected in various plant genera. Prenylation occur after

the construction of the basic skeleton of different flavonoids classes. Although, a prenyltransferase

activity for all classes of flavonoids has not been discovered, this hypothesis is corroborated by the

substrate specificity of prenyltransferase to isoflavones and pterocarpans [35].

CANNABIS FLAVONOIDS: THEIR BIOLOGICAL ACTIVITY

Although flavonoids have physiological functions for plant survival, just a few of those found in

cannabis have been reported to be endowed with biological activities of human interest. As

reported by Barrett and co-workers [27, 36], cannflavin A 13 and B are both able to inhibit

prostaglandin E2 production by cultured rheumatoid synovial cells. The mechanism of action is still

unknown but it is likely that cannflavins share the same pharmacodynamics of other flavonoids,

i.e. inhibition of both cyclo-oxygenase and lipo-oxygenase [37, 38], which would suggest that the

anti-inflammatory activity is not restricted to synovial cells. More recently, an antimicrobial as well

as anti-leishmanial activity has been demonstrated for cannflavin B 14 [28]. Moreover, Radwan

and co-workers [21] isolated several new non-cannabinoid constituents from Cannabis sativa L.,

among which cannflavin C 15. This latter compound also appears to possess a moderate anti-

leishmanial activity together with a strong antioxidant activity; on the contrary, cannflavin A 13

exhibited a strong anti-leishmanian efficacy but a moderate antioxidant activity.

Flavonoids are well recognized antioxidant agents, and this has made them candidates for human

health as drugs or nutraceutics. For example, a very recent paper of Smeriglio and co-workers [39]

has demonstrated that Finola seed oil possesses a significant antioxidant potential that might

depend especially on flavonoids, including quercetin 12.

Last, apigenin 8 and other flavonoids interact with estrogenic receptors, and it has been

demonstrated to be the primary estrogenic agents in cannabis smoke [40]. Albeit its high affinity

to β-estrogenic receptor, apigenin 8 has low estrogenic activity and is able to inhibit estradiol-

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induced proliferation of breast cancer cells [41].

SYNTHESIS OF CANNFLAVIN B

Cannflavins are present in Cannabis sativa, in a yield approximatively of 6 mg/Kg for cannflavin A

13 and 0.8 mg/Kg for cannflavin B 14 [26]. A synthetic strategy could provide an easier and

alternative source of these flavonoids. Unfortunately, the only reported synthesis is based on a

regiodivergent approach that afforded compound 14 and its C-8 isomer isocannflavin B 16,

through the synthesis of two complementary C-prenylated acetophenones 17, 18 [42].

The first synthetic step (Fig. 4) is the O-prenylation, under Mitsunobu condition, of the bis-

protected trihydroxyacetophenone 19 followed by a tandem Claisen-Cope rearrangement leading

to the formation of the key intermediate 17. The access to 18 was allowed by a protecting group

swap between the ortho-hydroxy groups achieved in 72% yield. The compounds 17 and 18 were

condensate with the acyl chloride of protected vanillic acid 20 to give the Baker-Venkratraman

intermediates 21 and 22 cycled under acidic conditions using copper

chloride/chlorotrimethylsilane (CuCl

/TMS-Cl). The complete removal of the protecting groups

furnished the desired compounds 14 and 16.

STILBENOIDS

Stilbenoids comprehend a small group of phenolic compounds known for their intricate structures

[43] characterized by the presence of the 1,2-diphenylethylene backbone deriving from the basic

unit 3,5,4’-trihydroxy-trans-stilbenes although other structures are found in particular plant

families as bis(bibenzyls), dihydrostilbenes, phenanthrenes, 9,10-dihydriphenanthrenes and

related prenylated, geranylated and glycosydated derivatives [44].

Stilbenoids occur in unrelated plant species expressing the pivotal enzyme involved in their

biosynthesis pathway, the stilbene synthase, not ubiquitously present in the plant kingdom but

evolved only in a limited number of family plants [45]. Frequently these phenylpropanoids are

constituents of heartwood and roots [4] but they are also found in other lignified organs as stems

or in berry skin and foliar buds [45].

They play important roles in the constitutive and inducible defence responses, that means pre-

existing in plant tissues or being synthesized after microbial attack respectively [45, 46]. Their

function in plants include therefore antimicrobial properties preventing wood from decay by

microorganisms, they act as deterrent towards herbivores, fungi and in response to insect’s

attacks as natural insecticidal agents [47, 48, 49]. In addition, they act as chemical or

allelochemical signals among plant species [4, 45, 50]. Although genetic proofs are still missing,

stilbenoids presence is often positively correlated with disease resistance [45].

STILBENOIDS IN Cannabis sativa

Stilbenoids identified in Cannabis sativa could be divided into three main structural types:

phenanthrenes, dihydrostilbenes and spiroindans.

The occurrence of dihydrophenanthrenes in cannabis were discovered by Crombie who first

isolated two novel 9,10-dihydrophenanthrene named cannithrene-1 23 and cannithrene-2 24 from

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a Thailand Cannabis-leaf drug grown in Nottingham under controlled condition [51]. Moreover,

the 4,7-dimethoxy-1,2,5-trihydroxyphenanthrene 25 together with the corresponding

dihydropolymethoxylated-derivatives 4,5-dihydroxy-2,3,6-trimethoxy-9,10-dihydrophenanthrene

26 and 4-hydroxy-2,3,6,7-tetramethoxy-9,10-dihydrophenanthrene 27, were isolated from female

buds of Mexican variety high potency Cannabis sativa by Radwan and co-workers [21] who

assigned the structures based on spectral evidence.

Between phenanthrene derivatives, denbinobin 28 needs particular consideration for its

interesting biological activity [52] and for its unique recurrence. Denbinobin 28 (5-hydroxy-3,7-

dimethoxy-1,4-phenanthrenequinone) is an uncommon natural compound of non-terpenoid

origin, a system relatively rare in plant kingdom [53] and usually generated by the oxidative

coupling of stilbene precursor or by aromatization of diterpenoids [54]. Moreover, this 1,4

phenanthrenequinone is typical of several orchidaceous plants, like Dendrobium nobile [55],

Dendrobium moniliforme [56] and Ephemerantha lonchophylla [57] that together with D.

moniliforme, is known as Shi Hu herb in Chinese medicine. Incredibly, denbinobin 28 has been

extracted and purified from flowers and leaves of a Cannabis sativa chemotype, named Carma,

cultivated in Rovigo (Italy) [53] (Fig. 5).

The eight dihydrostibenes reported in cannabis are: 3,4’-dihydroxy-5,3’-dimethoxy-5’ isoprenyl

bibenzyl 29 [4], and canniprene 30, first identified by Crombie [51], structure determined by

spectral data and confirmed by synthesis [58]. Cannabistilbene I 31, cannabistilbene IIa 32, IIb 33

were identified from a polar acidic fraction of a Panamanian variant of Cannabis sativa grown in

Mississippi. The structures were determined from spectral evidence and confirmed by synthesis

[59]. Three non prenylated dihydrostilbenes: 3,4’-dihydroxy-5-methoxy bibenzyl 34, 3,3’-

dihydroxy-5,4’-dimethoxy bibenzyl 35 and dihydroresveratrol 36, were first reported by Kettenes-

van den Bosch and Salemink [60, 61] from a methylene chloride extract of Mexican marijuana (Fig.

