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Spirobiflavonoid stereoisomers from the endangered conifer Glyptostrobus pensilis and their protein tyrosine phosphatase 1B inhibitory activity
Abstract
Six spirobiflavonoid stereoisomers including two new ones, spiropensilisols A (1) and B (2), were isolated from a mass-limited trunk barks of Glyptostrobus pensilis, an endangered conifer endemic to China. The new structures featuring a benzofuran-containing spirolactone and their absolute configurations were determined by extensive spectroscopic methods. All the isolates showed significant inhibitory activities against the human protein tyrosine phosphatase 1B (PTP1B) enzyme, a potential therapeutic target for diabetes and obesity, with IC50 values ranging from 3.3 to 17.1 µM. A preliminary SAR analysis with assistance of the molecular modeling approach was performed for the most potent compound (i.e., 1), to understand the nature of interactions governing the binding mode of spirobiflavonids within the active site of the PTP1B enzyme.
... Glyptostrobus pensilis (D.Don) K.Koch trunk bark 1-4, 10, 11 [35] Fabaceae ...
... Following this line of thought, it turns out that if the absolute configuration of 3,2′-epi-larixinol, i.e., (2S,3R,2R,3S), is taken as true, it corresponds exactly to yuccalechin B (6), but its optical rotations differ in sign and value (+25.0 vs. −175.0, respectively), and the chemical shifts of 1 H and 13 C differ significantly, e.g., for H-2/C-2, C-4, and H-2/C-2′ (δH/δC 5. 79 [35], which describes spiropensilisol A and B (10,11). The relative configurations of these compounds were determined using 3 JHH coupling constants, 13 C NMR anisotropic shielding effects, and NOEs. ...
... However, the authors did not attempt to determine the AbsC. (32)(33)(34)(35) Edgechrins (Table 4) are condensed daphnodorin dimers-daphnodorin C-(4′β→6‴)daphnodorin A, daphnodorin C-(4′β→6‴)-daphnodorin B, daphnodorin A-(4‴β→8)daphnodorin C (comp. 32-34, respectively), and their structures were elucidated by the 1 H-, 13 C-and DEPT, COSY, and NOESY NMR spectra [58]. ...
Based on the literature data from 1973 to 2022, this work summarizes reports on spiro-flavonoids with a spiro-carbon at the center of their structure and how this affects their isolation methods, stereochemistry, and biological activity. The review collects 65 unique structures, including spiro-biflavonoids, spiro-triflavonoids, spiro-tetraflavonoids, spiro-flavostilbenoids, and scillascillin-type homoisoflavonoids. Scillascillin-type homoisoflavonoids comprise spiro[bicyclo[4.2.0]octane-7,3′-chromane]-1(6),2,4-trien-4′-one, while the other spiro-flavonoids contain either 2H,2′H-3,3′-spirobi[benzofuran]-2-one or 2′H,3H-2,3′-spirobi[benzofuran]-3-one in the core of their structures. Spiro-flavonoids have been described in more than 40 species of eight families, including Asparagaceae, Cistaceae, Cupressaceae, Fabaceae, Pentaphylacaceae, Pinaceae, Thymelaeaceae, and Vitaceae. The possible biosynthetic pathways for each group of spiro-flavonoids are summarized in detail. Anti-inflammatory and anticancer activities are the most important biological activities of spiro-flavonoids, both in vitro and in vivo. Our work identifies the most promising natural sources, the existing challenges in assigning the stereochemistry of these compounds, and future research perspectives.
... The IR spectrum shows the main functional group information, including hydroxyl groups (a broad peak around 3204 cm −1 ), carbonyl groups (1671 cm −1 ), the benzene ring (1632 and 1530 cm −1 ), and γ-lactone (1809 cm −1 ) ( Figure S4). 46 Comparing the 1 H and 13 C NMR data of 1 and ECG, we can infer that 1 has an ECG skeleton (Table 1). In general, an odd molecular weight indicates a nitrogen atom in the molecule. ...
... Although spiro-flavoalkaloids were first found from tea here, spirocatechin dimers have been reported in different conifer resources before. 46 46 Our present study shows that spiro-flavoalkaloids have αglucosidase inhibition activity, which also suggests that they could be developed as potential antidiabetic agents. However, the low content of spiro-flavoalkaloids in tea suggests that other approaches such as the chemical synthesis of spiroflavoalkaloids deserve further investigation to develop them as potential therapeutic agents. ...
