Natural NO inhibitors from the leaves of Callicarpa kwangtungensis: Structures, activities, and interactions with iNOS

doi:10.1016/j.bmcl.2016.11.044

Bioorganic & Medicinal Chemistry Letters

Volume 27, Issue 3, 1 February 2017, Pages 670-674

https://doi.org/10.1016/j.bmcl.2016.11.044 Get rights and content

Abstract

A phytochemical investigation to obtain new NO inhibitors resulted in the isolation of a new diterpenoid with a rare 9,10-seco-abietane skeleton (1) and twelve known terpenoids (2–13) from Callicarpa kwangtungensis. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analyses, and the absolute configuration of compound 1 was established by comparison of the calculated and experimental electronic circular dichroism (ECD) spectra. The inhibitory activities on lipopolysaccharide-induced NO production in murine microglial BV-2 cells of these terpenoids were evaluated, and all of the compounds showed inhibitory effects. The following molecular docking studies showed interactions of the bioactive compounds with the iNOS protein.

Graphical abstract

Section snippets

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 21372125), the Natural Science Foundation of Tianjin, China (No. 16JCYBJC27700), and the State Key Laboratory of Medicinal Chemical Biology (No. 201602007).

References (38)

A. Contestabile
Brain Res Rev
(2000)
J. Zhu et al.
Mol Brain
(2016)
Y. Tu et al.
J Ethnopharmacol
(2013)
Y. Luo et al.
J Asian Nat Prod Res
(2016)
M. Yuan et al.
J Asian Nat Prod Res
(2015)
L. Dong et al.
Phytochem Lett
(2014)
P. Chung et al.
Fitoterapia
(2014)
Y. Luo et al.
Phytochem Lett
(2014)
L. Zhang et al.
Fitoterapia
(2013)
Z. Zhou et al.
Fitoterapia
(2013)

A.Z. Wu et al.

Fitoterapia

(2013)

J. Xu et al.

Fitoterapia

(2016)

J. Xu et al.

J Nat Prod

(2016)

J. Xu et al.

Bioorg Med Chem Lett

(2016)

J. Xu et al.

J Funct Foods

(2016)

R. Tanaka et al.

Phytochemistry

(1997)

S. Shen et al.

Neurochem Int

(2005)

D.S. Bredt et al.

Annu Rev Biochem

(1994)

C. Iadecola et al.

J Cereb Blood Flow Metab

(1994)

Cited by (18)