6).

The first indication that spiroindans were biosynthesised in this plant comes from the isolation of

cannabispirone 37 from Indian [62] and South African cannabis [63] whose structure was

established by spectral [63] and single crystal X-ray methods [62]. Crombie and Crombie in 1982

[51] subsequently identified this compound from a Thai cannabis together with

cannabispiradienone 38. The chiral cannabispirenone-A 39 occurred in Indian, South African and

Thai cannabis. Isomeric derivatives of 37, 38 and 39, in which the position of the methoxy- and

hydroxyl- groups are interchanged, are represented respectively by iso-cannabispirone 40,

identified from a Panamenian variant of Cannabis sativa [64]; iso-cannabispiradienone 41 from an

Italian fibre-hemp [6] and cannabispirenone-B 42 determined in Thai and Mexican plant varieties,

and synthesized by Crombie [51, 60]. β-cannabispiranol 43 was identified from Indian, Thai and

other plant type [51, 65, 66], and the axial β-form was established by spectral studies [65, 66]. The

equatorial α-form, α-cannabispiranol 44, occurs in Thai variety with the relative acetyl

cannabispirol 45, present also in Mexican variant of the plant [21, 51]. Cyclohexanes spirans from

Cannabis sativa are represented by 5,7-dihydroxyindan-1-spiro-cyclohexane 46 and by the two

methoxide-isomers 7-hydroxy-5-methoxyindan-1-spiro-ciclohexane 47 and 5-hydroxy-7-

methoxyindan-1-spiro-ciclohexane 48 [4]. Actually, cannabis stilbenoids have been isolated from

stem [51], leaves [60], resin [62] and flower heads [6] (Fig. 7).

STILBENOIDS BIOSYNTHESIS

Although no reports exist about spirans biosynthesis or about their pathway regulation in

Cannabis sativa, a common biogenetic connection has been suggested for bibenzyl, spiro-

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compounds and dihydrophenantrenes referred to as cannabis bibenzyl pathway to distinguish it

from the cannabinoid biosynthesis [4, 51, 66] (Fig. 8). It has been shown that dihydroresveratrol 36

originates from the condensation of a single molecule of dihydro-p-coumaroyl-CoA, after o-

hydroxylation, with a molecule of malonyl-CoA (step a). Subsequently, methylation links

dihydroresveratrol 36 to 3,4’-dihydroxy-5-methoxy bibenzyl 34 (step b) as its prenylation to

canniprene 30 (step c) [51, 67]. Flores-Sanchez and Verpoorte [4] suggested that in cannabis the

generation of the 3,3’,5-trihydroxy bibenzyl could have as intermediate the dihydro-m-coumaroyl-

CoA or dihydro-caffeoyl-CoA leading to the formation of 3,3’-dihydroxy-5,4’-dimethoxy bibenzyl 35

(step d). As flavonoids biosynthesis, methylation and prenylation occur as late stage-process to

define other plant bibenzyls.

It has been proposed that spirans and 9,10-dihydrophenanthrenes could be derived from o-p, o-o

or p-p bibenzyl coupling [4, 51]. The p-o mode coupling of 3,4’-dihydroxy-5-methoxy bibenzyl 34,

after one-electron oxidation, leads to cannabispiradienone 38 (step e) and successive reduction to

cannabispirenone-A 39 (step f), cannabispirone 37 (step g), β-cannabispiranol 43 and little amount

of the relative α-form (step h), 7-hydroxy-5-methoxyindan-1-spiro-ciclohexane 47 (step i) and

finally to acetyl cannabispirol 45 after acetylation of cannabispiranol (step l). Cannabispiradienone

38 undergoes an in vitro rearrangement under acid catalysis, or heating, forming cannithrene-1 23

(step m). This last pathway seems to be possibly performed in vivo. Cannabispirenone-B 42 is

generated from the p-p coupling of the 3,4’-dihydroxy-5-methoxy bibenzyl di-radical intermediate

(step n). Finally, cannithrene-2 24 seems to derive by the di-radical intermediate of 3,3’-dihydroxy-

5,4’-dimethoxy bibenzyl from o-o coupling (step o).

STILBENOIDS IN CANNABIS: BIOLOGICAL ACTIVITY

Several studies have reported different biological activities for some stilbenoids extracted by

diverse plants, but just few cannabis stilbenoids have so far been described with properties that

might be of interest for human health. One of the best-characterized cannabis stilbenoids is

denbinobin 28, first isolated and studied in cannabis by Gonzalo Sànchez-Duffhues and co-workers

[53]. They demonstrated that dendinobin is endowed with the ability to induce apoptosis in cells.

This effect by denbinobin 28 is possibly linked to protein kinase B (Akt) inactivation, followed by

Bcl-2-associated death promoter (Bad) activation, mitochondrial dysfunction, caspase 3 activation,

and apoptosis-inducing factor (AIF) release, as shown by Chen-Tzu Kuo and co-workers in human

lung adenocarcinoma cells [68].

An effect on the NF-kB pathway by denbinobin 28 has also been shown in at least two models.

First, denbinobin 28 is able to inhibit the transcriptional activity of the HIV-1-lentiviral (HIV-1-LTR)

promoter in Jurkat cells through inactivation of the NF-kB pathway. Second, it has been

demonstrated that denbinobin 28 is endowed with an important pro-oxidant and pro-apoptotic

activity in human leukaemia cell lines, always through the inhibition of the same pathway [54].

SINTHESYS OF DENBINOBIN

Denbinobin 28 has attracted considerable scientific interest due to its favorable biological profile

as anti-HIV, antiplatelet aggregation and for its antioxidant and antitumor activity [53, 54]. The low

yield of extraction consisting in 0.005% of 27 from CARMA chemotype of Cannabis sativa [53],

reduces the possibilities of a deep investigation of its biological potentialities, but inspired the

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scientific community to design an efficient synthetic route for this natural product. To date six

total syntheses have been reported, starting from the paper by Krohn and co-workers published in

2001 [69], ending with the synthesis published by Liou in 2016 [70]. Hereinafter we describe all the

approaches not in chronological order, but according to the strategy adopted to build up the

direct precursor of denbinobin 28: the phenanthrene quinone core 49. Krohn and co-workers [69]

have proposed the first total synthesis of denbinobin 28 based on a Diels-Alder reaction between

the styrene 50 and quinone 51 to give the key intermediate 49. The last selective demethylation of

compound 49, by the action of iodotrimethylsilane (TMS-I), is in common to almost all the

strategies published so far (Fig. 9)

Despite being attractive for the reduced number of synthetic steps, this approach suffers of two

important drawbacks: the low regioselectivity and the low yield (37%) of the Diels-Alder reaction.

