Cannabichromene

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Abstract
Cannabinochromene (CBC, 1a) is the archetypal member of a class of more than twenty isoprenylated 5-hydroxy-7-alkyl(aralky)benzo[2H]pyranes first reported from Cannabis sativa L. but also occurring in unrelated plants (Rhododendron species) as well as liverworts and fungi. The chemistry, synthesis, and bioactivity of CBC (1a) is reviewed, highlighting its underexploited pharmacological potential and rich chemistry.
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Natural Product Communications Vol. 13 (9) 2018
Published online (www.naturalproduct.us)
Editorial
Professor Masimo Curini
It is my privilege and pleasure to introduce this issue in honor of the outstanding achievements of Prof. Dr. Masimo Curini, Department of
Pharmaceutical Sciences, University of Perugia, Perugia, Italy, on the occasion of his 70
th
Birthday.
My thanks go to Profs. Francesco Epifano and Salvatore Genovese, Dipartimento di Farmacia, Università “G. d’Annunzio” Chieti-Pescara,
Chieti Scalo (CH), Italy, for their enormous efforts in organizing this honorarium issue, and the authors and reviewers who have made this
issue of Natural Product Communications possible, as well as to our production department for its efforts to put the issue in print.
The Editors and Advisory Board members of Natural Product Communications join me and all his colleagues and friends in paying tribute to
Professor Curini for his outstanding contributions to various aspects of natural products. We all express our deep appreciation for his
excellent contributions to natural products and wish him many more years of fruitful scientific research and all the best for his future.
Pawan K. Agrawal
Editor-in-Chief
Natural Product Communications Vol. 13 (9) 2018
Published online (www.naturalproduct.us)
Preface
In Honor of the 70
th
Birthday of Professor Masimo Curini
It is our great privilege and pleasure to introduce this special issue, which is dedicated to Professor Massimo Curini, Department of
Pharmaceutical Sciences (former Faculty of Pharmacy), of the University of Perugia, on the occasion of his 70th birthday.
His more than 40 years lasting research activity has been focused on several aspects of natural products and surely have represented a great
contribution to the progress of the chemistry of natural compounds, phytochemistry, pharmaceutical biology, organic chemistry, and
medicinal chemistry. He has published over 230 publications in international scientific journals, several book chapters, and a great number of
contributions in congress proceedings.
Prof. Curini’s efforts to promote scientific quality of academic research, have been acknowledged by the Italian Government through the
financing of numerous projects related to the isolation, structural characterization, and synthesis of biologically active natural products and
related chemical entities. Prof. Curini has been elected President of the Italian Society of Phytochemistry (SIF) for two mandates (2010-2012
and 2014-2016) and of the Italo-Latin-American Society of Ethnomedicine (SILAE) (2009-2011). He was also the Dean of the Faculty of
Pharmacy of the University of Perugia (2011-2012).
This issue, on occasion of his 70
th
birthday on September 14th 2018, represents a dutiful tribute for his outstanding scientific contributions
and an opportunity to express our congratulations and warm wishes from both of us, that had the honour of collaborating with him for more
than a decade in Perugia before moving to Chieti, as well as his numerous colleagues and friends, some of which enthusiastically agreed to
participate to this project. Our personal thanks go also to all the authors, mostly of them Massimo’s close and good friends, and reviewers
who have contributed to the success of this special issue.
Francesco Epifano and Salvatore Genovese
Dipartimento di Farmacia,
Università “G. d’Annunzio” Chieti-Pescara,
Chieti Scalo (CH), Italy
Cannabichromene
Federica Pollastroa, Diego Caprioglioa, Danilo Del Pretea, Federica Rogatia, Alberto Minassia,
Orazio Taglialatela-Scafatib, Eduardo Munozc and Giovanni Appendinoa*
aDipartimento di Scienze del Farmaco, Largo Donegani 2, 28100, Novara
bDipartimento di Farmacia, Università di Napoli Federico II, Via Montesano 49, 80131 Napoli, Italy
cVivaCell Biotechnology España, Parque Científico Tecnológico de Córdoba. 14014 Córdoba, Spain
giovanni.appendino@uniupo.it
Received: February 18th, 2018; Accepted: February 28th, 2018
Cannabinochromene (CBC, 1a) is the archetypal member of a class of more than twenty isoprenylated 5-hydroxy-7-alkyl(aralky)benzo[2H]pyranes first
reported from Cannabis sativa L. but also occurring in unrelated plants (Rhododendron species) as well as liverworts and fungi. The chemistry, synthesis, and
bioactivity of CBC (1a) is reviewed, highlighting its underexploited pharmacological potential and rich chemistry.
Keywords: Cannabichromene, CBC, Cannabis sativa, Enantiomeric purity, TRPA1.
