Giovanni Appendino

Amedeo Avogadro University of Eastern Piedmont | UNIPMN · Department of Pharmaceutical Sciences

Despite the very large number of phytocannabinoids isolated from Cannabis (Cannabis sativa L.), bioactivity studies have long remained focused on the so called “Big Four” [Δ9-THC (1), CBD (2), CBG (3) and CBC (4)] because of their earlier characterization and relatively easy availability via isolation and/or synthesis. Bioactivity information on th...

Polypharmacological targeting of lipid mediator networks offers potential for efficient and safe anti-inflammatory therapy. Because of the diversity of its biological targets, curcumin (1a) has been viewed as a privileged structure for bioactivity or, alternatively, as a pan-assay interference (PAIN) compound. Curcumin has actually few high-affinit...

The intrinsic histone acetyltransferase (HAT), p300, has an important role in the development and progression of heart failure. Curcumin (CUR), a natural p300-specific HAT inhibitor, suppresses hypertrophic responses and prevents deterioration of left-ventricular systolic function in heart-failure models. However, few structure–activity relationshi...

Since antiquity, the sense of smell (olfaction) is considered as a distance sense, just like sight and hearing. Conversely, the sense of taste (gustation) is thought to operate by direct contact, similarly to touch. With the progress of natural sciences, information at molecular, anatomical, and neurobiological levels has also contributed to the ta...

Reports on the occurrence of cannabidiol (CBD, 1) in non-cannabis plants are critically reviewed. The isolation of 1 from Humulus Kriya (sic) was fraudulent and from Trema orientalis and stevia dubious, while the occurrence of traces of 1 in flax needs additional confirmation. The presence of high concentration of cannabigerol (CBG, 3a) and its cor...

A phytochemical analysis of mother liquors obtained from crystallization of CBD from hemp (Cannabis sativa), guided by LC-MS/MS and molecular networking profiling and completed by isolation and NMR-based characterization of constituents, resulted in the identification of 13 phytocannabinoids. Among them, anhydrocannabimovone (5), isolated for the f...

Aminocannabinoquinones are an emerging class of next generation semi‐synthetic cannabinoids exemplified by VCE‐004.8 (1 c), a compound currently in phase 2 development for scleroderma. Aminocannabinoquinones have been so far obtained from resorcinolic cannabinoids by a two‐step protocol involving oxidation to a hydroxyquinone followed by tandem aza...

The stability of molecular curcumin (purcumin, 1a) in solution is strongly light-dependent. Under laboratory artificial light, a relative stability is observed only at neutral pH, while more intense light and/or solar light can trigger degradation via a combination of hydrolytic and oxidative fragmentation of the heptadiendione moiety. Minor curcum...

The neutral fraction of a juniper (Juniperus communis L.) berries acetone extract could positively modulate the activity of type 1 - cannabinoid receptor (CB1R). Bioactivity-directed fractionation identified the labdane diterpenoid agathadiol (4) as a positive allosteric modulator of CB1R, while closely related analogues were inactive. Agathadiol (...

Some cannabinoids showed anti-inflammatory and antifibrotic activities. EHP-101 is an oral lipidic formulation of the novel non-psychotropic cannabidiol aminoquinone VCE-004.8, which showed antifibrotic activity in murine models of systemic sclerosis induced by bleomycin. We herein examined the effect of EHP-101 on cardiac and other organ fibrosis...

The affinity of cannabinoids for their CB1 and CB2 metabotropic receptors is dramatically affected by a combination of α-branching and elongation of their alkyl substituent, a maneuver exemplified by the n-pentyl -> α,α-dimethylheptyl (DMH) swap. The effect of this change on other cannabinoid end-points is still unknown, an observation surprising s...

Huntington’s disease (HD) is a neurodegenerative disorder characterized by unwanted choreatic movements, behavioral and psychiatric disturbances, and dementia. The activation of the hypoxic response pathway through the pharmacological inhibition of hypoxia-inducing factor (HIF) prolyl-hydroxylases (PHDs) is a promising approach for neurodegenerativ...