Kraus [71] and Wu [72] proposed a different approach in which the cycloaddition step was

replaced by a nucleophilic attack of an activated aromatic ring to a functionalized quinone to form

a biphenyl intermediate. In the Kraus approach, orcinol dimethyl ether 52 reacts with quinone 53

leading to a mixture of separable isomers 54 and 55 in a 8:1 ratio. Biphenyl derivative 54, after the

installation of the formyl group 56, was cyclized by using phosphazene base (P

-tBu) and then

oxidized to give compound 49 (Fig. 10)

The group of Wu [72] modified the synthetic procedure of Kraus using quinone 57 instead of

compound 53, and with the ulterior introduction of the methoxy group on the phenanthrene

quinone 58 in the second to last step to obtain 49 (Fig. 11)

A third approach, proposed by Liou [70, 73], is based on the synthesis of a stilbene derivative as

key intermediate of the synthetic strategy. The synthesis published in 2005, starts with a Wittig

reaction between the phosphonium salt 59 and the aldehyde 60 leading to a mixture of the

geometric isomers 61 and 62 in a 3:5 ratio. The cis isomer 62 was subjected to

azobisisobutyrronitrile/tributyltin hydride-bearing (AIBN/Bu

SnH) free radical reaction and

subsequent de-protection of the phenolic group to afford the derivate 63 that was converted to

the related quinone 49 by Fremy’s salt (Fig. 12)

The same group in 2016 proposed a new synthetic strategy in which Wittig reaction, responsible of

the low selectivity in the synthesis of the cis isomer 62, has been replaced by Perkin reaction

between compounds 64 and 65 to give the corresponding stilbene 66. The obtained stilbene 66

presents a correct double bond geometry to be cyclised to the phenanthrene 67 using the eco-

friendly iron (III) chloride (FeCl

). Compound 67 was manipulated to give phenanthrene quinone

59 transformed to the corresponding derivate 49 by methoxylation of the quinone moiety (Fig. 13)

Lee and co-workers published the total synthesis of denbinobin 28 in 2011 [74] as part of the total

synthesis of moniliformediquinone 68 (Fig. 14), an active compound extracted from Dendrobium

moniliforme.

The synthetic pathway starts with a Corey-Fucks reaction to transform the aldehyde 69 into alkyne

70, that undergo to a Sonogashira reaction to afford compound 71. The latter was hydrogenated

to give the corresponding dihydrostilbene derivative 72 subsequently oxidized with silver oxide

(AgO) to obtain the quinone derivative 73. Compound 73 was cyclised under acidic condition

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giving the corresponding dihydrophenanthrene quinone 74 that, after demethylation and

subsequent oxidation, furnished denbinobin 28 (Fig. 15).

SINTHESYS OF CANNIPRENE

To date, only two total syntheses of the dihydrostilbene canniprene 30 exist in literature, both by

the group of Crombie [75, 76]. These two strategies have the convergent focus to obtain the main

structure of the target compound by a Wittig reaction. The difference of the synthetic route

consists in the integration of the prenyl moiety into the molecule. In the first strategy, the O-

prenylation occurred on the dihydrostilbene intermediate 75 at late stage of the synthesis; in the

second approach, isovanillin 76, an easily commercially available starting material, was

functionalized at the beginning of the entire process, thus making this second pathway more

practical (Fig. 16).

SYNTHESIS OF CANNABISTILBENE I AND CANNABISTILBENE II

The synthesis of cannabistilbene I 31 and II 32, reported by ElSohly and co-workers [59], follow the

previous Crombie pathway [75, 76]. The prenyl group in the synthesis of 31 was introduced at the

beginning directly on the p-hydroxy benzaldehyde 77, and the corresponding prenylated aldehyde

78 underwent to a Wittig reaction with phosphonium salt 79 to give compound 80 that after

selective hydrogenation furnished the target compound 31 (Fig. 17).

In the synthesis of compound 32 the phosphonium salt 79 was condensated with aldehyde 81,

derived by gallic acid 82, to give the corresponding stilbene derivative 83 that after complete

hydrogenation furnished cannabistilbene II 32 (Fig. 18).

SYNTHESIS OF CANNABISPIRONE, CANNABISPIRENONE A AND CANNABISPIRENONE B

In Cannabis sativa, the most occurring spiroindanes are cannabispirone 37, cannaspirenone A 39

and B 42. Different groups, from 1979 and 1984, reported the total synthesis of these derivatives.

El-Feraly and co-workers [77] proposed the first total synthesis of 37 consisting in a biogenetic

approach in which the key step was the oxidative cyclization of the stilbene derivative 84.

Different metals were tested as possible catalyst: molybdenum (IV) hypochlorite (MoOCl

)

furnished the best results leading to the mixture of the two isomers 85 and 86 in 35% as

inseparable mixture. Compound 37 was obtained as pure compound after complete

hydrogenation (Fig. 19).

Subsequently El-Feraly and co-workers [78] proposed a new synthetic pathway for the synthesis of

both cannabispirone 37 and (±)-cannaspirenone A 39, starting from the key intermediate 88

obtained after several synthetic steps from the commercially available 3,5-dimethoxycinnamic

acid 87. Condensation of aldehyde 88 with methyl vinyl ketone (MVK) under strong basic

conditions led to the spirenone 89 in 45% yield. Regioselective de-protection of the most hindered

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methoxy group afforded (±)-cannaspirenone A 39, which could be converted in cannabispirone 37

by catalytic hydrogenation (Fig. 20).

In 1982 Novak and co-workers [79] reported an optimized total synthesis of (±)-cannaspirenone B

42, in which the Micheal addition of the piperidine enamine 90 to MVK was used to obtain, after

hydrolysis, the spirenone 91. This new approach is due to the low yield of the annulation reaction

under strongly basic conditions, reported in a previous paper by the same group [80]. The key step

was the selective de-methylation of the less hindered methoxy group achieved by using lithium

iodide in 2,4,6-collidine getting (±)-cannaspirenone B 42 in 82% yield of the last step (Fig. 21).

Crombie [75, 76] described a general synthetic approach to obtain the three cannabis

spironindanes 37, 39 and 42. The key intermediate is the indacarbonitrile 92 obtained by the

action of p-tolylsulphonylmethylisocyanide (TOSMIC) on indanone 91 in 84 % yield. Compound 92

reacted with 4-iodobutanone ethylene acetal 93 leading to the intermediate 94 that, after

reduction, de-protection and treatment with potassium hydroxide (KOH), afforded the (±)-

spirenone 89. The latter compound furnished (±)-cannaspirenone A 39 by selective demethylation

with lithium 2-methyl-2-propanethiolate of the most hindered methoxy group, and (±)-

cannaspirenone B 42 by the action of boron tribromide (BBr

) at low temperature; cannabispirone

37 was obtained by hydrogenation of 39 (Fig. 22).

Natale and co-workers [81] reported an asymmetric synthesis of (+)-cannaspirenone A 39, in

which the key intermediate is the chiral enamine 96 deriving from the reaction between aldehyde

88 and (s)-methoxy-methylpyrrolidine 95. The obtained enamine 96 reacted with MVK to furnish

O-Methylcannabispirenone A 97 that, de-protected, afforded the natural compound 98 (Fig. 23).