... Although spiro-flavoalkaloids were first found from tea here, spirocatechin dimers have been reported in different conifer resources before. 46 46 Our present study shows that spiro-flavoalkaloids have αglucosidase inhibition activity, which also suggests that they could be developed as potential antidiabetic agents. However, the low content of spiro-flavoalkaloids in tea suggests that other approaches such as the chemical synthesis of spiroflavoalkaloids deserve further investigation to develop them as potential therapeutic agents. ...
... More recently, it has been reported that five abietane diterpenes isolated from the branches of G. pensilis are potential candidates for the prevention and treatment of SARS-CoV-2 [6]. Six spirobiflavonoid stereoisomers including two new ones, spiropensilisols A and B, were isolated from trunk bark [7]. The composition of leaf waxes has been investigated [8]. ...
Glyptostrobus pensilis (Staunton ex D. Don) K. Koch is a critically endangered species, native to southeastern China and also very locally found in Dak Lak Province, Vietnam. Essential oil isolated from leaves is a monoterpene-rich oil containing mainly limonene (33.3%), α-pinene (23.4%) and bornyl acetate (9.2%). The composition of G. pensilis wood oil is rather complex and the identification of individual components needed fractionation over column chromatography. The main components, identified by GC(RI), GC-MS and 13C NMR, were cedrol (29.3%), occidentalol (6.6%) and occidentalol isomer (5.9%).
... The phytochemical components of G. pensilis include abietane-type diterpenes and flavonoids. Especially among these isolated compounds, abietane-type diterpene glypensin A shows strong cytotoxic activities on human chronic myeloid leukemia cell line K562 and biflavonoid spiropensilisol A significantly exhibits the PTP1B inhibitory effect (Zhang et al. 2010;Xiong et al. 2020). ...
Using various chromatographic methods, five abietane-type diterpenes were isolated from the branches of Glyptostrobus pensilis for the first time. The chemical structures of the isolates were identified by modern spectroscopic techniques, including ¹H and ¹³C nuclear magnetic resonance spectroscopy and by comparison with the literature. In addition, the binding potential of the isolated compounds to replicase protein, SARS-CoV-2 main protease and papain-like protease, were examined using molecular docking studies. In silico results suggested that G. pensilis as well as abietane-types diterpenes are potential candidates for the prevention and treatment of SARS-CoV-2.
Glyptostrobus pensilis is an endangered species belonging to the Cupressaceae family. The comprehensive examination of soil characteristics and rhizosphere microbial communities is vital for conservation efforts, as it provides insights into the necessary environmental conditions for safeguarding and ensuring the viability of rare and endangered species. In this study, the diversity and composition of bacterial and fungal communities were compared in the roots and rhizosphere soils of cultivated and wild G. pensilis in Guangxi, China. The results revealed that, at the phylum level, the rhizosphere of cultivated G. pensilis was significantly enriched with Verrucomicrobiota, Acidobacteriota, Glomeromycota, and Chloroflexi, while wild G. pensilis was significantly enriched with Planctomycetota, Basidiomycota, and Ascomycota. Symbiotic network analysis indicated that the bacterial network in the cultivated G. pensilis rhizosphere had higher edge values, average degree, clustering coefficient, and network density, while the fungal network in the wild G. pensilis rhizosphere had higher node values, edge values, average degree, and clustering coefficient. Moreover, functional prediction results suggested that bacteria in cultivated G. pensilis showed higher metabolic activity, with fungi primarily acted as saprotrophs and symbionts. In contrast, bacteria in wild G. pensilis displayed lower metabolic activity, with fungi predominantly functioning as saprotrophs. The analysis linking rhizospheric microbial diversity to soil environmental factors showed a closer association for the wild G. pensilis microbial community, suggesting a stronger influence of soil environmental factors. The Random Forest (RF) highlighted that the total phosphorus and total potassium levels were key influencing factors for rhizospheric microbes in cultivated G. pensilis, while available potassium levels were crucial for those in wild G. pensilis. These differences underscore the significant strategies for G. pensilis in adapting to different habitats, which may be intricately linked to land management practices and soil environmental factors. Among these, phosphorus and potassium are significantly associated with the rhizosphere microorganisms of G. pensilis. Therefore, continuous monitoring of nutrient availability and regular supplementation of phosphorus and potassium fertilizers in the rhizosphere are recommended during the cultivation and ex-situ conservation of G. pensilis.