The cis-stereoisomers of Δ⁹-THC [(−)-3 and (+)-3] were identified and quantified in a series of low-THC-containing varieties of Cannabis sativa registered in Europe as fiber hemp and in research accessions of cannabis. While Δ⁹-cis-THC (3) occurs in cannabis fiber hemp in the concentration range of (−)-Δ⁹-trans-THC [(−)-1], it was undetectable in a...

Neutral cannabinoids are oxidatively unstable and are converted into quinone derivatives by atmospheric- and/or chemical oxidative dearomatization. The study of cannabinoquinones has long been plagued by their lability toward additional oxidative degradation, but full substitution of the quinone ring, as well as the introduction of steric hindrance...

Organic chemistry honors Icilio Guareschi (1847–1918) with three eponymic reactions, the best known ones being the Guareschi synthesis of pyridones and the Guareschi–Lustgarten reaction. A third Guareschi reaction, the so-called “Guareschi 1897 reaction”, is one of the most unusual reactions in organic chemistry, involving the radical-mediated para...

The long-standing perception of Protein Kinase C (PKC) as a family of oncoproteins has increasingly been challenged by evidence that some PKC isoforms may act as tumor suppressors. To explore the hypothesis that activation, rather than inhibition, of these isoforms is critical for anticancer activity, we isolated and characterized a family of 16 no...

The endocannabinoid system (ECS) is an important physiologic system that interacts with nearly all bodily ones, including the central nervous system (CNS). Overall, the ECS is involved in health and disease. From a therapeutic perspective, modulating and targeting the ECS could be a major disease-modifying medical strategy for the future, with impl...

As part of a study on the structure-activity relationships of the anticancer agent tigilanol tiglate (EBC-46, 2), the allylic oxidation of phorbol triacetate (1c) and of the acetonide of its 3αH-dihydroderivative (5) was investigated. The aim was to introduce an oxygen function at C-5 en route to point-like analogues of 2, but functionalization of...

Spurred by the remarkable biological profile of cannabinoquinoids, we have systematically investigated the periodinane oxidation of their resorcinolic precursors, discovering that the regiochemistry of oxidation, a critical maneuver for bioactivity, depends not only on the nature of the oxidant (λ3‐ vs. λ5‐iodanes), but also on post‐oxidative proto...

The Front Cover shows a crossroad, metaphorically representing the possibility of a phenol to be oxidized to an ortho‐ or a para‐quinone depending on the nature of the oxidant (λ3‐ vs λ5‐iodane). However, things are not so straightforward, since prototropic equilibria and valence tautomerization can provide a diversion from the selected pathway. Mo...

The literature on thia-Michael acceptors is vast and can be cherry-picked to show either that these compounds pollute chemical libraries displaying unselective binding and propensity to toxicity, or, alternatively, that the thiol-trapping reaction is highly selective and critical for bioactivity. Since the energy of the carbon–sulfur bond (ca 60 kc...

As part of a study on triterpenoid conjugates, the dietary pentacyclic triterpenoids oleanolic (2a) and ursolic acids (3a) were coupled with vanillamine, and the resulting amides (2b and 3b, respectively) were assayed for activity on the vanilloid receptor TRPV1. Despite a structural difference limited to the location of a methyl group in their con...

Cannabitwinol (CBDD, 3), the second member of a new class of dimeric phytocannabinoids in which two units are connected by a methylene bridge, was isolated from a hemp (Cannabis sativa L.) industrial extract. The structural characterization of cannabitwinol, complicated by broadening of 1H NMR signals and lack of expected 2D NMR correlations at roo...

Intestinal fibrosis is a common complication of inflammatory bowel disease (IBD) and is defined as an excessive accumulation of scar tissue in the intestinal wall. Intestinal fibrosis occurs in both forms of IBD: ulcerative colitis and Crohn’s disease. Small-molecule inhibitors targeting hypoxia-inducing factor (HIF) prolyl-hydroxylases are promisi...