Cannabichromene (CBC, 1a) was first isolated from Cannabis
sativa L. in 1966, only two years after the isolation of 9-
tetrahydrocannabinol (9-THC, 2a) [1,2], while its corresponding
acid (cannabichromenoic acid, CBCA, 1b) was isolated two years
later from the same plant source [3]. These compounds are the
archetypal members of a group of over twenty 5-hydroxy-7-
alkyl(aralkyl)benzo[2H]pyranes characterized by a limited
distribution in Nature, that encompasses, however, not only plants
but also fungi. Cannabichromene (1a) was isolated at the outset of
modern studies on the chemistry of Cannabis, but it has been less
investigated compared to other phytocannabinoids in terms of
biological profiling and chemical reactivity. It is traditionally
considered, along with 9-THC (2a), cannabidiol (CBD, 3a) and
cannabigerol (CBG, 4a), a major phytocannabinoid, and a member
of the so-called big four of Cannabis constituents. It was even
believed to be the second most abundant cannabinoid in recreational
marijuana [1,2], but its concentration in Cannabis seems to have
been substantially overestimated because of the difficulty to
separate CBC (1a) and CBD (3a) on the gas chromatography
conditions of those years [4], with the ensuing attribution of the
peak area exclusively to CBC (1a). The concentration of CBC (1a)
in Cannabis is actually much lower than the other “major”
phytocannabinoids. It rarely exceeds 0.2-0.3% on dry weight basis,
and CBC (1a) has never been found to accumulate in modern
medicinal and recreational strains of Cannabis at the one- or two-
digit percentage concentrations typical of the other major
phytocannabinoids [5].
There is considerable confusion in the literature on the physical
properties of natural CBC, that was originally reported as an
optically active [1,2] crystalline compound [2]. CBC is actually an
oil or a gum, and, unlike the other major phytocannabinoids, is
scalemic, as shown by chromatography on chiral stationary phases
[6]. After the isolation of CBC, various analogues and derivatives
(cannabichromenoids) were discovered not only from Cannabis but
also from unrelated plants as well as from liverworts and even from
fungi [5]. The orcinoids cannabiorcichromenic acid (5a),
chlororcichromenic acid (5b) [7], and confluentin (6) [8] are the
only phytocannabinoids of non-plant origin, and were isolated from
Cylindrocarpon olidum Wollenw. a fungal parasite of a nematode
(5a and 5b) [7], and from a mushroom (6) [8]. Interestingly,
confluentin (6) is also a constituent of Rhododendron dauricum L.,
a popular ornamental plant but a protected species in its natural
environment [9].
The cannabichromenoid chemical space: Diversity of natural
cannabichromenoids is mostly associated to the modular scheme of
their biosynthesis, as expressed by prenylation or deprenylation of
the isoprenyl residue, and/or shortening of the pentyl residue
(Figure 1) [5]. Replacement by a phenethyl-type group as well as
isomerization to the abnormal series (ortho-relationship between the
resorcinyl substituents) have also been observed outside Cannabis
[5]. As with all other classes of phytocannabinoids, n-alkyl residues
(methyl-, propyl-, pentyl-) are typical of Cannabis and higher plants
(Figure 1, type A cannabichromenoids), while the phenethyl type
substituents are mostly, but not exclusively, found in liverworts
(type B cannabichromenoids) [5]. Diversity in the natural
cannabichromenoids is the result of the combination of a diverse
iteration of the elongation step of the isoprenoid pathway that
generates the electrophilic isoprenylating agent, and of the nature of
the polyketide starter that eventually generates the alkyl-substituent
NPC Natural Product Communications 2018
Vol. 13
No. 9
1189 - 1194
1190 Natural Product Communications Vol. 13 (9) 2018 Pollastro et al.
of the resorcinyl core. Thus, the isoprenylating agent can be prenyl-,
geranyl-, or farnesyl pyrophosphate [10], while the polyketide
starter can be hexanoic acid [cannabichromene (CBC)-type
compounds], propanoic acid [cannabivarichromene (CBCV)-type
compounds], acetic acid [cannabiorcichromene (CBOC)-type
compounds], or cinnamic acid (phenethyl and stiryl-type
compounds). All these phytocannabinoids are assumed to be
generated in carboxylated form, and to be next decarboxylated
enzymatically or, most probably, during storage of the plant
material. Modifications of the benzochromene moiety are rare, and
involve hydratation of the pyrane double bond as well as
functionalization of the “peri-position” of the chromene core by
chlorination or acetoxylation [5]. Also rare is the oxidative
modification of the isoprenoid group at the terminal and electron-
rich double bond.
Figure 1: Diversity of naturally occurring cannabichromenoids.
The original biogenetic numbering of phytocannabinoids was based
on their meroterpenoid structure, and used two distinct systems for
the resorcinyl and the isoprenyl moieties. The numbering of 9-
THC was later changed to a systematic one, based on the polycyclic
heterocyclic core [5]. Two systems are therefore possible for CBC
(Figure 2), but the systematic one (A) is more popular, and will be
use throughout.
