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 .     

Two New Abietane Diterpenoids from Selaginella moellendorffii Hieron.

Two new abietane diterpenoids, (3S,5R,10S)‐3‐hydroxy‐12‐O‐demethyl‐11‐deoxy‐19(4→3)‐abeo‐cryptojaponol, 12,19‐dihydroxyabieta‐8,11,13‐trien‐7‐one, were isolated from Selaginella moellendorffii Hieron., together with one known abietane diterpenoid and four known tetracyclic triterpenoids. Their structures were characterized by their 1D‐ and 2D‐NMR, ECD and mass spectral studies. All compounds were tested for their inhibitory effects on proliferation of three human cancer cells (human non‐small‐cell lung carcinoma cell lines A549 and human breast adenocarcinoma cell lines MDA‐MB‐231 and MCF‐7) in vitro. Among them, three compounds displayed modest cytotoxic activities against the above three human cancer cell lines with IC₅₀ values ranging from 16.28 to 40.67 μM.     

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 .     

Diterpenoids from Euphorbia neriifolia and Their Related Anti‐HIV and Cytotoxic Activity

Fifteen diterpenoids ( 1 – 15 ), including three undescribed ones with ent‐atisane skeleton, eupnerias G–I ( 1 – 3 ), were obtained from Euphorbia neriifolia. Compounds 1 – 3 were established through comprehensive spectroscopic analysis. Compounds 4 and 5 exhibited obvious anti‐HIV‐1 effect, and their EC₅₀ were 6.6±3.2 and 6.4±2.5 μg mL^?1, respectively. Compound 6 exhibited moderate cytotoxicity on HepG2 and HepG2/Adr cells with IC₅₀ at 13.70 and 15.57 μm , respectively. In addition, compound 15 exhibited significant cytotoxicity on HepG2 cell lines (IC₅₀=0.01 μm ), while it did not show any cytotoxicity against HepG2/Adr cell lines.     

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 .     

Composition and Bioactivity of Lipophilic Metabolites from Needles and Twigs of Korean and Siberian Pines (Pinus koraiensis Siebold & Zucc. and Pinus sibirica Du Tour)

Lipophilic extractive metabolites in different parts of the shoot system (needles and defoliated twigs) of Korean pine, Pinus koraiensis, and Siberian pine, Pinus sibirica, were studied by GC/MS. Korean pine needles comprised mainly bornyl p‐coumarate, heterocyclic 15‐O‐functionalized labdane type acids (lambertianic acid), 10‐nonacosanol, sterols and their esters. While Siberian pine needles contained less bornyl p‐coumarate, lambertianic acid, sterols and their esters, but were richer in other 15‐O‐functionalized labdane type acids. The major components of the twig extract of P. koraiensis were lambertianic acid, abietane and isopimarane type acids, cembrane type alcohols, 8‐O‐functionalized labdanoids, sterols, sterol esters, and acylglycerols. The same extract of P. sibirica differed in larger amounts of other 15‐O‐functionalized labdane type acids and pinolenic acid glycerides, but in less quantities of cembranoids and 8‐O‐functionalized labdanoids. The labdane type pinusolic acid was detected for the first time in Korean pine. P. koraiensis was found to be unique in the genus for an ability to synthesize phyllocladane diterpenoids. The content of bound Δ⁵‐unsaturated polymethylene‐interrupted fatty acids in the twig extracts of the both pines was similar or superior to that in their seed oil. Among the pines’ metabolites tested isocembrol was strongest in inhibition of both α‐glucosidase (IC₅₀ 2.9 μg/ml) and NO production in activated macrophages (IC₅₀ 3.6 μg/ml).     

