- VCE-004.3, a cannabidiol aminoquinone derivative, prevents bleomycin-induced skin fibrosis and inflammation through PPARγ- and CB2 receptor-dependent pathways
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Background and Purpose: The endocannabinoid system and PPARγ are important 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 study its anti-inflammatory and anti-fibrotic activities. Experimental Approach: The binding of VCE-004.3 to CB1 and CB2 receptors and PPARγ and its effect on their functional activities were studied in vitro and in silico. Anti-fibrotic effects of VCE-004.3 were investigated in NIH-3T3 fibroblasts and human dermal fibroblasts. To assess its anti-inflammatory and anti-fibrotic efficacy in vivo, we used two complementary models of bleomycin-induced fibrosis. Its effect on ERK1/2 phosphorylation induced by IgG from SSc patients and PDGF was also investigated. Key Results: VCE-004.3 bound to and activated PPARγ and CB2 receptors and antagonized CB1 receptors. VCE-004.3 bound to an alternative site at the PPARγ ligand binding pocket. VCE-004.3 inhibited collagen gene transcription and synthesis and prevented TGFβ-induced fibroblast migration and differentiation to myofibroblasts. It prevented skin fibrosis, myofibroblast differentiation and ERK1/2 phosphorylation in bleomycin-induced skin fibrosis. Furthermore, it reduced mast cell degranulation, macrophage activation, T-lymphocyte infiltration, and the expression of inflammatory and profibrotic factors. Topical application of VCE-004.3 also alleviated skin fibrosis. Finally, VCE-004.3 inhibited PDGF-BB- and SSc IgG-induced ERK1/2 activation in fibroblasts. Conclusions and Implications: VCE-004.3 is a novel semisynthetic cannabidiol derivative that behaves as a dual PPARγ/CB2 agonist and CB1 receptor modulator that could be considered for the development of novel therapies against different forms of scleroderma.
- del Rio, Carmen,Cantarero, Irene,Palomares, Belén,Gómez-Ca?as, María,Fernández-Ruiz, Javier,Pavicic, Carolina,García-Martín, Adela,Luz Bellido, Maria,Ortega-Castro, Rafaela,Pérez-Sánchez, Carlos,López-Pedrera, Chary,Appendino, Giovanni,Calzado, Marco A,Mu?oz, Eduardo
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- Synthesis and antitumor activity of quinonoid derivatives of cannabinoids
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Three cannabis constituents, cannabidiol (1), Δ8 -tetrahydrocannabinol (3), and cannabinol (5), were oxidized to their respective para-quinones 2, 4, and 6. In the 1960s, the oxidized product 4 had been assigned a para-quinone structure, which was later modified to an ortho-quinone. To distinguish between the two possible quinone structures, a detailed NMR investigation was undertaken. The original para-quinone structure was confirmed. X-ray crystallography elucidated the structures of the crystalline 2 and 6. All three compounds displayed antiproliferative activity in several human cancer cell lines in vitro, and quinone 2 significantly reduced cancer growth of HT-29 cancer in nude mice.
- Kogan, Natalya M.,Rabinowitz, Ruth,Levi, Paloma,Gibson, Dan,Sandor, Peter,Schlesinger, Michael,Mechoulam, Raphael
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- The Oxidation of Phytocannabinoids to Cannabinoquinoids
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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 hypervalent iodine reagents). The best results in terms of reproducibility and scalability were obtained with λ5-periodinanes (Dess-Martin periodinane, 1-hydroxy-1λ5,2-benziodoxole-1,3-dione (IBX), and SIBX, a stabilized, nonexplosive version of IBX). With these reagents, the oxidative dimerization that plagues the reaction under basic aerobic conditions was completely suppressed. A different reaction course was observed with the copper(II) chloride-hydroxylamine complex (Takehira reagent), which afforded a mixture of the hydroxyiminodienone 11 and the halogenated resorcinol 12. The λ5-periodinane oxidation was general for phytocannabinoids, turning cannabigerol (CBG, 18), cannabichromene (CBC, 10), and cannabinol (CBN, 19) into their corresponding hydroxyquinones (20, 21, and 22, respectively). All cannabinoquinoids modulated to a various extent peroxisome proliferator-activated receptor gamma (PPAR-γ) activity, outperforming their parent resorcinols in terms of potency, but the iminoquinone 11, the quinone dimers 3 and 23, and the haloresorcinol 12 were inactive, suggesting a specific role for the monomeric hydroxyquinone moiety in the interaction with PPAR-γ.
- Appendino, Giovanni,Caprioglio, Diego,Chianese, Giuseppina,Collado, Juan A.,Lopatriello, Annalisa,Mattoteia, Daiana,Minassi, Alberto,Munoz, Eduardo,Negri, Roberto,Pollastro, Federica,Taglialatela-Scafati, Orazio
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- FORMULATIONS OF CANNABIDIOL DERIVATIVES AND THEIR USE AS MODULATORS OF CANNABINOID RECEPTOR TYPE 2 (CB2)
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Compositions, comprising the cannabidiol derivatives of Formula (I) in pharmaceutical formulations displaying increased bioavailability and solubility are described. Cannabidiol derivatives of Formula (I) and compositions comprising the same for use in the treatment of various conditions, and diseases, including diseases associated with demyelination.
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(2020/08/22)
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- NOVEL CANNABIDIOL QUINONE DERIVATIVES
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The present invention relates to novel cannabidiol quinone derivatives of formula (I) (I) wherein R is the carbon atom of a, linear or branched group, represented by: alkyl, aryl, alkenyl, alkynyl, acyl or alkoxycarbonyl groups; or wherein R is the nitrogen atom of a, linear or branched group represented by: alkylamine, arylamine, alkenylamineor alkynylamine groups. The invention also relates to the use of any of the compounds of formula (I)as medicamentsin therapy, particularly for treating diseasesand conditions responsive to PPARg modulationdue to their high PPARg agonistic effect lacking electrophilic (Nrf2 activation) and cytotoxic activities. This invention also provides pharmaceutical compositions comprising said compounds and method of treating diseases with said compounds.
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(2015/11/09)
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- THERAPEUTIC USE OF QUINONOID DERIVATIVES OF CANNABINOIDS
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The present invention relates to cannabinoic quinone compounds, and especially to their medical use. In particular five cannabinoic quinones, designated HU-331, HU-336, HU-345, HU-395 and HU-396 are herein described as active agents in pharmaceutical compositions. Said compounds and compositions thereof are intended for the treatment of inflammatory, infectious, auto-immune and particularly hyperproliferative disorders. Thus, the compounds of the invention may be used as anti-tumor agents, or for the treatment of cancer. Furthermore, three of these compounds, HU-345, HU-395 and HU-396, are novel cannabinoic quinones and thus are also claimed herein.
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Page/Page column 30; Fig.1A
(2008/06/13)
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