Figure 2: The systematic (A) and the biogenetic (B) numbering system of
cannabichromene (CBC, 1a).
Biosynthesis and enzymology: The skeletal diversity of
phytocannabinois is generated by the oxidative cyclization of linear
isoprenyl precursors (cannabigerolic acid, CBGA, 4b) for the
terpenyl (C10)-derivatives), with a convergence of the cyclase and
the oxidase phases, as observed also in other classes of
meroterpenoids (Figure 3). Thus, the enzyme cannabichromenic
acid (CBCA, 1b) synthase is a FAD-oxido-cyclase with little
specificity for the length of the alkyl chain of the resorcinyl core,
accepting both olivetolic acid and its lower homologue divarinic
acid as substrate. Compared to the tetrahydrocannabinolic acid
(THCA, 2b)- and the cannabidiolic acid (CBDA, 3b) synthases,
CBCA synthase has a higher substrate affinity (Km = 23 M vs 134
M and 137 M for, respectively, CBDA- and THCA synthases)
but a lower catalytic capacity (kcat = 0.04 s-1 vs 0.19 s-1 and 0.20 s-1
for CBDA- and THCA-synthases) [11]. CBCA synthase is encoded
at a fixed locus (C) distinct from the allelic loci of CBDA- and
THCA-synthases (BD and BT, respectively, with B0 corresponding to
poor functioning synthases and the accumulation of CBG). C is
expressed mostly in juvenile tissues of Cannabis, declining with
maturation. As a result, the concentration of CBC in the flower
heads is generally much lower than the one of CBD and THC, and
plants whose cannabinoid profile is dominated by CBC are very
rare. Overall, the genetic control of CBC synthesis is poorly
understood. A substantial accumulation could be related to the
persistence of a juvenile gene expression profile related to a not yet
characterized inheritable factor [12].
It has also been observed that CBC is accumulated differently
compared to and 9-THC (2) and CBD (3). In general, cannabinoids
have a single site for synthesis and accumulation, being produced
and stored in the secretory cavity of specialized glandular
trichomes, three types of which are, however, present in Cannabis.
The large capitate-stalked trichomes only develop on the bracts that
surround the flowers and in the bracteols that enclose the ovary, and
can accumulate large amounts of phytocannabinoids. Conversely,
the small bulbous- and the large capitate-sessile trichomes, that
develop all over the leaves , have a 20-fold minor capacity to
produce and accumulate phytocannabinoids [12]. CBCA synthase is
apparently little, if any, expressed in the cannabinoid-rich capitate-
stalked trichomes, and this explain why CBC does not benefit from
the cannabinoid biosynthetic bonanza associated to flowering,
rather peaking soon after seedling formation, declining during
development, and eventually stabilizing at a low level in mature
plants. As a result, although pure CBC Cannabis breeds have been
produced, the isolation yield remains much lower compared to the
other three major phytocannabinoids [12]. Traces (ppm) of
cannabinoids were recently detected in the roots of various strains
of Cannabis. The highest concentrations of CBC were associated to
narcotic high-THC plants, as often observed also in the aerial parts
[13].
CBCA synthase performs a chemistry basically distinct from the
one leading to CBDA (3b) and THCA (2a). After initial FAD-
mediated hydride removal from the benzallyl carbon, a process
common to all three cannabinoid synthases [11,12] (Figure 3),
electrocyclization of the resulting quinonmethide (8) to a chromene
takes place, in line with the classic Ollis-Sutherland proposal for the
biosynthesis of chromenes from ortho-isoprenylated phenolics [14].
This reaction is, formally, a 6-endo-trig process, sometimes referred
to in the literature as a Wacker cyclization. Alternatively, oxidative
removal of the benzallylic hydrogen is associated to removal of the
configurational barrier to intramolecular cyclization represented by
the proximal E-double, as expressed by the resonance formulas 9a-
d. This makes it possible, depending on the folding of the terpenyl
residue, intramolecular cyclization by electrophilic addition to the
electron-rich terminal double bond, leading to either to CBDA (3b)
or to THCA (2b) according to the nature of the termination step
(proton loss or oxygen trapping of the cationic intermediate, Figure
3, a and b, respectively).
Figure 3: Mechanism of formation of the three main phytocannabinoid chemotypes
from cannabigerolic acid (4b).
The quinonmethide substrate for the electrocyclization is achiral,
and chirality in the final product derives solely from enzymatic
Chemistry, synthesis, and bioactivity of cannabichromene Natural Product Communications Vol. 13 (9) 2018 1191
inprinting. Natural CBC (1a) is scalemic [6], but analogues from
Rhododendron species like daurichromenic acid (6b) have been
isolated in high optical purity [15]. The daurichromenic acid
(DCRA) synthase from R. dauricum has been cloned and shows
high similarity to CBCA synthase from Cannabis sativa [16]. An
enantioselective transgenic production of (+)-daurichromenic has
been developed in Aspergillus oryzae by heterologous expression of
this synthase coupled to the one of its precursor (grifolic acid, 11)
from the fungus Stachybotrys bisbyi (Figure 4) [17].