LIGNANS

Lignans, distributed widely in vascular plants but not ubiquitously [82], represent a numerous class

of phenylpropanoids whose carbon skeleton consists in the linking of C

unit biosynthesized

through the shikimate pathway. Haworth [83] was the first to introduce the term “lignan”

referring to woody tissue from witch many of these natural compounds derive. This abundant

family of phenylpropanoid dimers shows incredible variations not only in the oxidation level,

substitutions, structures of their basic carbon framework and enantiomeric forms, but even in

their biosynthesis and phylogenetic distribution [82]. The considerable heterogeneity led to the

distinction, nowadays adopted by UPAC [84], between lignans and neolignans [85] to identify

phenylpropane units linked in C8-C8’ or in other manners. Between neolignans, tri- and tetra-

linkages can occur generating respectively sesquineolignans and dineolignans [84]. Lignans,

instead, could be divided into eight subgroups consisting in furofuran, furan, dibenzylbutane,

dibenzylbutyrolactone,

aryltetralin, arylnaphthalene, dibenzocyclooctadiene and

dibenzylbutyrolactol [86, 81].

Lignans have several important biological activities in plants: their accumulation in response to

wounding and UV light suggests chemical protection against pathogen attacks [87] they play a key

role as antifeedant, insecticidal and natural pesticides [88, 89]. Furthermore, it has been suggested

phytotoxic properties with significant inhibition on plant germination [90].

LIGNANS IN Cannabis sativa

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Lignans, detected in Cannabis sativa fruits, seeds and roots, belong to two main groups: phenolic

amides and lignanamides [4, 5, 91, 92] (Fig. 24).

Three phenolic amides have been isolated from cannabis: the first was N-trans-

coumaroyltyramine 99 detected from Mexican Cannabis sativa roots grown in Missisipi [93]. N-

trans-feruloyltyramine 100 and N-trans-caffeoyltyramine 101 were characterized from both seeds

and fruits of the plant [86, 89].

Cannabis is a prolific accumulator of unique arylnapthalene bis-amides [4, 94] called cannabisins

which the first, named cannabisin-A 102, was isolated and structure determined with spectral data

by Sakakibara from fruits of the plant and then detected also in seeds [5, 92]. Cannabisin-B 103

and cannabisin-G 104 were not detected in seeds but only in fruits and roots. Instead, cannabisin-

C 105, cannabisin-D 106, cannabisin-E 107, cannabisin-F 108 and grossamide 109 were

characterized from roots, fruits and seeds [5, 92, 95]. Finally, a detailed phytochemical

characterization of a Chinese hemp seeds led to the isolation of 3,3’-demethyl-grossamide 110,

cannabisin-M 111, cannabisin-N 112, (2,3-trans)-3-(3-hydroxy-5-methoxyphenyl)-N-(4-

hydroxyphenethyl)-7-{(E)-3-[(4-hydroxyphenethyl) amino]-3-oxoprop-1-enyl}-2,3-dihydro-benzo

[b] [1,4] dioxine-2-carboxamide 113, cannabisin-O 114 and 3,3’-demethyl-heliotropamide 115 [5].

LIGNANS BIOSYNTHESIS

Although the biosynthetic pathway of several lignans and derivatives have been well established,

biosynthetic studies are still necessary to elucidate their origin. According to Flores-Sanchez and

Verpoorte [4], lignanamides and phenolic amides structures suggest condensation and

polymerization reaction starting from the CoA-esters of coumaric, caffeic and coniferic acid with

the common precursor tyramine (Fig. 25). The results of condensation reactions catalyzed by the

enzyme hydroxycinnamoyl-CoA:tyramine hydroxycinnamoyltransferase, E.C. 2.3.1.110 (THT)

between the three CoA-esters and tyramine lead to the formation of phenolic amides respectively

N-trans-coumaroyltyramine 99, N-trans-caffeoyltyramine 101 and N-trans-feruloyltyramine 100. It

has been suggested that these phenolic amides could represent the monomeric intermediates in

the biosynthesis of cannabis lignanamides. From the monomeric intermediate N-trans-

feruloyltyramine 100 derive cannabisin-C 105, cannabisin-D 106, cannabisin-E 107, cannabisin-F

108, cannabisin-G 104, cannabisin-O 114, grossamide 109 and demethyl-grossamide 110.

The polymerization of N-trans-caffeoyltyranime 101 results in cannabisin-A 102, cannabisin-B 103,

cannabisin-M 111, cannabisin-N 112, 3,3’-demethylheliotropamide 115 and compound 113.

Anyway, it is believable that that cannabis lignanamides could be formed by a random coupling

mechanism in vivo, but there is the hypothesis that could be also isolation’s artefacts processes

[96, 97].

CANNABIS LIGNANS: BIOLOGICAL ACTITVITY

Diverse functions are attributed to lignans [4] and a number of compounds have been designated

as interesting candidates for new types of insecticides [89]. Since then, many studies have

concentrated the attention on the biological properties of lignans that might be useful for human

health. For example, lignans isolated from Hibiscus tiliaceus L. and from the root of Solanum

melongena L. have shown an important cytotoxicity [98] and inhibition of NO production [99],

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respectively, in a murine macrophages cell line.

Cannabisin-B 103, isolated from the seed of cannabis by Chen and co-workers [98], was

demonstrated to be endowed of a strong anti-oxidative scavenging activity. Since then, numerous

studies have confirmed the anti-oxidant activity and have also shown anti-cancer efficacy [100,

101, 102]. Moreover, it has been demonstrated that cannabisin-B 103 is able to arrest cell cycle in

the S phase and to induce autophagic death in hepatoma cells [103].

Four new lignanamides, cannabisin-M 111, cannabisin-N 112, cannabisin-O 114 and 3,3’-demethyl-

heliotropamide 115, have been recently isolated from hemp and tested for their bioactive

potential [5]. In particular, it was investigated whether these compounds had an effect on

acetylcholinesterase (AChE), the enzyme that degrades achetylchomine in synapses and that is the

target of Alzheimer’s Disease drugs currently on the market. Interestingly cannabisin-M 111

exhibited a powerful DPPH• (2,2-diphenyl-1-picrylhydrazyl

)

radical-scavenging activity, while

cannabisin-N 112 showed a weak acetylcholinesterase inhibitory activity [5]. Deepening on this

topic to find compounds with both antioxidant and AChE inhibitory activities would be warranted

given the paucity of current treatments in dementia.

SYNTHESIS OF LIGNANAMIDES

Here below we repot the total synthesis of some members of lignanamides in chronological order.

Grossamide 109 was synthesized by Ley and co-workers [104] in 2006, in a flow chemistry mode. They used

a supported peroxidase enzyme for the dimerization of intermediate 130, obtained from the condensation

of ferulic acid 131 and tyramine 132 (Fig. 26).

The total synthesis of Cannabisin-G 104 was published in 2010 by two different groups. The

approach proposed by Hou [105] was based on an oxidative coupling of compound 116 by the

action of potassium ferricyanide (K

[Fe(CN)

]) in a basic medium affording the dimeric derivative

117 in good yield (92%). The latter was transformed into dyadic 118, that after condensation with

tyramine hydrochloride, furnished cannabisin-G 104.

The second approach, proposed by Xia [106], was based on a Stobbe reaction between compound

119 and O-benzyl vanillin 120 to furnish the dimeric compound 121 that after condensation with

tyramine hydrochloride and de-protection of the phenolic groups, furnished cannabisin-G 104.

In 2014 Li [107] and Xia [108] published the syntheses of cannabisin-D 106 and cannabisin-F 108.

Cannabisn-D was obtained from compound 117 that underwent to a Friedel-Craft and a

subsequent cyclization to furnish the intermediate 122. The latter after hydrolysis and

condensation with tyramine hydrochloride furnished the natural compound 106.