Six undescribed naturally occurring abietane-O-abietane dimers (squamabietenols A-F) together with one 3,4-seco-totarane-type, a pimarane-type, and 17 related known mono-/dimeric diterpenoids were isolated and characterized from the needles and twigs of the ornamental conifer Juniperus squamata. The undescribed structures and their absolute configurations were established by extensive spectroscopic methods, GIAO NMR calculations with DP4+ probability analyses, and ECD calculations. Squamabietenols A and B showed significant inhibitory effects against ATP-citrate lyase (ACL, a novel drug target for hyperlipidemia and other metabolic disorders), with IC50 values of 8.82 and 4.49 μM, respectively. A molecular docking study corroborated the findings by highlighting the interactions between the bioactive compounds and the ACL enzyme (binding affinities: -7.1 to -9.0 kcal/mol). The unique abietane-O-abietane dimeric diterpenoids are quite rare in the vegetable kingdom, and they are of chemotaxonomic significance for the Cupressaceae family.
A joint phytochemical investigation on the MeOH extracts of the twigs and needles of two endangered Pinaceae plants endemic to the Chinese Qinling Mountains, Picea neoveitchii (an evergreen spruce) and Larix potaninii var. chinensis (a deciduous larch), led to the isolation and characterization of 34 and 24 structurally diverse terpenoids, respectively. Among them, seven are previously undescribed, including a picane-type [i.e., 14(13 → 12)abeo-12αH-serratane] (neoveitchin A) and a serratane-type (neoveitchin B) triterpenoids, and an abietane-type (neoveitchin C) as well as four labdane-type (potalarxins A–D) diterpenoids. Their structures and absolute configurations were established by extensive spectroscopic methods and/or X-ray diffraction analyses. All isolates were evaluated for their inhibitory activities against the human protein tyrosine phosphatase 1B (PTP1B). Serrat-14-en-3α,21β-diol, betulinic acid, 3β-hydroxy-11-ursen-13(28)-olide, ursolic acid, and oleanolic acid were found to have considerable inhibitory effects against PTP1B, with IC50 values ranging from 1.1 to 18.1 μM. The interactions of the bioactive triterpenoids with PTP1B were thereafter performed by employing molecular docking studies. In addition, 7-oxo-dehydroabietic acid (an abietane-type diterpenoid) and mangiferonic acid (a cycloartane-type triterpenoid) inhibited acetyl-coenzyme A carboxylase 1 (ACC1), with IC50 values of 3.4 and 6.6 μM, respectively.
A preliminary phytochemical investigation on the MeOH extract of the twigs and needles of Pseudotsuga gaussenii (a ‘vulnerable’ plant endemic to China) led to the isolation and characterization of 25 structurally diverse mono- and dimeric triterpenoids. 19 of them are previously undescribed, including eight cucurbitane-type triterpenoids (gaussenols A–H, 1–8, resp.), one serratene-type triterpene (gaussenol I, 9), and 10 triterpenic dimers (gaussenols J–S, 10–19, resp.). Their chemical structures were elucidated by means of spectroscopic data, some chemical transformations, the modified Mosher’s method, and single crystal X-ray diffraction analyses. Compound 9 is the first 13R diastereoisomeric serratene-type triterpenoid derivative from nature. The unprecedented dimeric triterpenoids are constructed either through ester linkage (10–18) or via ether bond (19) among the side chains of same or different types of triterpenoid skeletons (e.g., cucurbitane-type, lanostane-type, and/or cycloartane-type). Compounds 9, 15, 21, and 25 exhibited inhibitory effects against the human protein tyrosine phosphatase 1 B (PTP1B, a potential drug target for the treatment of type-II diabetes and obesity), with IC50 values of 3.1, 8.6, 9.0, and 5.6 μM, respectively. The interactions of the bioactive compounds with PTP1B were thereafter performed by employing molecular docking studies, with binding affinities ranging from −6.9 to −7.3 kcal/mol. The above findings could reveal the important role of protecting plant species diversity in support of chemical diversity and potential sources of new therapeutics.
A phytochemical investigation on the MeOH extract of the leaves and twigs of the endangered conifer Torreya jackii Chun led to the isolation and characterization of 21 structurally diverse diterpenoids. Among them, six are previously undescribed, including four abietane-type (torreyins A−D, resp.) and two labdane-type diterpenoids (torreyins E and F). Their structures and absolute configurations were determined by a combination of spectroscopic methods, calculated/experimental electronic circular dichroism (ECD) data, and single-crystal X-ray diffraction analyses. In particular, torreyins A−C are rare 11,12-seco-abietane type diterpenoids possessing a dilactone moiety, and their biosynthetic pathway starting from a co-occurring abietane derivative (i.e., cyrtophyllone B) was briefly proposed. Among the isolates, 7-oxo-dehydroabietic acid and 15-methoxy-7,13-abietadien-18-oic acid showed considerable inhibitory effects against acetyl-coenzyme A carboxylase 1 (ACC1) and protein tyrosine phosphatase 1 B (PTP1B), with IC50 values of 3.1 and 6.8 μM, respectively.