Figure 4: Enzymatic synthesis of daurichromenic acid (6b) from grifolic acid (11).
Synthesis: CBC (1a) is the only phytocannabinoids from Cannabis
that can be obtained relatively easily by synthesis. The classic
preparation is based on a tandem Knoevenagel-electrocyclic
reaction between citral (12) and olivetol (5-n-pentylresorcinol, 13).
The course of the reaction is different in basic and acidic conditions.
CBC could be obtained, via the quinonmethide 14, only under basic
conditions (Figure 5), and the yield was strongly dependent on the
base used. With pyridine (Crombie-Razdan conditions [18,19]), the
yield was poor (ca 10-15%), due to the formation of a complex
reaction mixture that included also cannabicyclol (15), the product
of formal [2+2] intramolecular cycloaddition of CBC, as well as
cannabicitran (17), resulting from the intramolecular [4+2]
cycloaddition of the heterodiene 16 [18, 19]. The formation of the
post-condensation products 15 and 17 is surprising, since acid or
light promotion would be necessary for the [2+2] cycloaddition that
generates cannabicyclol (15), and acid conditions for the generation
of the heterodiene 16 for the [4+2] cycloaddition to cannabicitran
(17).
Figure 5: Reaction of citral (12) and olivetol (13) under basic conditions.
Cannabicyclol (15) and cannabicitran (17) are formed only with pyridine as the base.
The formation of the post-condensation products could be prevented
when the reaction of citral and olivetol was carried out in refluxing
toluene in the presence of tert-butylamine (ElSohly conditions).
CBC is obtained in 50-60% yield [20], with abnormal-CBC (18)
and the product of bis-chromenylation (19) as major by-product
[20].
Under acidic conditions, the reaction of citral and olivetol afforded
instead cis-9-THC as the major reaction product (20), the result of
a terpenic-type intramolecular cationic cyclization (Figure 6)
[18,19].
Figure 6: Reaction of citral (12) and olivetol (13) under acidic conditions
The reaction of citral and olivetol is interesting, and well worth re-
investigation to clarify its mechanistic ambiguities and subtleties.
An organo-catalytic version was developed based on a pre-formed
iminium salt of piperidine and citral, complicating, however, the
reaction protocol and without improving the yield [21]. Also the use
of the classic Tietze conditions for the reaction (ethanediammonium
diacetate, methanol, RT) did not substantially improve the yield
[22], even when dihydro-olivetol (5-n-pentyl-1,3-
cyclohexanedione) was used for the tandem reaction and the
resulting adduct was then aromatized by selenylation-
oxadeselenylation [23]. Taken together, these observations show
that CBC can be obtained from citral (12) and olivetol (13) under
basic conditions, even though yield are only in the range of 50%
and chromatography is necessary to purify the product, an oil, from
the reaction mixture.
Analogs of CBC could be synthesized in the same way, using
prenylogous isoprenic aldehydes or analogues of olivetol where the
n-pentyl is replace by a n-propyl- (viridinol) or a methyl- (orcinol)
group [20]. On the other hand, the synthesis of enantiopure
analogues requires a different strategy, since the configuration at C-
2 cannot be controlled during the electrocyclic step. Of relevance is
an organocatalytic strategy based on a formal [4+3]cycloaddition
(actually a domino aldol-oxa-Michael reaction) that was developed
by Woggon for the enantioselective synthesis of S-daurichromenic
acid (S-6b)[24]. Chirality was introduced by reacting 2-hydroxy-4-
methyl-6-methoxybenzaldehyde (23) with the chiral dienamine 22.
The resulting and optically active semiacetal 24 was next oxidized
to a lactone, and the extra carbon removed in a 6-step sequence that
eventually afforded the natural S-enantiomer of daurichromenic
acid (6b) (Figure 7)[24].
CBC (1a) could also be obtained by the biogenetic oxidation of
cannabigerol (CBG) (Figure 3) with dichlorodicyanobenzoquinone
(DDQ), a biogenetic reaction typical of ortho-isoprenylated phenols
first reported by Campbell and extensively investigated by Merlini
in the late Sixties [25]. Reaction with chloranil
(tetrachlorobenzoquinone) gave a more complicated reaction
mixture, containing also cannabicyclol and cannabicitran-type
compounds [26].
1192 Natural Product Communications Vol. 13 (9) 2018 Pollastro et al.
OH
HO
24
O
H
N
R
H
OHOH
HO
N R
OHOH
O
N
R
OH
O
O
HO
22 PhCOOH
Toluene
(63%)
H
Figure 7 : Enantioselective step of the asymmetric synthesis of S-daurichromenic acid
(6b). R = trimethylsilyloxy(bis)(3,5-trifluoromethylphenyl)methyl.