Background and purpose: Δ9 -THCA-A, the precursor of Δ9 -THC, is a non-psychotropic phytocannabinoid that shows PPARγ agonistic activity. Herein, we investigated Δ9 -THCA ability to modulate classic cannabinoid receptors (CB1 and CB2 ) and evaluated its anti-arthritis activity. Experimental approach: Cannabinoid receptors binding and intrinsic a...

Eupatilin is a dietary flavonoid isolated from the alpine wormwoods, used for the genepy liqueur production. This flavone protects cells and tissues towards oxidative stress and targets cancer cells, inducing cytotoxicity, cell circle arrest, apoptosis and mitochondrial dysfunction. This study examines the EUP in vitro antioxidant effects on choles...

Spurred by a growing interest in cannabidiolquinone (CBDQ, HU-313, 2) as a degradation marker and alledged hepatotoxic metabolite of cannabidiol (CBD, 1), we performed a systematic study on the oxidation of CBD (1) to CBDQ (2) under a variety of experimental conditions (base-catalyzed aerobic oxidation, oxidation with metals, oxidation with hyperva...

Phytocannabinoids (pCBs) are a large family of meroterpenoids isolated from the plant Cannabis sativa. Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best investigated phytocannabinoids due to their relative abundance and interesting bioactivity profiles. In addition to various targets, THC and CBD are also well-known agonists of perox...

Medicinal cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ9-tetrahydrocannabinol (Δ9-THC). However, the biological profile of the carboxylated, non-narcotic native precursor of Δ9-THC, the Δ9-THC acid A (Δ9-THCA-A), remains largely unexplored. Here we present evidence that Δ9-THCA-A is...

The Alpine wormwood Artemisia vallesiaca All. was considered the most valuable ingredient of vermouth, a celebrated aromatized wine. A. vallesiaca has a very limited geographical distribution, and the booming market of vermouth decimated its natural population, resulting in the eventual replacement of this rare species with more common and less exp...

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...

The renewed interest in dimeric salicylates as broad-spectrum anti-inflammatory and anti-diabetic agents provided a rationale to investigate the dimerization of the substituted salicylate Δ9-tetrahydrocannabinolic acid (THCA-A, 3a) as a strategy to solve its instability to decarboxylation and to generate analogues and/or pro-drugs of this native pr...

Cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC). Surprisingly, the biological profile of the non-narcotic native precursor of Δ ⁹ -THC (Δ ⁹ -THC acid A, Δ ⁹ -THCA-A) is still largely unexplored. We present evidence that Δ ⁹ -THCA-A is a partial and s...

A general protocol for the selective mono-O-methylation of resorcinyl phytocannabinoids was developed. The availability of semisynthetic monomethyl analogues of cannabigerol, cannabidiol, and cannabidivarin (1a–3a, respectively) made it possible to quantify these minor phytocannabinoids in about 40 different chemotypes of fiber hemp. No chemotype s...

The dietary sesquiterpene dienone zerumbone (ZER) targets selectively cancer cells inducing mitochondrial dysfunction and apoptosis, but protects non-cancerous cells towards oxidative stress and insult. This study examines the in vitro effect of ZER on lipid peroxidation in biological systems (cholesterol and phospholipid membrane oxidation) and ex...

The endocannabinoid system (ECS) may play a role in the pathophysiology of systemic sclerosis (SSc). Cannabinoids acting as dual PPARγ/CB 2 agonists, such as VCE-004.8 and Ajulemic acid (AjA), have been shown to alleviate skin fibrosis and inflammation in SSc models. Since both compounds are being tested in humans, we compared their activities in t...

Correction for ‘The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research’ by James B. McAlpine et al. , Nat. Prod. Rep. , 2018, DOI: 10.1039/c7np00064b.

The sesquiterpene-coumarin ether samarcandone provided a suitable framework to replace the apocarotenoid A-C ring system of strigol (1), replicating, after linking to a butenolide moiety, the activity of the natural phytohormone on Nrf2 and also showing potent NF-kB inhibitory activity, overall modulating two critical pathways of inflammation and c...