Liver plays a pivotal role in maintaining blood glucose levels through complex processes which involve the disposal, storage, and endogenous production of this carbohydrate. Insulin is the hormone responsible for regulating hepatic glucose production and glucose storage as glycogen, thus abnormalities in its function lead to hyperglycemia in obese or diabetic patients because of higher production rates and lower capacity to store glucose. In this context, two different but complementary therapeutic approaches can be highlighted to avoid the hyperglycemia generated by the hepatic insulin resistance: 1) enhancing insulin function by inhibiting the protein tyrosine phosphatase 1B, one of the main enzymes that disrupt the insulin signal, and 2) direct regulation of key enzymes involved in hepatic glucose production and glycogen synthesis/breakdown. It is recognized that medicinal plants are a valuable source of molecules with special properties and a wide range of scaffolds that can improve hepatic glucose metabolism. Some molecules, especially phenolic compounds and terpenoids, exhibit a powerful inhibitory capacity on protein tyrosine phosphatase 1B and decrease the expression or activity of the key enzymes involved in the gluconeogenic pathway, such as phosphoenolpyruvate carboxykinase or glucose 6-phosphatase. This review shed light on the progress made in the past 7 years in medicinal plants capable of improving hepatic glucose homeostasis through the two proposed approaches. We suggest that Coreopsis tinctoria, Lithocarpus polystachyus, and Panax ginseng can be good candidates for developing herbal medicines or phytomedicines that target inhibition of hepatic glucose output as they can modulate the activity of PTP-1B, the expression of gluconeogenic enzymes, and the glycogen content.
Malvidin-3-O-galactoside (M3G) is known to lower blood sugar levels and enhance glucose uptake; however, the underlying mechanism remains unclear. Here, we aimed to elucidate the mechanism underlying the inhibitory effects of M3G on protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase using enzyme kinetic analysis, circular dichroism spectroscopy, fluorescence quenching, and molecular docking. The results showed that M3G strongly inhibited PTP1B and α-glucosidase through reversible mixed inhibition and reversible non-competitive inhibition, respectively. M3G binding altered the secondary structures of PTP1B and α-glucosidase and regulated the microenvironment of specific amino acid residues. Additionally, different M3G concentrations quenched the intrinsic fluorescence of PTP1B/α-glucosidase. Thermodynamic studies revealed that M3G binding to PTP1B and α-glucosidase was spontaneous, whereas molecular docking analysis provided information on the interaction between M3G and PTP1B/α-glucosidase amino acid residues. These findings clarified that M3G effectively inhibited PTP1B/α-glucosidase and highlighted its role as a functional food ingredient for regulating type 2 diabetes.
Protein tyrosine phosphatase-1B (PTP1B) is a novel and indispensable drug target for the treatment of type 2 diabetes mellitus (T2DM). Procyanidins are flavonoids that exhibit a significant hypoglycemic function. However, the potential inhibitory effects of procyanidins on PTP1B are unclear. In this study, the interaction mechanisms of PTP1B with procyanidin B1 (PB1) and procyanidin B2 (PB2) were investigated through kinetics analysis, UV-visible spectroscopy, fluorescence spectroscopy, circular dichroism spectroscopy and molecular docking. The results showed that PB1 and PB2 could inhibit the activity of PTP1B in a mixed inhibition mode, which was one of the reversible inhibition types. Multi-spectral analysis showed that PB1/PB2 formed complexes with PTP1B, which effectively quenched the intrinsic fluorescence of PTP1B based on the static mechanism. The values of the binding constants were KS(PTP1B-PB1)=4.06×10² L·mol⁻¹ and KS(PTP1B-PB2)=2.53×10² L·mol⁻¹, indicating that the binding affinity of PTP1B to PB1 was higher than that for PB2. PB1 and PB2 both changed the secondary structure of the enzyme, thereby decreasing the PTP1B activity. Thermodynamic investigations revealed that the binding of procyanidin B1 and B2 to PTP1B was spontaneous in both cases, and highlighted the key role of hydrophobic interactions. Molecular docking analysis provided further information regarding the interactions between PB1 or PB2 and the amino acid residues of PTP1B. Moreover, PB1 and PB2 were found to down-regulate the expression level of PTP1B in insulin-resistant HepG2 cells. These findings are the first to elucidate the inhibitory effects of PB1 and PB2 on PTP1B, and highlight the role of procyanidins as dietary supplements in regulating T2DM.