Reactivity: The scalemic nature of natural CBC could be due to
racemization via the same electrocyclic mechanism underlying its
formation. In this context, it is remarkable that daurichromenic acid
(6b) and its derivatives were isolated in high optical purity [9],
suggesting that the presence of a carboxylic function para-to the
chromene oxygen could slow down or even prevent racemization,
possibly by an increased resonance stabilization of the chromene
benzenoid moiety that imposes a higher activation energy for the
dearomative electrocyclic opening. If so, decarboxylation of CBCA
could be the trigger for the poor optical purity of CBC.
CBC is photochemically unstable, easily undergoing [2+2]
photocycloaddition to cannabicyclol (15) [27]. The structure
originally proposed for this compound [2] involved
photocycloaddition from a chair-like transition with bonding of C-2
of the chromene to the gem-dimethyl substituted isoprenyl carbon,
opposite to the one actually observed that involves a more compact
transition state and bonding of C-3 to the terminal olefinic carbon
[27]. The same reaction can occur under acidic conditions,
representing a remarkable example of the Gassman [2+2]cationic
cycloaddition [22, 28]. The presence of acids also promotes a
different reaction course, leading to cannabicitran (17) via a [4+2]
cycloaddition [22] (Figure 5). On the other hand, treatment of CBC
with BF3.Et2O or p-toluenesulfonic acid afforded a complex
reaction mixture, dominated by compounds originating from
formation of a benzyl cation and its trapping from the distal olefin
double bond, with formation of compounds from the iso-THC (25)
series (Figure 8, path a) [29]. The formation of these compounds is
mechanistically related to the one of cannabicitran (17), being
triggered by formation of a benzylic cation by electrophilic or protic
attack to the chromene double bond (cf. Figure 5 and Figure 8).
Compounds originating from the heterolytic cleavage of the bond
between the chromene oxygen and C-2 and ultimately generating
compounds of the THC-series (26) via trapping of the resulting
benzallyl cation by the terminal olefin bond were not observed
(Figure 8, path b) [29].
Of great interest is the observation that, under thermal conditions,
CBC (1a) could isomerize to tetrahydrocannabinol derivatives like
26 via a cycloreversion-cycloaddition reaction involving in the
electrocyclization the terminal olefin bond and not the terminal
bond of the quinonmethide intermediate (Figure 9) [30]. Support for
this chromene metatesis was observed in a model compound
(Figure 9), but no data are available for cannabichromene (1a)
itself, a surprising observation because of the reaction could occur
during vaporization of Cannabis products, and could be therefore of
biomedical relevance.
Figure 8: Formation of iso-THC derivatives from the acidic treatment of
cannabichromene (1a)
Overall, many aspects of the chemistry of cannabichromene are
unclear and need further investigation. Given the thermal and
photochemical instability of cannabichromene, it is surprising that
this compound could be detected in historical samples of Cannabis
[31].
Figure 9: Thermal isomerization of a simplified analogue of canabichromene.
Bioactivity: Most studies on cannabichromenoids were done on
CBC (1a), and limited information exists on the biological profile
of its naturally occurring analogs. The first studies on the
pharmacology of CBC were spurred by the wrong assumption that it
was the second most abundant cannabinoid in recreational
marijuana, an observation due to the poor resolution capacity of the
GC columns of the Sixties and Seventies [4]. In in vivo
experiments, CBC was not narcotic, but at high dosages, it could,
nevertheless, induce the tetrad response typical of 9-THC
(hypomotility, catalepsy, hypothermia, analgesia) [32,33]. Since
CBC has only marginal affinity for CB1 and CB2, and the tetrad
response was not blocked by the CB1 reverse agonist rimonabant,
other mechanisms could operate [34,35].
CBC was reported to outperform the other major cannabinoids in
terms of anti-bacterial and anti-fungal activity [20], but no
significant difference with THC, CBD and CBG was observed on
various drug-resistant strains of Staphylococcus aureus (MTRSA)
[36]. The most important target of CBC is the ion channel TRPA1,
that is activated at two-digit nanomolar concentrations (IC50 = 90
nM), and desensitized to allylisothiocyanate activation at higher
concentration (IC50 = 370 nm) [35]. Most potent ligands of TRPA1
are covalent ligands [37], while CBC is devoid of the electrophilic
sites necessary to trap reactive cysteine residues, and behaves
therefore as a non-covalent modulator. At micromolar
concentration, CBC increases the endocannabinoid tone by
inhibiting the cellular uptake of anandamide and the enzymatic
Chemistry, synthesis, and bioactivity of cannabichromene Natural Product Communications Vol. 13 (9) 2018 1193
degradation of 2-arachidonoyl glycerol [35], an activity in principle
potentially involved in the potentiation in vivo of the
antinociceptive effects of 9-THC in the mouse-tail flick assay
[32,33]. Thus, intratecal administration of CBC reduced tail-flick
nociception in a way that was blocked by AM251, a CB1 antagonist
[33]. The same effect was, however, blocked by DPCPX, an
Adenosine A1-selective antagonist, as well as by the TRPA1
antagonist AP18 [33]. The antinoniceptive effects of CBC might
therefore be mediated not only by modulation of the
endocannabinoid system, but also by interaction with adenosine and
TRPA1 receptors, a well as with other yet-to-be discovered end-
points.
