New Cannabinoid-Like Chromane and Chromene Derivatives from Rhododendron anthopogonoides

Iwata, Naoki; Kitanaka, Susumu

doi:10.1248/cpb.59.1409

Cited by 50 publications

(46 citation statements)

References 12 publications

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“…The ability to prenylate OSA and DVA, in addition to the previously demonstrated substrate OLA, would enable the synthesis of precursors to or direct medicinal compounds. For example, 5‐geranyl‐OSA is the precursor of anthopogochromenic and anthopogocyclolic acids, which are potential anti‐inflammatory drugs (Iwata & Kitanaka, ) and 3‐farnesyl‐OSA, also called grifolic acid, has been identified as a natural antitumor compound (Zhao et al, ) and is the precursor for the HIV drug daurichromenic acid (Taura et al, ). Furthermore, 3‐geranyl‐DVA and OLA, cannabigerovarinic acid (CBGVA) and cannabigerolic acid (CBGA), respectively, are precursors for synthesizing a variety of functionalized cannabinoids with different pharmaceutical applications (Citti et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…Isoprenoids (specifically C 10 geranoid alcohols) in the aqueous phase were extracted from 2 ml samples (including 50 mg/L (Iwata & Kitanaka, 2011) and 3-farnesyl-OSA, also called grifolic acid, has been identified as a natural antitumor compound (Zhao et al, 2018) and is the precursor for the HIV drug daurichromenic acid (Taura et al, 2014). Furthermore, 3-geranyl-DVA and OLA, cannabigerovarinic acid (CBGVA) and cannabigerolic acid (CBGA), respectively, are precursors for synthesizing a variety of functionalized cannabinoids with different pharmaceutical applications (Citti et al, 2018).…”

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confidence: 99%

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Engineering Escherichia coli as a platform for the in vivo synthesis of prenylated aromatics

Qian

Clomburg

González

2019

Biotech & Bioengineering

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Prenylated aromatics (PAs) are an important class of natural products with valuable pharmaceutical applications. To address current limitations of their sourcing from plants, here, we present a microbial platform for the in vivo synthesis of PAs based on the aromatic prenyltransferase NphB from Streptomyces sp. strain CL190. As proof of concept, we targeted the prenylation of phenolic/phenolcarboxylic acids, including orsellinic (OSA), divarinolic (DVA), and olivetolic (OLA) acids, whose prenylated products have important biopharmaceutical applications. Although the ability of wild‐type NphB to catalyze the prenylation reaction with each acid was validated by in vitro characterization, improvement of product titers in vivo required protein modeling and rational design to engineer NphB variants with increased activity and product selectivity. When a designed NphB variant with eightfold improved catalytic efficiency toward OSA was expressed in an Escherichia coli host engineered to generate geranyl pyrophosphate at high flux through the mevalonate pathway, we observed up to 300 mg/L prenylated products by exogenously supplying OSA. The improved properties of engineered NphB were also utilized to demonstrate the diversification of this in vivo platform by using both different aromatic acceptors and different prenyl donors to generate various PA compounds, including medicinally important compounds such as cannabigerovarinic, cannabigerolic, and grifolic acids.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Engineering Escherichia coli as a platform for the in vivo synthesis of prenylated aromatics

Qian

Clomburg

González

2019

Biotech & Bioengineering

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“…[170], liverworts [171], [172], and fungi [173]–[175]. Falcarinol is a skin irritant found in several plants that causes contact dermatitis.…”

Section: Resultsmentioning

confidence: 99%

Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

2014

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BackgroundThe “classic” endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the “eCB deficiency syndrome” as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system—ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation.Methodology/Principal FindingsWe searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as “complementary and alternative medicine” also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances—alcohol, tobacco, coffee, cannabis) also modulate the eCB system.Conclusions/SignificanceFew clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.