Phytochemical investigation of the ethanolic extract of Anneslea fragrans twigs resulted the isolation of two new highly-oxygenated and sterically hindered spiro-biflavanoids, named fragranols B and C (1 and 2), together with a known compound 3-epilarixinol (3). The structural elucidation was achieved by HRFABMS, NMR spectroscopic analysis, and quantum ECD calculations. A plausible biogenetic pathway of the isolated compounds is also proposed.
A phytochemical investigation of the MeOH extract of the leaves and twigs of Amentotaxus argotaenia, a relict vulnerable coniferous species endemic to China, led to the isolation and characterization of 35 diterpenoids/norditerpenoids. Twenty of these are new, including 11 ent-kaurane-type (amentotaxins C-M, 1-11, respectively), three icetexane-type [= 9(10→20)abeo-abietane-type (amentotaxins N-P, 12-14, respectively)], four ent-labdane-type (amentotaxins Q-T, 15-18, respectively), and two isopimarane-type [amentotaxins U (19) and V (20)] compounds. Their structures were elucidated on the basis of spectroscopic data, single-crystal X-ray diffraction, the modified Mosher's method, and electronic circular dichroism data analyses. Compounds 1-9 are rare 18-nor-ent-kaurane-type diterpenoids featuring a 4β,19-epoxy ring. All the isolates were evaluated for their cytotoxic effects against a small panel of cultured human cancer cell lines (HeLa, A-549, MDA-MB-231, SKOV3, Huh-7, and HCT-116), and some of them exhibited cytotoxicities with IC50 values ranging from 1.5 to 10.0 μM.
Fourteen previously undescribed naturally occurring C-23 carboxylated triterpenoids, stewartiacids A–N (1–14), were isolated and characterized from the twigs and leaves of the ornamental and medicinal plant Stewartia sinensis (Chinese Stewartia), a ‘vulnerable’ species endemic to China. The new structures were elucidated on the basis of spectroscopic data, single crystal X-ray diffraction, and electronic circular dichroism (ECD) analyses. Stewartiacids A (1) and B (2) are isoursenol derivatives. Stewartiacid C (3) is a 12-oxo-γ-amyrin analogue. Both isoursenol and γ-amyrin derivatives are quite rare in nature. Stewartiacids D (4) and E (5) are 13,27-cycloursane-type compounds. Stewartiacids K (11) and L (12) are ursane-type triterpene and phenylpropanol adducts built through a 1,4-dioxane ring, which are also seldom reported in the literature. The rest are common C-23 carboxylated ursane-type (6–10) and oleanane-type (13, 14) pentacyclic triterpenoids. Stewartiacids G (7), K (11), and L (12) showed moderate inhibitory effects against ATP-citrate lyase (ACL), with IC50 values of 12.5, 2.8, and 10.6 μM, respectively. Stewartiacid K (11) also exhibited moderate inhibition (IC50: 16.8 μM) of NF-κB.
Significance
In this report we describe a group of highly complex glycosides active against hepatitis C virus and a separate group of natural products active against established targets for the control of diabetes mellitus. These complex metabolites were found in the rare plant Diplostephium rhododendroides Hieron. from the mountains of Ecuador. This report illustrates the human health significance of protecting rare and endangered plants for the control of new and emerging diseases. The extinction of this particular plant would have taken with it promising opportunities to develop unique treatments for the control of two modern-day disease challenges. The genus Diplostephium is represented by several plant species with a history of use in traditional medicine in Central and South America.
Many drugs are nature derived. Low drug productivity has renewed interest in natural products as drug-discovery sources. Nature-derived drugs are composed of dozens of molecular scaffolds generated by specific secondary-metabolite gene clusters in selected species. It can be hypothesized that drug-like structures probably are distributed in selective groups of species. We compared the species origins of 939 approved and 369 clinical-trial drugs with those of 119 preclinical drugs and 19,721 bioactive natural products. In contrast to the scattered distribution of bioactive natural products, these drugs are clustered into 144 of the 6,763 known species families in nature, with 80% of the approved drugs and 67% of the clinical-trial drugs concentrated in 17 and 30 drug-prolific families, respectively. Four lines of evidence from historical drug data, 13,548 marine natural products, 767 medicinal plants, and 19,721 bioactive natural products suggest that drugs are derived mostly from preexisting drug-productive families. Drug-productive clusters expand slowly by conventional technologies. The lack of drugs outside drug-productive families is not necessarily the result of under-exploration or late exploration by conventional technologies. New technologies that explore cryptic gene clusters, pathways, interspecies crosstalk, and high-throughput fermentation enable the discovery of novel natural products. The potential impact of these technologies on drug productivity and on the distribution patterns of drug-productive families is yet to be revealed.