The desensitization of TRPA1 and the inhibition of
endocannabinoid degradation seemingly also underlie the activity of
CBC to ameliorate murine colitis induced by dinitrobenzensulfonic
acid (DNBS) [38]. CBC could also selectively reduce
inflammation-induced intestinal hypermotility, but neither
cannabinoid receptors nor TRPA1 were involved in this activity
[39]. CBC showed potent anti-inflammatory activity in the
carrageenan-induced rat paw edema assay, outperforming oral
phenylbutazone upon peritoneal administration, and being
equipotent upon oral administration [40].
In a systematic screening of the potential of non-narcotic
phytocannabinoids for the treatment of acne, CBC, along with
CBDV and THCV, emerged as the best candidate due its capacity to
normalize excessive sebaceous lipid production induced by pro-
acne agents, reduce proliferation and alleviating inflammation [41].
Limited information is available on the pharmacokinetics and
metabolism of CBC. Allylic hydroxylation of the isoprenyl residue
and hydroxylation of the n-pentyl substituents were the major
metabolic pathways in various rodents and not rodent species
[42,43,44,45], but many metabolites could not be identify, and some
appear to be artefact from the spontaneous degradation of CBC. The
brain penetration from smoke is inferior to the one of THC and
CBD, possibly because of the higher reactivity and thermal
instability of CBC compared to these two other cannabinoids. CBC
has also been reported to increase the brain concentrations of THC
after iv co-administration of these compounds [33]. Unlike CBD,
CBC is not endowed by significant cytotoxicity against cancer or
non-mutated cells [46].
CBC aside, only daurichromenic acid (6b) and some of its
analogues have received attention because of their bioactivity.
These compounds are potent HIV1 inhibitors [16], and are toxic to
the producing cells, being only accumulated extracellularly in the
apoplasts of glandular scales attached on the surface of young
leaves [46]. The molecular mechanisms underlying the antiviral and
the phytotoxic activities of daurichromenic acids have not been
elucidated.
Taken together, the studies we have summarized show that CBC
(1a) is endowed with interesting bioactivity, not completely
rationalizable on the basis of its agonistic activity on TRPA1, the
only high-affinity target identified so far. Equally interesting is its
chemistry, since the chromene system can isomerize to other
structural types of phytocannabinoids. In the light of the
straightforward availability by synthesis, CBC (1a) represents
therefore an interesting tool to explore the biological space
associated to the cannabinoid chemotype.
Acknowledgments GA and EM are grateful to Emerald Health
Therapeutics, Victoria, Canada for supporting their cannabinoid
research projects.
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Natural Product Communications Vol. 13 (9) 2018
Published online (www.naturalproduct.us)
Accounts/Reviews
Cannabichromene
Federica Pollastro, Diego Caprioglio, Danilo Del Prete, Federica Rogati, Alberto Minassi, Orazio Taglialatela-Scafati, Eduardo Munoz and
Giovanni Appendino 1189
A Systematic Review on Natural Antioxidant Properties of Resveratrol
Carmela Colica, Maja Milanović, Nataša Milić, Vincenzo Aiello, Antonino De Lorenzo and Ludovico Abenavoli 1195
Phytochemistry of the Genus Trichocolea
Francesca Preziuso, Vito Alessandro Taddeo, Salvatore Genovese, Francesco Epifano and Serena Fiorito 1205
Phytochemistry of Commiphora erythraea: A Review
Maria Carla Marcotullio, Ornelio Rosati and Daniela Lanari 1209
Secondary Metabolites Isolated from Tricholoma Species (Basidiomycota, Tricholomatacee): A Review
Marco Clericuzio, Giorgio Giacomo Mellerio, Paola Vita Finzi and Giovanni Vidari 1213
The Chemistry behind Tomato Quality
Dario Paolo, Giulia Bianchi, Roberto Lo Scalzo, Carlo F. Morelli, Marco Rabuffetti and Giovanna Speranza 1225
Natural Product Communications
2018
Volume 13, Number 9
Contents
Editorial
Pawan K. Agrawal i
Preface
Francesco Epifano and Salvatore Genovese iii
Original Paper
New Terpenoids from Tricholoma saponaceum
Davide Gozzini, Giorgio Giacomo Mellerio, Gianluca Gilardoni, Marco Clericuzio and Giovanni Vidari 1097
A New Triterpene Glucoside from Genista numidica
Feryal Benayache, Massimiliano D’Ambola, Roberta Cotugno, Massika Chaouche, Samir Benayache, Fadila Benayache,
Alessandra Braca and Nunziatina De Tommasi 1101
Biological Effects of Saponin Fractions from Astragalus verrucosus in Tumor and Non-tumor Human cells
Maria Sole Facioni, Joana Soares, Barabara Adinolfi, Sara Gomes, Liliana Raimundo, Adele Contini, Barbara Ruffoni,
