Four New Kaurane Diterpenoids from the Chinese Liverwort Jungermannia comata Nees

In our continuing program to find new bioactive compounds from the Chinese liverworts, four new kaurane‐type diterpenoids, (6β)‐kaur‐16‐ene‐6,9‐diol ( 1 ), (6β,12β)‐kaur‐16‐ene‐6,9,12‐triol ( 2 ), (6β)‐kaur‐16‐ene‐5,6,9‐triol ( 3 ), and kaur‐16‐ene‐9,19‐diol ( 4 ), have been isolated from the Chinese liverwort Jungermannia comata Nees . Five known kaurane‐type diterpenoids ( 5  –  9 ) and four known trachylobane‐type diterpenoids ( 10  –  13 ) were also obtained. The structures of the new compounds were established unequivocally on the basis of spectroscopic data. The absolute configuration of compound 1 was established by comparing experimental and calculated electronic circular dichroism spectra.     

New Bioactive Macrocyclic Diterpenoids from Euphorbia helioscopia

Three new macrocyclic diterpenoids, euphoscopoids A – C ( 1 – 3 ), including two new jatrophanes and a new lathyrane, were isolated from the whole plant of Euphorbia helioscopia. Their structures were elucidated by spectroscopic methods. Antifeedant and cytotoxic activities of these isolates were evaluated. All compounds showed significant antifeedant activity against a generalist plant‐feeding insect, Helicoverpa armigera, with EC₅₀ values ranging from 2.05 to 4.34 μg/cm². In addition, compound 2 showed moderate cytotoxicity against tumor cell lines NCI‐H1975, HepG2, and MCF‐2, while compounds 1 and 3 were not active at 80 μm . The results suggested not only the defensive function of macrocyclic diterpenoids in E. helioscopia against insect herbivores, but also their potential applications as new natural insect antifeedants.     

Halogenated Briarane Diterpenes with Acetyl Migration from the Gorgonian Coral Junceella fragilis

Chemical examination of the gorgonian coral Junceella fragilis resulted in the isolation of four pairs of acetyl isomers belonging to briarane diterpenoids, including five new compounds. Their structures were determined on the basis of extensive spectroscopic (IR, MS, NMR, and single‐crystal X‐ray diffraction) analysis in association with the chemical conversion. Each pair of isomers featured by dynamical interconversion through as acetyl migration in 1,2‐diol, which was postulated to be generated under the formation of a cyclic orthoacetate intermediate. All compounds exerted the inhibitory activities against the nitric oxide production in RAW264.7 macrophage cells.     

Diterpenoids from the Whole Plants of Ajuga nipponensis and Their Inhibition of RANKL-Induced Osteoclastogenesis

Two new diterpenoids, ajudecunoid A ( 1 ) and ajudecunoid B ( 14 ), along with thirteen known diterpenoids, were isolated from the whole plants of Ajuga nipponensis Makino. Their structures were elucidated by the extensive spectroscopic analysis (UV, IR, MS, and NMR). The absolute configurations of ajudecunoid A ( 1 ) and ajudecunoid B ( 14 ) were defined through analysis of X-ray crystallography. Fifteen compounds were evaluated for inhibition of the formation of osteoclasts in bone marrow-derived macrophages (BMM) cells. Two neo-clerodane diterpenoids ajuganipponin B ( 5 ) and (12S)-6α,19-diacetoxy-18-chloro-4α-hydroxy-12-tigloyloxy-neo-clerod-13-en-15,16-olide ( 12 ) showed significant inhibition of osteoclastogenesis with IC₅₀ values of 0.88 and 0.79 μM, respectively. Here we firstly reported diterpenoids with anti-osteoclastogenesis activity from A. nipponensis.     

Bioactive Dimeric Diterpenoids from Taiwania cryptomerioides (Hayata) and Their Biological Activities

Taiwania cryptomerioides Hayata is an endangered relict plant belonging to Taxodiaceae, and it is also an endemic plant to China. The decay-resistant of Taiwania timber can provide highly quality wood for building and furniture. Plenty of regenerative of leaves of T. cryptomerioides also has been used as a resource for the discovery of new dimeric diterpenoids. In a search for structurally diverse dimeric diterpenoids and potent bioactive isolates, ten new heterodimeric diterpenoids, taiwaniadducts K−T ( 1 – 4 , 6 , 8 – 11 , and 14 ), along with five known ones ( 5 , 7 , 12 , 13 , and 15 ), were isolated from the leaves of T. cryptomerioides. These new compounds were defined by comprehensive spectroscopic analyses, putative biosynthetic pathways, and the values of optical. Biologically, anti-multidrug resistance (MDR) activities of compounds were evaluated. Compounds 4 and 10 exerted a 9.18-fold potentiation effect on bortezmib (BTZ) susceptibility at a tested concentration (20 μM) better than the positive control verapamil. The research of the leaves of T. cryptomerioides not only added the new data to the structural diversity and activities of dimeric diterpenoids but also could provide support for the medical and industrial application of the leaves of this endangered relict plant.     