Biological Activities of Phenolics from the Fruits of Phyllanthus emblica L. (Euphorbiaceae)

Seven phenolic compounds, 1 – 7 , including a new organic acid gallate, mucic acid 1‐ethyl 6‐methyl ester 2‐O‐gallate ( 7 ), were isolated from the MeOH extract of the fruits of Phyllanthus emblica L. (Euphorbiaceae). The structures were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. Upon evaluated for their antioxidant abilities by 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH), 2,2′‐azinobis(3‐ethylbenzthiazoline‐6‐sulfonic acid) (ABTS), and ferric reducing antioxidant power (FRAP) assays. The inhibitory activities against melanogenesis in B16 melanoma cells induced by α‐MSH, as well as cytotoxic activities against four human cancer cell lines were also evaluated. All phenolic compounds, 1 – 7 , exhibited potent antioxidant abilities (DPPH: IC₅₀ 5.6 – 12.9 μm ; ABTS: 0.87 – 8.43 μm Trolox/μm ; FRAP: 1.01 – 5.79 μm Fe²⁺/μm , respectively). Besides, 5 – 7 , also exhibited moderate inhibitory activities against melanogenesis (80.7 – 86.8% melanin content), even with no or low toxicity to the cells (93.5 – 101.6% cell viability) at a high concentration of 100 μm . Compounds 1 – 3 exhibited cytotoxic activity against one or more cell lines (IC₅₀ 13.9 – 68.4%), and compound 1 with high tumor selectivity for A549 (SI 3.2).     

Cytotoxic and Apoptosis‐Inducing Activities of Steviol and Isosteviol Derivatives against Human Cancer Cell Lines

Seventeen steviol derivatives, i.e., 2 – 18 , and 19 isosteviol derivatives, i.e., 19 – 37 , were prepared from a diterpenoid glycoside, stevioside ( 1 ). Upon evaluation of the cytotoxic activities of these compounds against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK‐BR‐3) cancer cell lines, nine steviol derivatives, i.e., 5 – 9 and 11 – 14 , and five isosteviol derivatives, i.e., 28 – 32 , exhibited activities with single‐digit micromolar IC₅₀ values against one or more cell lines. All of these active compounds possess C(19)‐O‐acyl group, and among which, ent‐kaur‐16‐ene‐13,19‐diol 19‐O‐4′,4′,4′‐trifluorocrotonate ( 14 ) exhibited potent cytotoxicities against four cell lines with IC₅₀ values in the range of 1.2–4.1 μM . Compound 14 induced typical apoptotic cell death in HL60 cells upon evaluation of the apoptosis‐inducing activity by flow‐cytometric analysis. These results suggested that acylation of the 19‐OH group of kaurane‐ and beyerane‐type diterpenoids might be useful for enhancement of their cytotoxicities with apoptosis‐inducing activity.     

Nitric Oxide Production‐Inhibitory Activity of Limonoids from Azadirachta indica and Melia azedarach

Seventy‐three limonoids isolated from three Meliaceae plants, Azadirachta indica, A. indica var. siamensis, and Melia azedarach, or semi‐synthesized from the Meliaceae limonoids, were evaluated for their inhibitory activity against nitric oxide (NO) production in mouse macrophage RAW 264.7 cells induced by lipopolysaccharide (LPS), as a primary screening test for anti‐inflammatory agents. Of the compounds tested, 21 compounds exhibited inhibitory activity (IC₅₀ 4.6 – 58.6 μm ) without any significant toxicity (IC₅₀ > 100 μm ) which were more potent than l ‐NMMA (NO‐production inhibitory activity, IC₅₀ 65.6 μm ; cytotoxicity, IC₅₀ > 100 μm ), and among which, nine compounds, i.e., 17‐hydroxy‐15‐methoxynimbocinol ( 6 ), ohchinin ( 20 ), 1‐cis‐cinnamoyl‐1‐decinnamoylohchinin ( 24 ), salannin ( 27 ), methyl nimbidate ( 32 ), isosalannin ( 55 ), nimbolinin D ( 58 ), mesendanin E ( 69 ), and 7‐deacetylgedunin ( 73 ) exhibited potent inhibitory activity (IC₅₀ 4.6 – 29.3 μm ). In particular, compounds 6 (IC₅₀ 7.3 μm ), an azadirone‐type limonoid, and 73 (IC₅₀ 4.6 μm ), a gedunin‐type limonoid, exhibited remarkable activity. Western blot analysis revealed that 27 and 73 reduced the expression levels of the inducible NO synthase and cyclooxygenase‐2 proteins in a concentration‐dependent manner. These findings suggest that limonoids of A. indica, A. indica var. siamensis, and M. azedarach, and their semi‐synthetic derivatives may be effective against inflammation.     