Abstract Over the past few years, the endocannabinoid system (ECs) has emerged as a crucial player for the regulation of food intake and energy metabolism, and its pharmacological manipulation represents a novel strategy for the management of metabolic diseases. The discovery that VCE-004.8, a dual PPARγ and CB2 receptor agonist, also inhibits prol...

Pentacyclic triterpenoid acids (PCTTAs) are pleiotropic agents that target many macromolecular end-points with low to moderate affinity. To explore the biological space associated with PCTTAs, we have investigated the carboxylate-to-hydroxamate transformation, discovering that it de-emphasizes affinity for the transcription factors targeted by the...

Unlike all other caffeinated plants, guayusa (Ilex guayusa Loes.) and maté (Ilex paraguariensis A. St. Hill) contain high amounts of pentacyclic triterpenoid acids and alcohols. A phytochemical investigation on these plants revealed a similar triterpenoid profile and a content of ursolic acid (0.7–1%) and amyrin esters (up to 0.5%), quite unusual f...

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, highlight...

Systemic sclerosis (SSc) or scleroderma is a chronic multi-organ autoimmune disease characterized by vascular, immunological, and fibrotic abnormalities. The etiology of SSc is unknown, but there is growing evidence that dysfunction of the endocannabinoid system (ECS) plays a critical role in its development. Since the semi-synthetic cannabinoquino...

The skin is the largest organ of the body and has a complex and very active structure that contributes to homeostasis and provides the first line defense against injury and infection. In the past few years it has become evident that the endocannabinoid system (ECS) plays a relevant role in healthy and diseased skin. Specifically, we review how the...

Covering: up to 2018 With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets....

Background and purpose: The endocannabinoid system (ECS) as well as PPARγ are relevant targets for the development of novel compounds against fibrotic diseases such as Systemic Sclerosis (SSc), also called Scleroderma. The aim of this study was to characterize VCE-004.3, a novel cannabidiol derivative, and to study it anti-inflammatory and anti-fi...

Electrophilic attack to a double bond, the classic trigger of intramolecular isoprenoid cyclizations, is apparently silent in Cannabis and the diversity of the cannabinome can be ultimately traced to the oxidative cyclization of cannabigerolic acid (CBGA, 1a), a process triggered by the generation of an aromatic electrophilic species. To expand the...

Helichrysum umbraculigerum Less. has been reported to be a prolific producer of phytocannabinoids from the alkyl-, aralkyl-, normal-, and abnormal types. Investigation of an acetone extract from the aerial parts of the plant afforded two novel amorfrutin-type phytocannabinoids (3b, 4) and the new geranylated phloroglucinol 5a. The presence of canna...

The guaianolide 11,13-dehydrogrilactone (2) was previously described as alleged chemotaxonomic marker of the Sardo-Corsican endemic species Ferula arrigonii Bocchieri. In the present work, the presence of this component could not be confirmed in various extracts obtained from plants harvested in Sardinia and Corsica island as well as in its vegetal...

Background: Multiple sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes variously dominant in different stages of the disease. Thus, immunosuppression is the goal standard for the inflammatory stage, and novel remyelination therapies are pursued to restore lost function. Cannabinoids such as9Δ-THC and...

Cannabinoids are a complex group of molecules that comprise phytocannabinoids, endocannabinoids, and synthetic cannabinoids. Cannabinoids were initially identified by their ability to bind and activate the classical cannabinoid receptors CB1 and CB2. However, cannabinoids are pleiotropic in nature, and also activate other type of receptors, such as...

Treatment with iodine cleanly converts various p-menthane-type phytocannabinoids and their carboxylated precursors into cannabinol (CBN, 1a). The reaction is superior to previously reported protocols in terms of simplicity and substrate range, which includes not only tricyclic tetrahydrocannabinols such as Δ⁹-THC (2a) but also bicyclic phytocannabi...

Helichrysum umbraculigerum Less. has been reported to be a prolific producer of phytocannabinoids from the alkyl-, aralkyl-, normal-, and abnormal types. Investigation of an acetone extract from the aerial parts of the plant afforded two novel amorfrutin-type phytocannabinoids (3b, 4) and the new geranylated phloroglucinol 5a. The presence of canna...