Cassane-Type Diterpenoids from the Seeds of Caesalpinia bonduc (L.) Roxb.

Ten new cassane-type diterpenoids were isolated from the seeds of Caesalpinia bonduc (L.) Roxb., including 6α-hydroxycaesalpinin P ( 1 ), 14-epi-caesalpinin E1 ( 2 ), 6-deacetylcaesalmin Z ( 3 ), 14-epi-caesalmin Z ( 4 ), caesalpinolides I ( 5 ), K ( 6 ), L ( 7 ), M ( 9 ) and N ( 10 ), and 14-epi-neocaesalpin L ( 8 ). Their planar structures and absolute configurations were fully determined by comprehensive spectroscopic methods, including 2D NMR and electronic circular dichroism spectra. Compounds 1 – 4 are tetracyclic cassane diterpenoids possessing a furan ring, and compounds 5 – 10 are tetracyclic cassane diterpenoids possessing a fused butenolide moiety. The anti-inflammatory and cytotoxic activities of the isolates were evaluated, while none of them showed obvious effects. The current study identified ten new cassane-type diterpenoids from the seeds of C. bonduc (L.) Roxb., which enriched the chemical diversity of the titled herbal medicine.     

Diterpenes from the Roots of Oryza sativa L. and Their Inhibition Activity on NO Production in LPS‐Stimulated RAW264.7 Macrophages

Two new pimarane diterpenoids, momilactone D ( 3 ) and momilactone E ( 5 ), along with three known diterpenoids, momilactone A ( 1 ), sandaracopimaradien‐3‐one ( 2 ), and oryzalexin A ( 4 ) were isolated from Oryza sativa roots. The chemical structures of the compounds were determined by spectroscopic data analysis. The isolated diterpenoids were evaluated for their ability to inhibit NO production and iNOS mRNA and protein expression in LPS‐stimulated RAW264.7 macrophages. Compound 4 showed strong inhibition activity on NO production, and compounds 1 and 4 decreased the expression of iNOS mRNA and protein levels.     

Terpenoids and More Polar Compounds from the Male Cones of Wollemia nobilis

The analysis of metabolites contained in the male cones of Wollemia nobilis was investigated for the first time in this study. Several diterpenoids of chemosystematic relevance were recognized for the first time from the genus and/or from the Araucariaceae family, namely isocupressic acid ( 1 ), acetyl‐isocupressic acid ( 2 ), methyl (E )‐communate ( 3 ) and sandaracopimaric acid ( 4 ). All these terpenoids are also endowed with interesting biological activities and may play a primary role in the self defence toward herbivores. The presence of a new norlabdane (norlabda‐8(16)‐12‐dien‐14,17‐diol) trivially named as wollemol ( 5 ) was also recognized. Norditerpenes are scarcely distributed in Plant Kingdom and in particular in Gymnosperms and this aspect was discussed. The structure of 5 was determined by extensive NMR analysis employing mono‐ and bidimensional experiments. The 7‐4?‐dimethoxyagathisflavone ( 6 ), a biflavonoid already recognized in Araucariaceae and W. nobilis , was also isolated from male cones together with shikimic acid ( 7 ), a biogenetic precursor of polyphenolic compounds, besides carbohydrates such as glucose ( 8 ) and saccharose ( 9 ), and arginine ( 10 ) a quite common amino acid.     

Hypofolins A – L,ent‐Labdane Diterpenoids from the Roots of Hypoestes phyllostachya ‘Pink Splash’

Twelve new ent‐labdane diterpenoids, hypofolins A – F ( 1 – 6 ) and hypofolins G – L ( 7a / 7b , 8a / 8b , and 9a / 9b ), were isolated from the roots of Hypoestes phyllostachya ‘Pink Splash’. Their structures were elucidated by extensive 1D‐ and 2D‐NMR spectroscopic and HR‐MS data. The absolute configurations of 1 , 2 , 5 , and 7a / 7b were determined by single crystal X‐ray diffraction and ECD analysis, as well as chemical transformations. Compounds 7a / 7b , 8a / 8b , and 9a / 9b were isolated as three pairs of interconverting mixture of two isomers between ketone and hemiketal types. Compound 1 showed weak cytotoxicity against SMMC‐7721 cell line with IC₅₀ value of 31.40 μm .     

