New chromane and chromene meroterpenoids from flowers of Rhododendron rubiginosum Franch. var. rubiginosum

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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“…var. rubiginosum, a shrub endemic to Southwest China, was found to contain anthopogochromenes A and B, as well as rubiginosins A-G [8].…”

Section: Illustration Of the Structural Characteristics Of Cannabinoimentioning

confidence: 99%

Phytocannabinoids: Origins and Biosynthesis

Gülck

Møller

2020

Trends in Plant Science

239

240

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“…It also increases DNA damage by the formation of γH2AX foci and or the phosphorylation of Chk2 and H2AX, which proteins are generally associated with DNA damage [100]. Chromane/chromene meroterpenoids (CMs), the rubiginosins A-G (306-312) (Figure 34) and anthopogochromenes A (313) and B (314), were reported from Rhododendron rubiginosum [101]. In addition to spectroscopic techniques, their absolute structures were established by making use of the chromane/chromene helicity rule, X-ray crystallography and CD analysis.…”

Section: Chromane/chromene and Flavone Derived Meroterpenoidsmentioning

confidence: 99%

“…Compound 310 was the most active against all cell lines with IC 50 values of 10.91, 13.89, 11.71 and 7.40 µM, respectively and then followed compounds 306, 308 and 314. The other tested metabolites are reported to be inactive [101]. Doxorubicin (IC 50 = 0.01-0.2 µM) was used as positive control in this study.…”

Section: Chromane/chromene and Flavone Derived Meroterpenoidsmentioning

confidence: 99%

Meroterpenoids: A Comprehensive Update Insight on Structural Diversity and Biology

et al. 2021

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Meroterpenoids are secondary metabolites formed due to mixed biosynthetic pathways which are produced in part from a terpenoid co-substrate. These mixed biosynthetically hybrid compounds are widely produced by bacteria, algae, plants, and animals. Notably amazing chemical diversity is generated among meroterpenoids via a combination of terpenoid scaffolds with polyketides, alkaloids, phenols, and amino acids. This review deals with the isolation, chemical diversity, and biological effects of 452 new meroterpenoids reported from natural sources from January 2016 to December 2020. Most of the meroterpenoids possess antimicrobial, cytotoxic, antioxidant, anti-inflammatory, antiviral, enzyme inhibitory, and immunosupressive effects.

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“…The double bonds in both side chains were assigned to E geometry based on the chemical shifts of the olefinic methyl carbons (<20 ppm) and the NOE interaction. Based on the electronic circular dichroism (ECD) rule for chromenes (Crabbe’s rule) [17,18], the Cotton effect at around 270 nm for the 1Lb excitation reflected the absolute configuration of the chiral center in chromene chromophore. The negative Cotton effect at 270 nm in compound 1 was in accordance with the chromene P -helicity (Figure 3), which was in agreement with R configuration.…”

Section: Resultsmentioning

confidence: 99%

Reducing Effect of Farnesylquinone on Lipid Mass in C. elegans by Modulating Lipid Metabolism

Jia

Yang

et al. 2019

Marine Drugs

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Bioassay-guided fractionation of marine-derived fungi revealed that the EtOAc fraction from the fermentation broth of a mutated fungal strain Streptomyces nitrosporeus YBH10-5 had lipid-lowering effects in HepG2 cells. Chromatographic separation of the EtOAc fraction resulted in the isolation of 11 PKS-based derivatives, including a structurally unique meroterpenoid namely nitrosporeunol H (1). The structure of compound 1 was determined by the analysis of spectroscopic data. Further bioassay resulted in farnesylquinone (2) and its analogues to exert in vivo fat-reducing effects in C. elegans worm model. The underlying mode of action of compound 2 in the context of live worms was investigated, uncovering that compound 2 enhanced the mitochondrial β-oxidation rate and changed the transcriptional level of energy metabolism genes. Additional experiments revealed that compound 2 exerted its effects in C. elegans partially through repressing FAT-5, an isoform of stearoyl-CoA desaturase (SCD) which catalyzes the conversion of saturated fatty acids to monounsaturated fatty acids, thereafter leading to the modification of the fatty acid profile. Thus, compound 2 was suggested to be a promising lead for further optimization to treat obesity.

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New chromane and chromene meroterpenoids from flowers of Rhododendron rubiginosum Franch. var. rubiginosum

Cited by 28 publications

References 12 publications

Phytocannabinoids: Origins and Biosynthesis

Phytocannabinoids: Origins and Biosynthesis

Meroterpenoids: A Comprehensive Update Insight on Structural Diversity and Biology

Reducing Effect of Farnesylquinone on Lipid Mass in C. elegans by Modulating Lipid Metabolism

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