Background and purpose: Phytocannabinoids are produced in Cannabis sativa L. in acidic form and are decarboxylated upon heating, processing, and storage. While the biological effects of decarboxylated cannabinoids such as Δ(9) -tetrahydrocannabinol (Δ(9) -THC) have been extensively investigated, the bioactivity of Δ(9) -THCA is largely unknown, de...

Bardoxolone methyl (1) is the quintessential member of triterpenoid cyanoacrylates, an emerging class of bioactive compounds capable of transient covalent binding to thiols. The mechanistic basis for this unusual "pulsed reactivity" profile and the mode of its biological translation are unknown. To provide clues on these issues, a series of Δ(1)-de...

Background: Croton oil is the only commercial source of the diterpenoid phorbol (1a), the starting material for the semi-synthesis of various diesters extensively used in biomedical research to investigate cell function and to evaluate in vivo anti-inflammatory activity. While efficient chemoselective esterification protocols have been developed fo...

ESI-HRMS and 1H and 13C NMR spectra of compounds 1d and 1e.

Spurred by the alleged relevance of the thia-Michael reaction in the bioactivity of various classes of cinnam(o)yl natural products and by the development of a quick NMR assay to study this reaction, we have carried out a systematic study of the “native” reactivity of these compounds with dodecanethiol and cysteamine as models, respectively, of sim...

Background and purpose: The mechanism of the antimigraine action of butterbur [Petasites hybridus (L.) Gaertn.] is unknown. Here, we investigated the ability of isopetasin, a major butterbur constituent, to specifically target the transient receptor ankyrin 1 (TRPA1) channel and to affect functional responses relevant to migraine. Experimental ap...

An approach to biogenetically "overlooked", or not yet recognized as populated, areas of the isoprenoid chemical space is presented. This strategy is based on the generation of a cationic center in functionalized polyolefins by Lewis acid activation of a carbonyl rather than by electrophilic attack to a double bond. Starting from the monocyclic hum...

The heterodimeric phloroglucinyl pyrone arzanol (Arz) has raised considerable interest because of its antiviral, anti-inflammatory, and antioxidant activity. We have investigated the effect of methylation of the pyrone moiety on the antioxidant activity and cytotoxicity of Arz. This manoeuvre, that left the polyphenolic moiety unscathed, was nevert...

Canniprene (1), an isoprenylated bibenzyl unique to Cannabis sativa, can be vaporized and therefore potentially inhaled from marijuana. Canniprene (1) potently inhibited the production of inflammatory eicosanoids via the 5-lipoxygenase pathway (IC50 0.4 μM) and also affected the generation of prostaglandins via the cyclooxygenase/microsomal prostag...

The Italian herbal products market is the most prosperous in Europe. The proof is represented by the use of these products in several marketing categories, ranging from medicine to nutrition and cosmetics. Market and legislation in Italy are at the same time cause and consequence of this peculiar situation. In fact, the legislation on botanical foo...

Cannabis sativa L. is a prolific, but not exclusive, producer of a diverse group of isoprenylated resorcinyl polyketides collectively known as phytocannabinoids. The modular nature of the pathways that merge into the phytocannabinoid chemotype translates in differences in the nature of the resorcinyl side-chain and the degree of oligomerization of...

Arzanol (1) exemplifies a large number of heterodimeric bioactive natural products based on an alkylidene-bridged β-dicarbonyl-acylphloroglucinyl structural motif. The NMR spectra of these compounds are complicated by tautomeric and rotational equilibria that, despite growing synthetic and biomedical interest in the area, have not been systematical...

Cannabinoids have shown to exert neuroprotective actions in animal models by acting at different targets including canonical cannabinoid receptors and PPARγ. We previously showed that VCE-003, a cannabigerol (CBG) quinone derivative, is a novel neuroprotective and anti-inflammatory cannabinoid acting through PPARγ. We have now generated a non-thiop...