Sustainable biosynthesis of valuable diterpenes in microbes
2023, Engineering Microbiology
Diterpenes, or diterpenoids, are the most abundant and diverse subgroup of terpenoids, the largest family of secondary metabolites. Most diterpenes possess broad biological activities including anti-inflammatory, antiviral, anti-tumoral, antimicrobial, anticancer, antifungal, antidiabetic, cardiovascular protective, and phytohormone activities. As such, diterpenes have wide applications in medicine (e.g., the anticancer drug Taxol and the antibiotic pleuromutilin), agriculture (especially as phytohormones such as gibberellins), personal care (e.g., the fragrance sclareol) and food (e.g., steviol glucosides as low-calorie sweeteners) industries. Diterpenes are biosynthesized in a common route with various diterpene synthases and decoration enzymes like cytochrome P450 oxidases, glycosidases, and acyltransferases. Recent advances in DNA sequencing and synthesis, omics analysis, synthetic biology, and metabolic engineering have enabled efficient production of diterpenes in several chassis hosts like Escherichia coli, Saccharomyces cerevisiae, Yarrowia lipolytica, Rhodosporidium toruloides, and Fusarium fujikuroi. This review summarizes the recently discovered diterpenes, their related enzymes and biosynthetic pathways, particularly highlighting the microbial synthesis of high-value diterpenes directly from inexpensive carbon sources (e.g., sugars). The high titers (>4 g/L) achieved mean that some of these endeavors are reaching or close to commercialization. As such, we envisage a bright future in translating microbial synthesis of diterpenes into commercialization.
Callicarpnoids A–C, structurally intriguing ent-Clerodane diterpenoid dimers with cytotoxicity against MCF-7 and HCT-116 cell lines from Callicarpa arborea Roxb
2022, Bioorganic Chemistry
Callicarpnoids A–C (1–3), three new ent-clerodane diterpenoid dimers formed via a [4 + 2] hetero Diels-Alder cycloaddition, appeared as a third example of this type of dimers, were isolated from the stems of Callicarpa arborea Roxb.. Their structures were elucidated by comprehensive spectroscopic analysis, and the absolute configurations were confirmed by single-crystal X-ray diffraction and electronic circular dichroism (ECD) calculations, as well as DP4 + analysis. Cytotoxicity test in two cell lines indicated that compounds 2 and 3 had significant cytotoxic effect against breast cancer cell (MCF-7) and colorectal cancer cell (HCT-116) with IC₅₀ ranging from 5.2 to 7.2 μM, comparable to those of the positive control. Furthermore, the western blot analysis revealed that the protein expression levels of Bax were increased following compounds 2 and 3 treatment, whereas the expression levels of caspase 8, caspase 3, caspase 9 and Bcl₂ were decreased in a dose-dependent manner, indicating that compounds 2 and 3 may induce apoptosis via both intrinsic and extrinsic pathways in MCF-7 and HCT-116 cells.
Erinacine A and related cyathane diterpenoids: Molecular diversity and mechanisms underlying their neuroprotection and anticancer activities
2020, Pharmacological Research
The presence of a fused 5/6/7 tricyclic core characterizes the group of cyathane diterpene natural products, that include more than 170 compounds, isolated from fungi such as Cyathus africanus and Hericium erinaceus. These compounds have a common biosynthetic precursor (cyatha-3,12-diene) and can be produced bio- or hemi-synthetically, or via total syntheses. Cyathane diterpenes display a range of pharmacological properties, including anti-inflammatory (possibly through binding to the iNOS protein) and neuroprotective effects. Many cyathanes like cyahookerin C, cyathin Q and cyafranines B and G can stimulate neurite outgrowth in cells, whereas conversely a few molecules (such as scabronine M) inhibit NGF-stimulated neurite outgrowth. The main anticancer cyathanes are erinacine A and cyathins Q and R, with a capacity to trigger cancer cell death dependent on the production of reactive oxygen species (ROS). These compounds, active both in vitro and in vivo, activate different signaling pathways in tumor cells to induce apoptosis (and autophagy) and to upregulate the expression of several proteins implicated in the organization and functioning of the actin cytoskeleton. An analysis of the functional analogy between erinacine A and other natural products known to interfere with the actin network in a ROS-dependent manner (notably cucurbitacin B) further supports the idea that erinacine A functions as a perturbator of the cytoskeleton organization. Collectively, we provide an overview of the molecular diversity of cyathane diterpenes and the main mechanisms of action of the lead compounds, with the objective to encourage further research with these fungal products. The anticancer potential of erinacine A deserves further attention but it will be necessary to better characterize the implicated targets and signaling pathways.
Two new norneolignans from Callicarpa kwangtungensis
2020, Natural Product Research
Two new norneolignans, (7S,8R)-3-methoxy-3′,4,9-trihydroxy-4′,7-epoxy-8,3′-neolignane-1′-carboxylic acid (1) and (7R,8R)-3-methoxyl-4,9-dihydroxy-3′:7,4′:8-diepoxyneolignan-1′-carboxylic acid methyl ester (2) were isolated from Callicarpa kwangtungensis, together with ten known compounds, genistin (3), daidzin (4), silybin A (5), isosilybin A (6), isosilybin B (7), p-hydroxybenzaldehyde (8), syringic acid (9), lanceolatin A (10), icariside C5 (11), and (3S,6E,10R)-10-β-D-glucopyranosyloxy-3,11-dihydroxy-3,7,11-trimethyldodeca-1,6-diene (12). Compounds 1 and 2 were evaluated for their effects on the inhibition of nitric oxide (NO) production in lipopolysaccharide induced RAW264.7 cells. Compounds 1 and 2 exhibited inhibitory activity with IC₅₀ values of 31.45 ± 0.38 and 40.72 ± 0.54 μM, respectively.
Bioactive terpenoids from Euonymus verrucosus var. pauciflorus showing NO inhibitory activities
2019, Bioorganic Chemistry
Citation Excerpt :
The standard 3D structures (PDB format) of selected compounds for molecular docking were constructed by chem3D Pro 14.0 software, whose configurations were determined by their NOESY spectra and Chem3D modeling. The cubic grid box of 20 Å size (x, y, z) with a spacing of 1.000 Å and grid maps were built [38,39]. All of the other parameters were used according to default settings of AutoDock Vina.
In our continuous search for new nitric oxide (NO) inhibitory compounds as potential anti-inflammatory agents or lead compounds for inflammatory diseases, the chemical constituents of Euonymus verrucosus var. pauciflorus were investigated, leading to the isolation of eleven terpenoids including six new diterpenoids, designated as euonymupenes A–F. The structures were elucidated on the basis of NMR and ECD data analysis. Euonymupenes A, C, and F feature rare labdane-type norditerpenoid skeletons. The NO inhibitory effects were evaluated and all of the isolates were found to inhibit lipopolysaccharide (LPS)-induced NO production in murine microglial BV-2 cells. Western blotting analysis indicated that the most active compound (5) can regulate iNOS (inducible nitric oxide synthase) expression. The further molecular docking studies exhibited the affinities of bioactive compounds with iNOS.
NO inhibitory phytochemicals as potential anti-inflammatory agents from the twigs of Trigonostemon heterophyllus
2019, Bioorganic Chemistry
Studies on the relationship of nitric oxide (NO) and inflammation have revealed that compounds with NO inhibitory effects are potentially useful for inflammation and related inflammatory disorders. A phytochemical investigation to obtain new NO inhibitors resulted in the isolation of two new cleistanthane diterpenoids (1 and 2) and 11 known terpenoids (3–13) from Trigonostemon heterophyllus. The structures of these terpenoids were established by analysis of their NMR, MS, and electronic circular dichroism (ECD) data. Compounds 1 and 2 possess rare 3,4-seco-cleistanthane diterpenoid skeletons. All of the isolates were evaluated biologically for their NO inhibitory effects in lipopolysaccharide (LPS)-induced murine microglial BV-2 cells and compounds 1, 6, and 8–10 showed strong NO inhibitory effects with IC₅₀ values less than 40 μM. Using Western blotting experiments and molecular docking, the possible mechanism of NO inhibition was investigated.

View all citing articles on Scopus

View full text

Natural NO inhibitors from the leaves of Callicarpa kwangtungensis: Structures, activities, and interactions with iNOS

Abstract

Graphical abstract

Section snippets

Acknowledgments

Brain Res Rev

Mol Brain

J Ethnopharmacol

J Asian Nat Prod Res

J Asian Nat Prod Res

Phytochem Lett

Fitoterapia

Phytochem Lett

Fitoterapia

Fitoterapia

Fitoterapia

Fitoterapia

J Nat Prod

Bioorg Med Chem Lett

J Funct Foods

Phytochemistry

Neurochem Int

Annu Rev Biochem

J Cereb Blood Flow Metab