New Diterpenoids from Andrographis paniculata （Burm. f.） Nees

To investigate diterpenoids from the aerial parts of Andrographis paniculata （Burm. f.） Nees, three new ent-labdane diterpenoids, namely 19-norandrographolides A-C （compounds 1-3）, were isolated from the ethanolic extract of A. paniculata. Their structures were established by HRESIMS and NMR spectral data in combination with X-ray crystallographic analysis.     

New 4,5‐seco‐20(10→5)‐abeo‐Abietane Diterpenoids with Anti‐Inflammatory Activity from Isodon lophanthoides var. graciliflorus (Benth.) H.Hara

Three new 4,5‐seco‐20(10→5)‐abeo‐abietane diterpenoids, 16‐hydroxysalvilenone ( 1 ), 15‐hydroxysalprionin ( 2 ), and 11β,15‐dihydroxysalprionin‐12‐one ( 3 ), and nine known abietane diterpenoids, 4 – 12 , along with one known sempervirane diterpenoid, hispidanol A ( 13 ), were isolated from the aerial parts of Isodon lophanthoides var. graciliflorus. The structures of compounds 1 – 3 were determined on the basis of spectroscopic methods including extensive analysis of NMR and mass spectroscopic data. All diterpenoids were tested for their TNF‐α inhibitory effects on LPS‐induced RAW264.7 cells. Compound 9 (16‐acetoxyhorminone) was the most potent with an IC₅₀ value of 3.97±0.70 μm .     

Vibsane‐Type Diterpenoids from Viburnum odoratissimum and Their Cytotoxic and HSP90 Inhibitory Activities

Four new vibsane‐type diterpenoids, vibsanol I ( 1 ), 15‐hydroperoxyvibsanol A ( 2 ), 14‐hydroperoxyvibsanol B ( 3 ), 15‐O‐methylvibsanin U ( 4 ), and a new natural product, 5,6‐dihydrovibsanin B ( 5 ), as well as six known analogues, were isolated from the twigs and leaves of Viburnum odoratissimum. Their structures were elucidated by spectroscopic analyses and chemical derivatization method. All compounds showed different levels of cytotoxicity against five cell lines (HL‐60, A‐549, SMMC‐7721, MCF‐7, and SW480). Remarkably, 14,18‐O‐diacetyl‐15‐O‐methylvibsanin U ( 4a ) showed significant cytotoxicity against HL‐60, A‐549, SMMC‐7721, MCF‐7, and SW480, with IC₅₀ values of 0.15 ± 0.01, 0.69 ± 0.01, 0.41 ± 0.02, 0.75 ± 0.03, and 0.48 ± 0.03 μm , respectively. In addition, vibsanin K ( 10 ) was identified as a HSP90 inhibitor with an IC₅₀ value of 19.16 μm .     

Bioactive Constituents of Juniperus turbinata Guss. from La Maddalena Archipelago

A comprehensive phytochemical study of Juniperus turbinata (Cupressaceae) collected from La Maddalena Archipelago (Sardinia, Italy) is reported. Both the essential oil and the ethanolic extract obtained from the aerial parts were analyzed. The essential oil appears to belong to a new chemotype compared to other Mediterranean juniper accessions, as it was favored by geographic isolation of the isles. It showed a low content of monoterpene hydrocarbons and α‐terpineol, ent‐manoyl oxide, 1,10‐di‐epi‐cubenol as the major constituents. The ethanolic fraction contained mainly diterpenoids. Among these, 15‐formyloxyimbricatolic acid ( 7 ) is a new natural product since it has hitherto been obtained only by synthetic route. The phenolic fraction contained biflavonoids: cupressuflavone ( 9 ), followed by minor amounts of amentoflavone ( 10 ) and hinokiflavone ( 11 ). The essential oil and six purified compounds ( 1 – 4 , 8 and 9 ) were assessed for biological activities, namely antioxidant (assessed by DPPH^·, ABTS^·+ and FRAP methods) and cytotoxic effects towards selected human tumor cell lines (MDA‐MB 231, A375 and HCT116 cells). Compound 3 exhibited higher radical scavenging activity against ABTS^·+ radical than the reference Trolox. Noteworthy, compound 8 showed powerful effects towards tumor cell lines, with IC₅₀ values in the range of 0.060 – 0.201 μm , which make it a promising anticancer drug candidate.     