The group of Xia proposed a synthetic approach for cannabisin-F 108, based on the formation of

the key intermediate 125, deriving from the condensation of compounds 123 and 124. Finally,

compound 125 was amidated and deprotected to furnish the desired product 108.

The group of Xia in 2015 [109] published the synthesis of cannabisin-B 103 in which the bis-

dimethoxy derivative 126 was condensed with veratraldehyde 127 to give after cyclisation the

intermediate 128. The latter, after treatment with trifluoracetic acid (TFA) and subsequent

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hydrolysis, furnished compound 129 that was condensed with tyramine hydrochloride and fully

deprotected to give cannabisin-B 103.

CONCLUSIONS

Cannabis sativa L. has an incredible biosynthetic capacity. The plant not only produces

cannabinoids, typical terpenophenolic compounds, but also a plethora of non-cannabinoids

second metabolites which are unique of this plant, such as prenylated flavonoids, stilbenoids

derivatives and lignanammides. Little attention, compared to cannabinoids, has been given to

identify other kind of non-cannabinoids compound and to clarify their roles in the plant.

Moreover, enzymes involved in the biosynthesintetic pathway of cannabinoid precursors

belonging to the polyketide synthase group, could be involved in the biosynthesis of flavonoid and

stilbenoid precursors [4]. From a biological point of view, THC 1 is the only pharmacologically and

toxicologically most relevant and best studied metabolite of cannabis without paying attention to

the polypharmaceutical potential of the plant due to the presence of hundreds of biologically

active compounds. The combination of other cannabinoids together with non-cannabinoid

components could enhance the beneficial effects of THC 1 and could reduce undesirable side

effects. Cannabis flavonoids could modulate the pharmacokinetics of THC 1, via a mechanism

shared by CBD, the inhibition of P450 3A11 and P450 3A4 enzymes. Apigenin 8 is the characterized

anxiolytic agent of Matricaria chamomilla L. and provides beneficial suppression of TNF-α (Tumor

Necrotic Factor-α), whether in concert with THC 1 or counteracting THC 1 [110]. Cannflavin A 13 is

a stronger inhibitor of cyclooxygenase enzymes and lipoxygenase enzymes than THC 1 [37].

Research on non-cannabinoids compounds deserve more efforts to comprehend the biosynthetic

pathway in the perspective to regulate the production of already existing metabolites or new

second metabolites important for their therapeutic value and for the potential contribution to

therapeutic cannabis.

ACKNOWLEDGEMENTS

Declared none.

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Krohn, K.; Fiebich, B. L.; Muñoz, E. Denbinobin, a naturally occurring 1,4-phenanthrenequinone, inhibits

HIV-1 replication through an NF-kB-dependent pathway. Biochem. Pharmacol. 2008, 76, 1240 – 1250.

[54] Sànchez-Duffhues, G.; Calzado, M. A.; de Vinuesa, A. G.; Appendino, G.; Fiebich, B. L.; Loock, U.;

Lefarth-Risse, A.; Krohn, K.; Muñoz, E. Denbinobin inhibits nuclear factor-kB and induces apoptosis via

reactive oxygen species generation in human leukemic cells. Biochem. Pharmacol. 2009, 77, 1401–1409.

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Ma, G. E.;

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A. Crystal and

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Iso-cannabispiran, a new spiro compound isolated from Panamenian

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stem wood of Hibiscus tiliaceus. Planta Med. 2006, 72, 935–938.

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peels. Food Chem. 2010, 118(2), 199–207.

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cancer cell antiproliferative and antioxidant activities of Juglans regia L. Food Chem. Toxicol. 2010, 48(1),

441–447.

[103] Chen, T.; Hao, J.; He, J.; Zhang, J.; Li, Y.; Liu, R.; Li, L. Cannabisin B induces autophagic cell death by

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product grossamide by a continuous-flow process. Synlett 2006, 3, 0427–0430.

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for the synthesis of aryldihydronaphthalene lignans. Eur. J. Org. Chem. 2014, 3475–3482.

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HOOC NH2HOOC

Phenylalanine p-cinnamic acid p-coumaric acid

HOOC

bOH

p-coumaroyl CoA

CoASOC

cOH

HO OH

naringenin chalcone

HO O

naringenin

HO O

apigenin

HO O

vitexin

HO O

isovitexin

Glu

HO O

dihydrokaempfer ol

HO O

kaempferol

HO O

dihydroquercetin

HO O

quercetin

HO O

eriodictyol

HO OH

eriodictyol chalcone

caffeoyl CoA

CoASOC

HO O

luteolin

HO O

orientin

Glu

HO O

cannflavin B

OMe

HO O

cannflavin A

OMe

feruloyl CoA

CoASOC

OMe

HO OH

homoeriodictyol chalcone

OMe

HO O

cannflavin B

OMe

HO O

cannflavin A

OMe

Fig. 3 General flavonoids biosynthetic pathway in Cannabis sativa

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MeO OMe

59 60

P+Ph3Br-

Br OMe

OTBDMS

n-BuLi

MeO OMe

OMe

OTBDMS

MeO

OMe

Br OMe

OTBDMS

MeO OMe

OMe

MeO OH

OMe

TMS-I Fremy's salt

MeO OMe

OMe

1)AIBN/Bu3SnH

2)TBAF

Fig. 12 Synthesis of denbonobin proposed by Liu and co-workers

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MeO OMe

64 65

COOH

MeO

MeO OMe

OMe

MeO OH

OMe

TMS-I

MeO OMe

OMe

OMe 1)Ac2O, TEA

2)MeOH, H2SO4

MeOOC

OMe

MeO OMe

Fe2(SO4)3, MeOH

FeCl3

Fig. 13 Second synthesis of denbinobin proposed by Liu and co-workers

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MeO

OBz

OMe

Cl MeO

OBz

OMe

MeO

OMe

Fig. 16 Synthesis of canniprene

OH OH

-Br(Ph)3+P

OMe

77 78 79

Fig.17 Synthesis of cannabistilbene I

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OH OBn

OMe

-Br(Ph)3+P

OMe

BnO

OMe

82 81 79

Fig.18 Synthesis of cannabistilbene II

HO O

HO OH MeO

MeO

OMe

MeO

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OMe

MeO

OMe

MeO

MVK

OMe

MeO

OMe

NaI

2,4,6-collidine

Fig. 21 Synthesis of cannabispirenone B

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OMe

MeO

OMe

MeO

TOSMIC

OMe

MeO

OMe

MeO

H2Pd/C

S+Li-

OMe

BBr3

Fig. 22 Synthesis of cannabispirone, cannabispirenone A and cannabispirenone B

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OEtO

H3CO

t-But

K3[Fe(CN)6]/KOH

benzene/H2O

OEt

H3CO

OEt

H3CO

t-But

Tyramine

hyrochloride

H3CO

116 117 118

H3CO

104

Fig. 27 Synthesis of cannabisin-G proposed by Hou and co-workers

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OMOM

123

OCH3

H3CO

MOMO O

H3CO OH

H3CO

HO OH

H3CO N

124 125

108

Fig. 30 Synthesis of cannabisi-F

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Federica Pollastro

Novara, November the 28th

To: Atta-ur-Rahman

Editor-in-Chief, Current Medicinal Chemistry

Dear Prof. Atta-ur-Rahman,

Please find enclosed the revised version of the manuscript BSP-CMC-2016-HT 54-2

entitled “Cannabis phenolics and their bioactivities” by Pollastro, Minassi and Fresu,

to be considered for publication in Current Medicinal chemistry.