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“…grows in Southern China and is used as expectorant and for the treatment of chronic bronchitis [11,12]. Phytochemical studies revealed that it contains the cannabinoid-like chromane and chromene derivatives anthopogocyclolic acid, anthopogochromenic acid, cannabiorcichromenic acid, and cannabiorcicyclolic acid [11,12]. Lastly, Rhododendron rubiginosum Franch.…”

Section: Illustration Of the Structural Characteristics Of Cannabinoimentioning

confidence: 99%

“…Rhododaurichromanic acid A also showed potent anti-HIV activity, with an EC 50 of 370 ng ml −1 and a therapeutic index of 92 [94]. Anthopogocyclolic acid (CBL-type), anthopogochromenic acid (CBL-type), and cannabiorcichromenic acid (CBC-type) from R. anthopogonoides inhibit histamine release and thus exhibit antiallergic effects [11,12,91].…”

Section: Cannabinoid Acidsmentioning

confidence: 99%

Phytocannabinoids: Origins and Biosynthesis

Gülck

Møller

2020

Trends in Plant Science

262

240

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Phytocannabinoids are bioactive natural products found in some flowering plants, liverworts, and fungi that can be beneficial for the treatment of human ailments such as pain, anxiety, and cachexia. Targeted biosynthesis of cannabinoids with desirable properties requires identification of the underlying genes and their expression in a suitable heterologous host. We provide an overview of the structural classification of phytocannabinoids based on their decorated resorcinol core and the bioactivities of naturally occurring cannabinoids, and we review current knowledge of phytocannabinoid biosynthesis in Cannabis, Rhododendron, and Radula species. We also highlight the potential in planta roles of phytocannabinoids and the opportunity for synthetic biology approaches based on combinatorial biochemistry and protein engineering to produce cannabinoid derivatives with improved properties. Phytocannabinoids The term phytocannabinoid (see Glossary, also cannabinoid) defines meroterpenoids with a resorcinyl core typically decorated with a para-positioned isoprenyl, alkyl, or aralkyl side chain [1]. The alkyl side chain typically contains an odd number of carbon atoms, where orcinoids contain one carbon, varinoids three, and olivetoids five. Cannabinoids with an even number of carbon atoms in the side chain are known but rare. The term cannabinoid generally refers to molecules with a characteristic chemical structure; however, the term may also refer to pharmacological ligands of human endocannabinoid receptors [2]. In this review we use the chemical definition of cannabinoids. Phytocannabinoids occur in flowering plants, liverworts, and fungi (Figure 1, Key Figure). They were first isolated from Cannabis sativa L. (Cannabaceae), a plant with a long and controversial history of use and abuse [3]. The mammalian brain has receptors that respond to compounds found in C. sativa. Accordingly, these receptors were named cannabinoid receptors (CB x) and are the basis of the endocannabinoid system. Studies in human and animals demonstrated that the endocannabinoid system regulates a broad range of biological functions, including memory, mood, brain reward systems, and drug addiction, as well as metabolic processes such as lipolysis, glucose metabolism, and energy balance [2]. More than 113 different cannabinoids have been isolated from C. sativa and these are classified into distinct types: cannabigerols (CBGs), cannabichromenes (CBCs), cannabidiols (CBDs), (−)-Δ 9-trans-tetrahydrocannabinols (Δ 9-THCs), (−)-Δ 8-trans-tetrahydrocannabinols (Δ 8-THCs), cannabicyclols (CBLs), cannabielsoins (CBEs), cannabinols (CBNs), cannabinodiols (CBNDs), cannabitriols (CBTs), and the miscellaneous cannabinoids (Figure 2) [4]. C. sativa predominantly produces alkyl type cannabinoids that carry a monoterpene isoprenyl moiety (C10) and a pentyl side chain (C5) [1]. The most abundant constituents are trans-Δ 9-THC, CBD, CBC, and CBG, together with their respective acid forms (Δ 9-THCA, CBDA, CBCA, and CBGA) [5]. Cannabinoid biosynthetic pathways ty...

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New Cannabinoid-Like Chromane and Chromene Derivatives from Rhododendron anthopogonoides

Cited by 50 publications

References 12 publications

Engineering Escherichia coli as a platform for the in vivo synthesis of prenylated aromatics

Engineering Escherichia coli as a platform for the in vivo synthesis of prenylated aromatics

Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

Phytocannabinoids: Origins and Biosynthesis

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