Diterpenoids from Wedelia prostrata and Their Derivatives and Cytotoxic Activities

One new ent‐kaurane diterpenoid, 11β,16α‐dihydroxy‐ent‐kauran‐19‐oic acid ( 1 ), together with eight known analogues 2 – 9 were isolated from the aerial parts of Wedelia prostrata. One of the acidic diterpenoids, kaurenoic acid ( 3 ), was converted to seven derivatives, 10 – 16 . All compounds were evaluated for their cytotoxic activity in vitro against human leukemia (K562), liver (HepG‐2), and stomach (SGC‐7901) cancer cell lines. Only four kaurenoic acid derivatives, 13 – 16 , with 15‐keto and substitutions at C(19) position, exhibited notable cytotoxic activities on these tumor cell lines with IC₅₀ value ranging from 0.05 to 3.71 μm . Compounds 10 – 12 , with oxime on C(15) showed moderate inhibitory effects and compounds 1 – 9 showed no cytotoxicities on them. Structure–activity relationships were also discussed based on the experimental data obtained. The known derivative, 15‐oxokaurenoic acid 4‐piperdin‐1‐ylbutyl ester ( 17 ), induced typical apoptotic cell death in colon SW480 cells upon evaluation of the apoptosis‐inducing activity by flow‐cytometric analysis.     

Pierisformotoxins A – D,Polyesterified Grayanane Diterpenoids from Pieris formosa and Their cAMP‐Decreasing Activities

Four highly acylated diterpenoids, designated as pierisformotoxins A–D ( 1 – 4 , resp.), along with 26 known compounds, were isolated from the flowers of Pieris formosa. Among them, pierisformotoxins A and B ( 1 and 2 , resp.) were new highly acylated grayanane diterpenoids, of which the five‐membered ring A has undergone an oxidative cleavage between C(3) and C(4), followed by lactonization, to give rise to a five‐membered lactone ring between C(3) and C(5), differing from the previously reported grayanane diterpenoids with a 5/7/6/5 ring system. Results of the cAMP‐regulation‐activity assay showed that pierisformotoxin C ( 3 ) at 10 μM (inhibitory ratio (IR): 10.1%) or 2 μM (9.8%), and pierisformotoxin B ( 2 ) at 50 μM (13.9%) significantly decreased the cAMP level in N1E‐115 neuroblastoma cells (p<0.05).     

Three New Labdane-Type Diterpenoids from the Fruits of Amomum villosum and Their Anti-Inflammatory Activities

Three new labdane-type diterpenoids, calcaratarin E, villosumtriol, and 12-epi-villosumtriol ( 1 – 3 ) were isolated from the fruits of Amomum villosum, along with seven known diterpenoids ( 4 – 10 ). Through comprehensive analysis of chemical evidence and spectral data including UV, 1D and 2D NMR, HR-ESI-MS, IR, and X-ray crystallography, the structures of these novel compounds were successfully determined. Additionally, the inhibitory effects of compounds 2 – 10 on NO production in lipopolysaccharide (LPS)-induced RAW264.7 cells were evaluated. Notably, compound 6 exhibited the most significant inhibitory effect with an IC₅₀ value of 1.74±0.69 μM.     

Diterpenoids and a Diarylheptanoid from Hedychium coronarium with Significant Anti‐Angiogenic and Cytotoxic Activities

Two new labdane diterpenoids, namely hedycoronals A and B ( 1 and 2 , resp.), were isolated from the rhizomes of Hedychium coronarium, together with eight known diterpenoids, 4 – 11 , and a known diarylheptanoid, 3 . The structures of 1 and 2 were established by detailed interpretation of their 1D‐ and 2D‐NMR spectra and HR‐ESI‐MS data. Inhibitory activities against human umbilical vein endothelial cells (HUMECs) proliferation and cytotoxic activities against four cancer cell lines were assessed for all the isolates. Most of these metabolites showed moderate or potent cytotoxic activities against four cancer cell lines. Moreover, compounds 3 and 8 exhibited promising inhibitory activities against HUMECs with the IC₅₀ values of 6.4 to 3.3 μM .