Alessia Azzarà, Arianna Tavanti, Alessandra Bertoli, Luisa Pistelli, Lucilia Saraiva and Roberto Scarpato 1105
Alkaloid Profiles and Activity in Different Mitragyna speciosa Strains
Luisa Boffa, Corrado Ghè, Alessandro Barge, Giampiero Muccioli and Giancarlo Cravotto 1111
Eco-Friendly Synthesis of Lipophilic EGCG Derivatives and Antitumor and Antioxidant Evaluation
Rosina Paonessa, Monica Nardi, Maria Luisa Di Gioia, Fabrizio Olivito, Manuela Oliverio and Antonio Procopio 1117
LC-ESI/LTQOrbitrap/MS/MSn Analysis Reveals Diarylheptanoids and Flavonol O-glycosides in Fresh and Roasted
Hazelnut (Corylus avellana cultivar “Tonda di Giffoni”)
Antonietta Cerulli, Assunta Napolitano, Milena Masullo, Cosimo Pizza and Sonia Piacente 1123
Bioactive Constituents from the Traditional Kurdish plant Iris persica
Hawraz Ibrahim M. Amin, Faiq H. S. Hussain, Marcello Maggiolini and Giovanni Vidari 1127
Constituents of the Rhizomes of Sansevieria cylindrica
Mya Mu Aye, Hnin Thanda Aung, Zaw Min Thu, Myint Myint Sein, Yoshiaki Takaya, Yumiko Komori, Marco Clericuzio and
Giovanni Vidari 1129
Microscale Thermophoresis and Docking Studies Suggest Lapachol and Auraptene are Ligands of IDO1
Serena Fiorito, Francesco A. Greco, Alice Coletti, Daniela Dolciami, Silvia Viola, Ursula Grohmann and Antonio Macchiarulo 1133
A New Phytochemical and Anti-oxidant and Anti-inflammatory Activities of Different Lactuca sativa L. var. crispa Extracts
Badr Zekkori, Farid Khallouki, Amar Bentayeb, Serena Fiorito, Francesca Preziuso, Vito Alessandro Taddeo, Francesco Epifano and
Salvatore Genovese 1139
In vitro Digestion of Zingiber officinale Extract and Evaluation of Stability as a First Step to Determine its Bioaccesibility
Giannamaria Annunziato, Claudia Falavigna, Marco Pieroni, Andrea Faccini, Fabrizio Micheli and Gabriele Costantino 1143
In Vitro Culture for Ex Situ Conservation of “Roveja” and Nutritional Considerations on this Italian Rare Legume
Daniele Fraternale, Marco Bruno, Luigi Rocchi, Antonella Amicucci, Chiara Ceccarini and Donata Ricci 1147
Italian Lycium barbarum L. Berry: Chemical Characterization and Nutraceutical Value
Domenico Montesano, Gabriele Rocchetti, Lina Cossignani, Luigi Lucini, Maria Stella Simonetti and Francesca Blasi 1151
Plants Extracts Loaded in Nanocarriers: an Emergent Formulating Approach
Anna Rita Bilia, Vieri Piazzini, Martina Asprea, Laura Risaliti, Giulia Vanti and Maria Camilla Bergonzi 1157
Craft Beers made with Addition of Umbrian Legumes: Healthy and Nutritional Characterization
Stefano Luneia, Riccardo Zannoli, Marco Farchioni, Michele Sensidoni and Roberto Luneia 1161
Dithiosulfinates and Sulfoxides with Antifungal Activity from Bulbs of Allium sativum L. var. Voghiera
Bruna de Falco, Giuliano Bonanomi and Virginia Lanzotti 1163
Antioxidant Activity of Several Essential Oils from Different Rosmarinus officinalis Cultivars Grown in Sanremo (Italy)
Laura Pistelli, Silvia Giovanelli, Francesca D’Angiolillo, Kalina Karkleva, Michele Leonardi, Katarzyna Ambryszewska,
Claudio Cervelli and Luisa Pistelli 1167
Essential Oil of Achillea ligustica (Asteraceae) as an Antifungal Agent against Phytopathogenic Fungi
Laura Giamperi, Anahi Elena Ada Bucchini, Donata Ricci, Fabrizio Papa and Filippo Maggi 1171
Chemical Composition and Antifungal Activity of the Essential Oil of Cotinus coggygria from Marche Region (Italy)
Daniele Fraternale and Donata Ricci 1175
Volatile Components from Aerial Parts of Centaurea diffusa and C. micrantha ssp. melanosticta and Their Biocidal Activity
on Microorganisms Affecting Historical Art Crafts
Maurizio Bruno, Azzurra Milia, Giorgia Catinella and Svetlana Bancheva 1179
Potential Health Benefits of Origanum heracleoticum Essential Oil: Phytochemical and Biological Variability among
Different Calabrian Populations
Mariangela Marrelli, Fabrizio Araniti, Maria Rosa Abenavoli, Giancarlo Statti and Filomena Conforti 1183
Continued inside backcover
  • ... The hidden Bronsted acidity of iodine, that is, its capacity to generate HI by interaction with hydroxyl groups from the substrate or from traces of protic solvents, 25 was ruled out as a possible mechanism since treatment of CBC with Bronsted acids affords compounds resulting from the formation of a benzyl cation and not by cycloreversion. 7 A soft polarizability/polarization of the I−X bond seems, conversely, critical to avoid electrophilic attack to the electron-rich aromatic ring and the dihydropyrane double bond. Electroreversion could then be promoted by halogen bonding to the chromene oxygen and/or to its aromatic ring, 25 while the final aromatization eventually funnels the various equilibria toward the generation of dibenzochromenes. ...