In 2002, world leaders committed, through the Convention on Biological Diversity, to achieve a significant reduction in the
rate of biodiversity loss by 2010. We compiled 31 indicators to report on progress toward this target. Most indicators of
the state of biodiversity (covering species’ population trends, extinction risk, habitat extent and condition, and community
composition) showed declines, with no significant recent reductions in rate, whereas indicators of pressures on biodiversity
(including resource consumption, invasive alien species, nitrogen pollution, overexploitation, and climate change impacts)
showed increases. Despite some local successes and increasing responses (including extent and biodiversity coverage of protected
areas, sustainable forest management, policy responses to invasive alien species, and biodiversity-related aid), the rate
of biodiversity loss does not appear to be slowing.
Phytochemical investigation of the aerial parts of Abies chensiensis afforded two new (compounds 2 and 3) and 27 known compounds, including the related compound larixinol ( 1). The structures of spirobiflavonoids 1- 3 were established using 1D and 2D NMR spectroscopic techniques. In addition, the structure of larixinol ( 1) was confirmed by X-ray crystallographic analysis. Compounds 1- 3 were evaluated for inhibitory activities against LPS-induced NO production in macrophages. Larixinol ( 1) showed moderate effects, with an IC(50) value of 60.0 microg/mL. In addition, it did not show any cytotoxicity on RAW 264.7 macrophages at 100 microg/mL.
A phytochemical investigation on the MeOH extract of the twigs and needles of the endangered plant Picea brachytyla led to the isolation and characterization of thirty-eight structurally diverse terpenoids. Seven of these molecules are previously undescribed, including three abietane-type (brachytylins A-C) and one labdane-type (brachytylin D) diterpenoids, an unseparated C-24 epimeric mixture of cycloartane-type triterpenoids (brachytylins E/F, ratio: 1:1), and a rare rearranged 12(1 → 6)-abeo-megastigmane glycoside (brachytylins G). Their structures and absolute configurations were determined by extensive spectroscopic (e.g., detailed 2D NMR and ECD) methods and/or X-ray diffraction analyses. All the isolates were evaluated for their inhibitory activities against the adenosine triphosphate (ATP)-citrate lyase (ACL) and the Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2). Among them, abiesadine J showed inhibitory effect against ACL, displaying an IC50 value of 17 μM. 3S,23R-Dihydroxycycloart-24-en-26-oic acid exhibited inhibitory effect on SHP2, with an IC50 value of 19 μM. Meanwhile, 3R*,23S*-dihydroxycycloart-24-en-26-oic acid was found to have inhibitory effects against both ACL and SHP2, with IC50 values of 16 and 12 μM, respectively.
A preliminary phytochemical investigation on the MeOH extract of the leaves and twigs of the endangered ornamental plant Michelia shiluensis led to the isolation of 16 sesquiterpenoids. The isolated compounds comprised germacrane- (1–4, 13, 14), guaiane- (5–9, 15), amorphane- (10), and eudesmane-type (11, 12, 16) sesquiterpenoids. The new structures (1–12) were elucidated by spectroscopic and computational methods, and their absolute configurations (except for 9) were assigned by single-crystal X-ray diffraction crystallographic data and/or electronic circular dichroism spectra. Shiluolides (A–D, 1–4) are unprecedented C16 or C17 homogermacranolides, and their putative biosynthetic pathways are briefly discussed. Shiluone D (8) is a rare 1,10-seco-guaiane sesquiterpenoid featuring a new ether-containing spirocyclic ring, whereas shiluone E (9) represents the first example of a 1,5–4,5-di-seco-guaiane with a rare 5,11-lactone moiety. Shiluone F (10) is the first amorphane-type sesquiterpenoid possessing an oxetane ring bridging C-1 and C-7. Bioassay evaluations indicated that lipiferolide (13) showed noteworthy cytotoxicities toward human cancer cell lines MCF-7 and A-549, with IC50 values of 1.5 and 7.3 μM, respectively. Shiluone D (8) exerted inhibition against protein tyrosine phosphatase 1B (IC50: 46.3 μM).
Seven new naturally occurring barrigenol-like compounds, camellianols A–G (1–7), and 10 known triterpenoids were isolated from the twigs and leaves of the cultivated endangered ornamental plant Camellia crapnelliana. According to the ECD octant rule for saturated cyclohexanones, the absolute configurations of camellianols D (4) and E (5) were defined. The backbones of the remaining new isolates are assumed to have the same absolute configuration as compounds 4, 5, and harpullone (12). Compounds 2, 3, 9, 10, 13, and 16 exhibited inhibitory effects on the protein tyrosine phosphatase 1B (PTP1B) enzyme, with IC50 values less than 10 μM.