We have addressed all issues raised by the reviewers as detailed below. A copy of the

manuscript in which changes made are highlighted in bold is also attached to the

submission.

I would like to thank you for taking into consideration our work and for the possibility

of resubmitting the manuscript. I also wish to thank the Reviewers for their criticism,

comments and helpful advices that have improved the manuscript.

I hope that the new version of the manuscript will be suitable for publication in Curr.

Med. Chem. The content of the manuscript is original and it has not been published

or accepted for publication, in whole or in part. All the authors have approved this

submitted version.

Looking forward to hear from you

Yours sincerely,

Federica Pollastro

Corresponding author:

Federica Pollastro PhD, Lecturer in Phytochemistry and Medicinal Plants,

Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara,

Largo Donegani 2/3 - 28100 NOVARA (Italy)

Phone: +39 - 0321- 375844; Fax: +39 - 0321- 375621

E-mail: Federica.pollastro@uniupo.it

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ANSWERS to the Reviewer A

1. The referee asked to change “epatoblastoma cells” for “hepatoma cells” in

page 27, line 12. This has been now done in the manuscript.

2. The referee asked to rewrite the concluding paragraph (page 32): “The

combination of other cannabinoids together with non-cannabinoid components

enhances the beneficial effect of THC and can reduces undesirable side

effects” because is too assertive. This has been now changed in the

manuscript with: “The combination of other cannabinoids together with non-

cannabinoid components could enhance the beneficial effect of THC and

could reduce undesirable side effects”.

ANSWERS to the Reviewer B

1. The referee asked to reformulate the sentence in the abstract: “To totally

comprehend high pharmacological and nutrition values of cannabis it is not

possible to consider only cannabinoids”. The sentence has been reformulated

in: “Cannabis is a plant with high pharmacological and nutrition values, its

potentialities and applications are not only circumscribed to cannabinoids

biological activities, but also defined by non-cannabinoid compounds.”

2. The referee asked why “drug Group, CBD-drug Group, mixed THC-CBD-

drug Group, fibre-hemp Group, seed-oil Group etc...” in the introduction (page

1, lines 30-32) are reported with capitol letter. As according to the reference

(American Herbal Pharmacopoeia [3]), different groups of cannabis are

reported with the capitol letter.

3. The referee asked to correct the sentence: “The drug type, best known as

marijuana and hashish, contain THC 1 in concentration between 1 and 20%”

(introduction, page 1, line 34-35) because hashish and marijuana are not

synonyms and to specify a reference. The sentence has been corrected with:

“The drug type, best known as marijuana or hashish, contain THC 1 in

concentration between 1 and 20%” to point out that marijuana and hashish are

two different drugs. The reference has been specified: [5], the same as the

following sentence.

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4. The referee asked to check spelling of trigonellina (page 2, line 12). It has

been corrected with the right spelling “trigonelline”.

5. The referee asked to specify the reference in page 28, line 7. The reference has

been specified in the text: [5].

6. The referee pointed out that “pharmaceutical” in page 32, line 11 could be not

appropriate. We think that “biologically active” could be more appropriate.

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Cultivar-dependent phenotypic and chemotypic responses of drug-type Cannabis sativa L. to polyploidization

Article

Full-text available

Aug 2023

Cannabis sativa L. is a plant with a wide range of potential medicinal applications. In recent years, polyploidy has gained attention as a potential strategy for rapidly improving C. sativa , which, unlike other modern crops, has not yet benefitted from this established biotechnological application. Currently, no reports on high THCA and CBDA drug-type polyploid cultivars have been published. Moreover, it still needs to be clarified if different cultivars react similarly to polyploidization. For these reasons, we set out to evaluate and compare the phenotype and chemotype of three high Δ ⁹ -tetrahydrocannabinolic acid (THCA) and one high cannabidiolic acid (CBDA) drug-type cultivars in their diploid, triploid and tetraploid state through agronomic and metabolomic approaches. Our observations on plant morphology revealed a significant increase in plant height and leaf size with increasing ploidy levels in a cultivar-dependent manner. In contrast, cannabinoids were negatively affected by polyploidization, with the concentration of total cannabinoids, THCA, CBDA and cannabigerolic acid (CBGA) decreasing significantly in higher ploidy levels across all four cultivars. Headspace analysis of volatiles revealed that total volatile content decreased in triploids. On the other hand, tetraploids reacted differently depending on the cultivars. Two THCA dominant cultivars showed an increase in concentrations, while in the other two cultivars, concentrations decreased. Additionally, several rare compounds not present in diploids appeared in higher ploidy levels. Moreover, in one high THCA cultivar, a couple of elite tetraploid genotypes for cannabinoid and volatile production were identified, highlighting the role of cultivar and genotypic variability as an important factor in Cannabis sativa L. polyploids. Overall, our observations on plant morphology align with the giga phenotype observed in polyploids of other plant species. The decrease in cannabinoids and volatiles production in triploids have relevant implications regarding their commercial use. On the other hand, this study found that tetraploidization is a suitable approach to improve Cannabis sativa L. medicinal potential, although the response is cultivar and genotype-dependent. This work lays the ground for further improving, evaluating and harnessing Cannabis sativa L. chemical diversity by the breeding, biotechnological and pharmaceutical sectors.

Biochemical Changes Induced by the Administration of Cannabis sativa Seeds in Diabetic Wistar Rats

Article

Full-text available

Jun 2023

The present pilot study investigates the blood biochemical changes induced by hemp seeds in rats with diabetes. The composition of industrial hemp seeds, antioxidant activity, identification and quantification of phenols and fatty acids from hemp oil were determined. The Wistar adult rats used in the experiment were divided into three groups (n = 6) and kept under standard conditions. Group one, the control group (individuals without diabetes), and group two (diabetic individuals) received water and normal food ad libitum, while the third group, also including diabetic individuals, received specific food (hemp seeds) and water ad libitum. Subsequent blood biochemical parameters were determined. Hemp seeds had higher phenol (14 compounds), flavonoids and PUFA contents compared to other plants seeds. In addition, the antioxidant activity in Cannabis sativa was also increased. Moreover, the ratio between n-6 and n-3 was 4.41, ideal for different diseases. Additionally, all biochemical parameters showed significant changes following the treatment. It was shown that high doses of hemp seeds decreased diabetes-induced biochemical damage in rats most probably due to the high content of active compounds. In order to use these seeds in humans, it is essential to find out which hemp compounds are particularly responsible for these effects. Moreover, for the objective investigation of their effects, longer-term studies are needed.

Effect of THC, CBD, THCV, CBC and CBN Cannabinoids on β-Cells Exposed to High Glucose—High Lipids

Preprint

Full-text available

Sep 2023

Our findings indicate that all five phytocannabinoids reduce HG-HL-induced -cell loss likely through reducing apoptosis and pyroptosis. The protective effects of CBD, THCV, CBC, and CBN were seen in the GSIS impairment by HG-HL. Although all five phytocannabinoids tested in this research demonstrated the capability to inhibit β-cell dedifferentiation induced by HG-HL, CBD seems to be more effective compared to the other phytocannabinoids, as indicated by the specific biomarker responses of β-cells and progenitor cells to CBD.

Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management

Article

Full-text available

Aug 2023

Molecular docking is a computational technique that predicts the binding affinity of ligands to receptor proteins. Although it has potential uses in nutraceutical research, it has developed into a formidable tool for drug development. Bioactive substances called nutraceuticals are present in food sources and can be used in the management of diseases. Finding their molecular targets can help in the creation of disease-specific new therapies. The purpose of this review was to explore molecular docking's application to the study of dietary supplements and disease management. First, an overview of the fundamentals of molecular docking and the various software tools available for docking was presented. The limitations and difficulties of using molecular docking in nutraceutical research are also covered, including the reliability of scoring functions and the requirement for experimental validation. Additionally, there was a focus on the identification of molecular targets for nutraceuticals in numerous disease models, including those for sickle cell disease, cancer, cardiovascular, gut, reproductive, and neurodegenerative disorders. We further highlighted biochemistry pathways and models from recent studies that have revealed molecular mechanisms to pinpoint new nutraceuticals' effects on disease pathogenesis. It is convincingly true that molecular docking is a useful tool for identifying the molecular targets of nutraceuticals in the management of diseases. It may offer information about how nutraceuticals work and support the creation of new therapeutics. Therefore, molecular docking has a bright future in nutraceutical research and has a lot of potentials to lead to the creation of brand-new medicines for the treatment of disease.

Marijuana-i.e.-Cannabis-sativa -The-Quandary-of-Being-an-Amalgamate-of-a-Useful-and-Abusive-Medicinal-Herb (2)

Chapter

Full-text available

Jul 2023

Cannabis sativa, popularly known as "marijuana," poses a problem since it may have both beneficial and harmful effects. Cannabis has long been used for medicinal and recreational purposes, which demonstrates its value as a plant. Instead of this, enough evidence suggests that abusing this wonder herb can have negative effects on a number of organs and organ systems, such as the pulmonary system, the body's defense system, the cardiovascular system, etc. Additionally, it may affect both male and female potency and may also have clastogenic effects. Yet, it cannot be ruled out that there are some benefits to using marijuana responsibly, since it has been shown to be a miraculous treatment for atrophy, acute pain, a loss of muscular tone, motion sickness, and insomnia. This chapter will attempt to provide a thorough understanding of the various health effects of the herb and its extracted active bioactive ingredients.

Therapeutic Potential and Predictive Pharmaceutical Modeling of Stilbenes in Cannabis sativa

Article

Full-text available

Jul 2023

Cannabis sativa is a plant used for recreational and therapeutic purposes; however, many of the secondary metabolites in the plant have not been thoroughly investigated. Stilbenes are a class of compounds with demonstrated anti-inflammatory and antioxidant properties and are present in cannabis. Many stilbenes present in cannabis have been investigated for their therapeutic effects. Fourteen stilbenes have been identified to be present in cannabis, all of which are structurally dihydrostilbenoids, with half possessing a prenylated moiety. The stilbenes summarized in this analysis show varying degrees of therapeutic benefits ranging from anti-inflammatory, antiviral, and anti-cancer to antioxidant effects. Many of the identified stilbenes have been researched to a limited extent for potential health benefits. In addition, predictive in silico modeling was performed on the fourteen identified cannabis-derived stilbenes. This modeling provides prospective activity, pharmacokinetic, metabolism, and permeability data, setting the groundwork for further investigation into these poorly characterized compounds.

Chemistry and Biological Activities of Cannflavins of the Cannabis Plant

Article

Sep 2023

Identification of phenolic compounds from inflorescences of non-psychoactive Cannabis sativa L. by UHPLC-HRMS and in vitro assessment of the antiproliferative activity against colorectal cancer

Article

Sep 2023
J PHARMACEUT BIOMED

Does the “Entourage Effect” in Cannabinoids Exist? A Narrative Scoping Review

Article

Aug 2023

Background: The concept of an "entourage" effect in the cannabis and cannabinoids' field was first introduced in the late 1990s, during a period when most research on medical cannabinoids focused on the effects of isolated cannabinoids, such as cannabidiol and Δ9-tetrahydrocannabinol. Over the past decade, however, with the increased understanding of the endocannabinoid system, the discovery of other phytocannabinoids and their potential therapeutic uses, the term has gained widespread use in scientific reviews and marketing campaigns. Objective: Critically review the application of the term "entourage effect (EE)" in the literature and its endorsement by certain sectors of the cannabis market. Also, explore the perspectives for further interpretation and elaboration of the term based on current evidence, aiming to contribute to a more nuanced understanding of the concept and its implications for cannabinoid-based medicine. Methods: A comprehensive review of the literature was conducted to evaluate the current state of knowledge regarding the entourage effect. Relevant studies and scientific reviews were analyzed to assess the evidence of clinical efficacy and safety, as well as the regulation of cannabinoid-containing product production. Results: The EE is now recognized as a synergistic phenomenon in which multiple components of cannabis interact to modulate the therapeutic actions of the plant. However, the literature provides limited evidence to support it as a stable and predictable phenomenon. Hence, there is also limited evidence to support clinical efficacy, safety, and appropriate regulation for cannabinoid-containing products based on a "entourage" hypothesis. Conclusion: The EE has significant implications for the medical use of cannabinoid-containing products and their prescription. Nevertheless, a critical evaluation of the term's application is necessary. Further research and evidence are needed to establish the clinical efficacy, safety, and regulatory framework for these products. It's crucial that regulators, the pharmaceutical industry, the media, and health care providers exercise caution and avoid prematurely promoting the entourage effect hypothesis as a scientific proven phenomenon for cannabinoids and other cannabis-derived compound combinations.

Hemp ( Cannabis sativa L.) Agronomic Practices, Engineering Properties, Bioactive Compounds and Utilization in Food Processing Industry

Chapter

Jul 2023

Non-cannabinoid constituents from a high potency Cannabis sativa variety

Article

Jul 2008

As part of our program to study the phytochemistry of high potency Cannabis sativa L. [1,2], seven new non-cannabinoid constituents were isolated, namely 5-acetoxy-6-geranyl-3-n-pentyl-1,4-benzoquinone (1), 4,5-dihydroxy-2,3,6-trimethoxy-9,10-dihydrophenanthrene (2), 4-hydroxy-2,3,6,7-tetramethoxy-9,10-dihydrophenanthrene (3), 4,7-dimethoxy-1,2,5-trihydroxyphenanthrene (4), α-cannabispiranol (5), cannflavin C (6) and β-sitosteryl-3-O-β-D-glucopyranoside-2'-O-palmitate (7). In addition, four known compounds, chrysoeriol (8), 6-prenyl-apigenin (9), cannflavin A (10) and β-acetyl cannabispiranol (11), were identified, with 8 and 9 being reported for the first time form cannabis. The antimicrobial, antileishmanial, antimalarial and anti-oxidant activities of these isolates were evaluated. Furthermore the analgesic activity of 2, 3 and 4 was evaluated in mice using the hot-plate and tail-flick nociception models. Acknowledgements: The project described was supported by Grant Number 5P20RR021929–02 from the National Center for Research Resources and by the National Institute on Drug Abuse, contract # N01DA-5–7746. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. We are grateful to Dr. Bharathi Avula for assistance with the HR-ESI-MS, and to Dr. Melissa Jacob, Ms. Marsha Wright and Dr. Babu Tekwani for conducting the antimicrobial and antiprotozoal testing. References: 1. Radwan, M.M., et al. (2008). Planta Med. 74: 267–272. 2. Ahmed, S.A., et al. (2008)J. Nat. Prod. (In press).