    Article
    The thermal degradation of cannabichromene (CBC, 3) is dominated by cationic reactions and not by the pericyclic rearrangements observed in model compounds. The rationalization of these differences inspired the development of a process that coupled, in an aromatization-driven single operational step, the condensation of citral and alkylresorciniols to homoprenylchromenes and their in situ deconstructive annulation to benzo[c]chromenes. This process was applied to a total synthesis of cannabinol (CBN, 5) and to its molecular editing.
  • Article
    A liquid chromatography-tandem mass spectrometry single-laboratory validation was performed for the detection and quantification of the 10 major cannabinoids of cannabis, namely, (−)-trans-Δ9-tetrahydrocannabinol, cannabidiol, cannabigerol, cannabichromene, tetrahydrocannabivarian, cannabinol, (−)-trans-Δ8-tetrahydrocannabinol, cannabidiolic acid, cannabigerolic acid, and Δ9-tetrahydrocannabinolic acid-A, in the root extract of Cannabis sativa. Acetonitrile : methanol (80 : 20, v/v) was used for extraction; d3-cannabidiol and d3- tetrahydrocannabinol were used as the internal standards. All 10 cannabinoids showed a good regression relationship with r 2 > 0.99. The validated method is simple, sensitive, and reproducible and is therefore suitable for the detection and quantification of these cannabinoids in extracts of cannabis roots. To our knowledge, this is the first report for the quantification of cannabinoids in cannabis roots.
  • Article
    Six new pairs of bibenzyl-based meroterpenoid enantiomers, (±)-rasumatranin A–D (1–4) and (±)-radulanin M and N (5 and 6), and six known compounds were isolated from the adnascent Chinese liverwort, Radula sumatrana. Their structures were elucidated based on spectroscopic data and chiral phase HPLC-ECD analyses. The structures of 1 and 7 were also confirmed by single-crystal X-ray diffraction analysis. Cytotoxicity tests of the isolated compounds showed that 6-hydroxy-3-methyl-8-phenylethylbenzo[b]oxepin-5-one (8) showed activity against the human cancer cell lines MCF-7, PC-3, and SMMC-7721, with IC50 values of 3.86, 6.60, and 3.58 μM, respectively, and induced MCF-7 cell death through a mitochondria-mediated apoptosis pathway.
  • Article
    By using the Inverted Chirality Columns Approach (ICCA) we have developed an enantioselective UHPSFC method to determine the enantiomeric excess (e.e.) for (–)-Δ ⁹ -THC in medicinal marijuana (Bedrocan ® ). The e.e. was...
  • Article
    Daurichromenic acid (DCA) synthase catalyzes the oxidative cyclization of grifolic acid to produce DCA, an anti-HIV meroterpenoid isolated from Rhododendron dauricum. We identified a novel cDNA encoding DCA synthase by transcriptome-based screening from young leaves of R. dauricum. The gene coded for a 533-amino acid polypeptide with moderate homologies to FAD oxidases from other plants. The primary structure contained an N-terminal signal peptide, and conserved amino acid residues to form bicovalent linkage to FAD isoalloxazine ring at His112 and Cys175. In addition, the recombinant DCA synthase, purified from the culture supernatant of transgenic Pichia pastoris, exhibited structural and functional properties as a flavoprotein. The reaction mechanism of DCA synthase characterized herein partly shares a similarity with those of cannabinoid synthases from Cannabis sativa, whereas DCA synthase catalyzes a novel cyclization reaction of farnesyl moiety of a meroterpenoid natural product of plant origin. Moreover, in this study, we present evidence that DCA is biosynthesized and accumulated specifically in the glandular scales, on the surface of R. dauricum plants, based on various analytical studies at chemical, biochemical and molecular levels. Extracellular localization of DCA was also confirmed by a confocal microscopic analysis of its autofluorescence. These data highlight the unique feature of DCA; the final step of biosynthesis is completed in apoplastic space, and it is highly accumulated outside the scale cells.
  • Article
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