Pinus kwangtungensis is an endangered pine species native to China. In the present study, 15 diterpenoids including three new labdane-type analogs were isolated and characterized during a pioneer phytochemical investigation on a mass-limited sample of the needles and twigs of this plant, which is growing in a Cantonese garden. The new structures, (4S,5R,9S,10R)-6-oxo-labd-7,13-dien-16,15- olid-19-oic acid (1), 15(S)-n-butoxypinusolidic acid (2), and β-d-glucopyranosyl- (4S,5R,9S,10R)-labda-8(17),13-dien-15,16-olid-19-oate (3), were established by extensive spectroscopic methods and some chemical transformations. Among the isolates, lambertianic acid (10) and cassipourol (15) showed inhibitory activities against human protein tyrosine phosphatase 1 B (PTP1B), a target for the treatment of type-II diabetes and obesity, with IC50 values of 25.5 and 11.2 μM, respectively.
Ten diterpenoids including three new abietanes (1-3) were isolated from the twigs and needles of Podocarpus imbricatus, an endangered conifer growing in a Cantonese garden. The new structures were established by means of spectroscopic methods. Among the isolates, 3β-hydroxy-abieta-8,11,13-trien-7-one (5), decandrin G (6), and 7,15-pimaradien-18-oic acid (8) showed significant anti-neuroinflammatory activities by inhibiting the overproduction of nitric oxide (NO) in lipopolysaccharide (LPS)-stimulated murine BV-2 microglial cells, with IC50 values of 3.7, 11.1, and 4.5 μM, respectively.
Rare and endangered plants have proven to be better sources for drug discovery than other botanic sources. Pinus dabeshanensis is an endangered plant listed in the China Plant Red Data Book, and has never been phytochemically investigated. In the present study, 11 new (dabeshanensins A-K, 1-11, resp.) and 28 related known naturally occurring diterpenoids were isolated from the shed trunk bark of this plant. The new structures were established by extensive spectroscopic methods and molecular modeling. Among them, dabeshanensin C (3) has an unprecedented bicyclo[3.3.1]nonane ring system (rings B and C) by oxidative cleavage of the C-6/C-7 bond followed by the formation of a new C-C bond between C-6 and C-12. The plausible biosynthetic pathway to 3 is briefly discussed. Dabeshanensins A (1) and J (10), 12-hydroxydehydroabietic acid (33), abieta-8,11,13,15-tetraen-18-oic acid (35), and 15-hydroxy-7-oxo-8,11,13-abietatrien-18-oic acid (37) showed significant inhibitory effects against the human protein tyrosine phosphatase 1B (PTP1B) enzyme, a key target for the treatment of type-II diabetes and obesity, with IC50 values ranging from 5.4 to 50.9 μM.
Three new phenolic compounds, yuccalides A-C (1-3), were isolated from the roots of Yucca gloriosa L., along with four known compounds (4-7). The structures of the new compounds were established by extensive NMR spectroscopic analyses. Inducible nitric oxide synthase (iNOS) mRNA levels induced by lipopolysaccharide (LPS) in mouse macrophage-like RAW 264.7 cells were effectively suppressed by compounds 2, 4, and 6, all of which had the (2R*, 3R*)-configuration. IL-1β and IL-6 mRNA levels induced by LPS were significantly attenuated by compounds 4, 5, and 6, but not by 2.
Two rare rearranged cuparane-type sesquiterpenoid C-10 epimers [beshanzuenones A (1) and B (2)] and two bisabolane-type sesquiterpenoid spirolactones [beshanzuenones C (3) and D (4)] featuring an unusual [6/6/5]-fused tricyclic ring system were isolated from the shed trunk barks of Abies beshanzuensis, one of the critically endangered plant species in the world. The structures of these four new enone-containing sesquiterpenoids were determined by spectroscopic analyses and single-crystal X-ray diffraction or electronic circular dichroism (ECD) calculations. Compounds 1 and 2 showed considerable activity against the H3N2 virus, whereas 3 and 4 exhibited significant inhibition on PTP1B.