Isolation and Characterization of New Cannabis Constituents from a High Potency Variety

Article

Feb 2008

Cannabis sativa L., one of the oldest plants known in medicine, is the most widely used illicit drug in the world today. A total of almost 500 natural constituents have been isolated and/or identified from cannabis [1], with Δ⁹-THC the main biologically active component [2]. The availability of high potency marijuana on the illicit market with unprecedented Δ⁹-THC concentrations (> 20% by dry weight)[3] has renewed our interest in the discovery of new constituents from cannabis. Phytochemical investigation of a high potency variety of C sativa L. resulted in the isolation of six new metabolites, (±)-6,7-trans-epoxycannabigerolic acid (1), (±)-6,7-cis-epoxycannabigerolic acid (2), (±)-6,7-cis-epoxycannabigerol (3), (±)-6,7-trans-epoxycannabigerol (4), 5ʹ-methyl-4-pentylbiphenyl-2,2ʹ,6-triol (5), and 7-methoxycannabispirone (5), along with seven known compounds (cannabigerolic acid, 5ʹ-methoxycannabigerolic acid, cannabispirone, β-cannabispiranol, dehydrocannabifuran, cannaflavin B and cannabigerol). The antimicrobial and antileishmanial activities were investigated. Acknowledgements: This work is supported by the Center of Research Excellence in Natural Products Neuroscience, The University of Mississippi, contract # 1P20RR021929-01, and by the National Institute on Drug Abuse, contract # N01DA-5-7746. We are grateful to Dr. Bharathi Avula for assistance with the HR-ESI-MS, and to Dr. Melissa Jacob and Ms. Marsha Wright for conducting the antimicrobial testing. References: [1] Grotenhermen F, Russo E, In Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. Grotenhermen F, Russo E, Ed.; The Haworth Press, Inc.: Binghamton, New York, 2002; Definitions and Explanations, pp. xxvii–xxxi. [2] Clarke RC, Watson DP, In Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. Grotenhermen F, Russo E, Ed.; The Haworth Press, Inc.: Binghamton, New York, 2002; Chapter 1 – Botany of Natural Cannabis Medicines, p.3–14.

ChemInform Abstract: CANNABIS. PART 25. SYNTHESIS OF CANNABISPIRENONE-B AND ITS 5,7-DIFLUORO ANALOG

Article

Jan 1983

Die Titelverbindung (IIIb) (aus Cannabis sativa) wird aus dem Enamin (I) über die Dimethoxyverbindung (IIIa) synthetisiert, wobei die Verwendung von LiI in 2,4,6-Collidin zu der gewünschten selektiven Demethylierung führt.

Polyphenolic Compounds and Antioxidant Activity of Cold-Pressed Seed Oil from Finola Cultivar of Cannabis sativa L

Article

Apr 2016
PHYTOTHER RES

The aim of this study was to characterize the polyphenolic compounds and antioxidant activity of cold-pressed seed oil from Finola cultivar of industrial hemp (Cannabis sativa L.). Several methodologies have been employed to evaluate the in vitro antioxidant activity of Finola hempseed oil (FHSO) and both lipophilic (LF) and hydrophilic fractions (HF). The qualitative and quantitative composition of the phenolic fraction of FHSO was performed by HPLC analyses. From the results is evident that FHSO has high antioxidative activity, as measured by DPPH radical (146.76 mmol of TE/100 g oil), inhibited β-carotene bleaching, quenched a chemically generated peroxyl radical in vitro and showed high ferrous ion chelating activity. Reactivity towards 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical cation and ferric-reducing antioxidant power values were 695.2 µmol of TE/100g oil and 3690.6 µmol of TE/100 g oil respectively. FHSO contains a significant amount of phenolic compounds of which 2780.4 mg of quercetin equivalent/100 g of total flavonoids. The whole oil showed higher antioxidant activity compared with LF and HF. Our findings indicate that the significant antioxidant properties shown from Finola seed oil might generally depend on the phenolic compounds, especially flavonoids, such as flavanones, flavonols, flavanols and isoflavones.

Total Synthesis of Denbinobin

Article

Mar 2016
J NAT PROD

A total synthesis of denbinobin (1) in seven steps with an overall yield of 10% is reported. This synthesis used an FeCl3-assisted cyclization of stilbene to form a phenanthrene. The poor yields of the decarboxylation and methoxylation steps were improved upon to become essentially quantitative. This scalable methodology was carried out using ordinary laboratory reagents.

Oxygenated 1,2-diphenylethanes from Marihuana

Article

Jan 1979

The physiological activity of marihuana is generally attributed to its main psychoactive component, Δ1-tetrahydrocannabinol (Δ1-THC). However, many effects such as estrogenic activity, teratogenicity and inhibition of the prostaglandin biosynthesis are not likely to be caused by Δ-1THC alone. The presence of several hydroxy and methoxy-substituted 1,2-diphenylethanes in Mexican marihuana has been established. The structure of three of these compounds has been elucidated. The products may have physiological activity. Their role as precursors for cannabispiro compounds will be discussed.

Flavonoids in the living system: An introduction

Article

Jan 1998
ADV EXP MED BIOL

Polyketides and other secondary metabolites including fatty acids and their derivatives

Article

Jan 1999

N. Hamanaka

Characterization of Lignanamides from Hemp (Cannabis sativa L.) Seed and Their Antioxidant and Acetylcholinesterase Inhibitory Activities

Article

Nov 2015

Hempseed is known for its content in fatty acids, proteins and fiber, which contribute to its nutritional value. Here we studied the secondary metabolites of hempseed aiming at identifying bioactive compounds that could contribute to its health benefits. This investigation led to the isolation of four new lignanamides cannabisin M, 2, cannabisin N, 5, cannabisin O, 8 and 3,3'-demethyl-heliotropamide, 10, together with ten known lignanamides, among which 4 was identified for the first time from hempseed. Structures were established on the basis of NMR, HR-MS, UV, IR as well as by comparison with the literature data. Lignanamides 2, 7, 9-14 showed good antioxidant activity among which 7, 10 and 13 also inhibited acetylcholinesterase in vitro. The new identified compounds in this study added to the diversity of hempseed composition and the bioassays implied that hempseed, with lignanamides as nutrients, may be a good source of bioactive and protective compounds.

Total Synthesis of Cannabisin B

Article

Oct 2015

Cannabisin B, a naturally occurring lignanamide, has been synthesised for the first time in 15% overall yield. The convergent synthesis is based on the Stobbe reaction and Friedel–Crafts alkylation reaction as the C–C bond-forming steps to afford the skeleton of the lignanamide which was then condensed with 4-methoxyphenethylamine to obtain Cannabisin B.

Cannabis Phenolics and their Bioactivities

Abstract

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