Three unprecedented phloroglucinol-diterpene adducts, chlorabietols A-C (1-3), were isolated from the roots of the rare Chloranthaceae plant Chloranthus oldhamii. They represent a new class of compounds, featuring an abietane-type diterpenoid coupled with different alkenyl phloroglucinol units by forming a 2,3-dihydrofuran ring. Their structures were elucidated by detailed spectroscopic analysis, molecular modelling studies, and electronic circular dichroism calculations. Compounds 1-3 showed inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), with IC50 values of 12.6, 5.3 and 4.9 μM, respectively.
The unique spiro-biflavonoid structure of larixinol (1a) is described and a suggested pathway of biogenesis from dihydrokaempferol is proposed.
Eight spiro-biflavonoids named abiesinols A–H, along with three neolignans, quercetin, and protocatechuic acid were isolated from the MeOH extract of the bark of Abies sachalinensis. The structures of these phenolic compounds were characterized by spectroscopic methods including NMR and MS. The absolute configurations of the abiesinols were determined by Mosher's method, CD, and NOESY data.
This review summarizes the results of research aimed at isolation and structural characterization of flavonoid compounds belonging
to a new class, namely, spirobiflavonoids, from different plant sources.
Keywordsspiroflavonoids–structure–biosynthesis–biological activity–distribution–Larix sibirica Ledeb. Bark–Larix gmelinii (Rupr.) Rupr. Bark
Cancer chemoprevention, the prevention of cancer by ingestion of chemical agents that reduce the risk of carcinogenesis, is one of the potent ways to reduce morbidity and mortality. We have been searching for cancer chemopreventive agents from the leaves and barks of coniferous trees that have been treated as waste in the forestry industry. We have previously reported the isolation of spiro-biflavonoids, named as abiesinols, and a neolignan from the MeOH extract of the bark of Abies sachalinensis. These compounds were tested for their inhibitory effects on the activation of (±)-(E)-methyl-2-[(E)-hydroxyimino]-5-nitro-6-methoxyhex-3-enamide (NOR 1), a nitric oxide (NO) donor, as a primary screening test for anti-tumor initiators. All compounds tested exhibited potent inhibitory effects on NOR 1 activation. Furthermore, abiesinol A, bearing a spiro-biflavonoid skeleton, showed remarkable anti-tumor-initiating activity in the in vivo two-stage mouse skin carcinogenesis test using peroxynitrite (ONOO(-); PN) as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter.
A new abietane diterpene, glypensin A (1) and four known compounds, 12-acetoxy-ent-labda-8(17), 13E-dien-15-oic acid (2), quercetin 3-O-α-L-arabinofuranoside (3), quercetin 3-O-β-D-galactopyranoside (4), β-sitosterol (5) were isolated from the branches and leaves of Glyptostrobus pensilis (Staut.) Koch. Their structures were determined by MS, 1D- and 2D-NMR means. Compound 1 showed cytotoxicity on human chronic myeloid leukemia cell line K562 (IC(50) = 21.2μM).
Increased incidence of type 2 diabetes mellitus and obesity has elevated the medical need for new agents to treat these disease states. Resistance to the hormones insulin and leptin are hallmarks of both type 2 diabetes and obesity. Drugs that can ameliorate this resistance should be effective in treating type 2 diabetes and possibly obesity. Protein tyrosine phosphatase 1B (PTP1B) is thought to function as a negative regulator of insulin and leptin signal transduction. This article reviews PTP1B as a novel target for type 2 diabetes, and looks at the challenges in developing small-molecule inhibitors of this phosphatase.
Two new phenolic constituents with unusual spirostructures, named yuccaols D (1) and E (2), were isolated from the MeOH extract of Yucca schidigera bark. Their structures were established by spectroscopic (ESIMS and NMR) analysis. The new yuccaols D and E, along with resveratrol (3), trans-3,3',5,5'-tetrahydroxy-4'-methoxystilbene (4), yuccaols A-C (5-7), yuccaone A (8), larixinol (9), the MeOH extract of Yucca schidigera bark, and the phenolic portion of this extract, were assayed for antioxidant activity by measuring the free radical scavenging effects using two different assays, namely, the Trolox Equivalent Antioxidant Capacity (TEAC) assay and the coupled oxidation of beta-carotene and linoleic acid (autoxidation assay). The significant activities exhibited by the phenolic fraction and its constituents in both tests show the potential use of Y. schidigera as a source of antioxidant principles.
Structurally diverse diterpenoids and sesquiterpenoids from the vulnerable conifer Pseudotsuga sinensis
- Huang
Glyptostrobus pensilis. The IUCN Red List of Threatened Species
- P Thomas
- Y Yang
- A Farjon
- D Nguyen
- W Liao
Flavonoids from the leavers of Glyptostrobus pensilis
- Xiang