Naphthalene Derivatives and Quinones from Ventilago denticulata and Their Nitric Oxide Radical Scavenging,Antioxidant, Cytotoxic,Antibacterial, and Phosphodiesterase Inhibitory Activities

New naphthalene derivatives ( 1 and 2 ) and a new isomer ( 3 ) of ventilagolin, together with known anthraquinones, chrysophanol ( 4 ), physcion or emodin 3‐methyl ether ( 5 ), and emodin ( 6 ), were isolated from vines of Ventilago denticulata. The isolated compounds exhibited cytotoxic activity with IC₅₀ values of 1.15 – 40.54 μg/ml. Compounds 1 – 3 selectively exhibited weak antibacterial activity (MIC values of 200.0 – 400.0 μg/ml), while emodin ( 6 ) displayed moderate antibacterial activity with MIC value of 25.0 μg/ml. The isolated compounds showed nitric oxide and DPPH radical scavenging activities. Compounds 1 – 3 and 6 exhibited weak xanthine oxidase inhibitory activity, while emodin ( 6 ) acted as an aromatase inhibitor with the IC₅₀ value of 10.1 μm . Compounds 1 and 2 exhibited phosphodiesterase 5 inhibitory activity with IC₅₀ values of 8.28 μm and 6.48 μm , respectively.     

6,7-seco-ent-kaurane diterpenoids from Isodon sculponeatus with cytotoxic activity

Six new 6,7‐seco‐ent‐kaurane diterpenoids, sculponeatins N–S ( 1 – 6 , resp.), together with eleven known analogues, 7 – 17 , were isolated from the aerial parts of Isodon sculponeatus. The structures of compounds 1 – 6 were elucidated by spectroscopic methods including extensive 1D‐ and 2D‐NMR experiments, as well as HR‐ESI‐MS analysis. All diterpenoids obtained were assayed for their cytotoxic activity against K562 and HepG2 human tumor cell lines. Among them, compound 1 showed the most significant cytotoxicity with the IC₅₀ values of 0.21 and 0.29 μM , respectively. The structure–activity relationships are discussed.     

Cytotoxic and Nitric Oxide Production‐Inhibitory Activities of Limonoids and Other Compounds from the Leaves and Bark of Melia azedarach

Nine limonoids, 1 – 9 , one apocarotenoid, 11 , one alkaloid, 12 , and one steroid, 13 , from the leaf extract; and one triterpenoid, 10 , five steroids, 14 – 18 , and two flavonoids, 19 and 20 , from the bark extract of Melia azedarach L. (Chinaberry tree; Meliaceae) were isolated. Among these compounds, three compounds, 4 – 6 , were new, and their structures were established as 3‐deacetyl‐28‐oxosalannolactone, 3‐deacetyl‐28‐oxosalanninolide, and 3‐deacetyl‐17‐defurano‐17,28‐dioxosalannin, respectively, on the basis of extensive spectroscopic analyses and comparison with literature data. All of the isolated compounds were evaluated for their cytotoxic activities against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK‐BR‐3) cancer cell lines. 3‐Deacetyl‐4′‐demethyl‐28‐oxosalannin ( 3 ) against HL60 and AZ521 cells, and methyl kulonate ( 10 ) against HL60 cells exhibited potent cytotoxicities with IC₅₀ values in the range of 2.8–5.8 μM . In addition, upon evaluation of compounds 1 – 13 against production of nitric oxide (NO) in mouse macrophage RAW 264.7 cells induced by lipopolysaccharide (LPS), seven, i.e., trichilinin B ( 1 ), 4 , ohchinin ( 7 ), 23‐hydroxyohchininolide ( 8 ), 21‐hydroxyisoohchininolide ( 9 ), 10 , and methyl indole 3‐carboxylate ( 12 ), inhibited production of NO with IC₅₀ values in the range of 4.6–87.3 μM with no, or almost no, toxicity to the cells (IC₅₀ 93.2–100 μM ). Western blot analysis revealed that compound 7 reduced the expression levels of the inducible NO synthase (iNOS) and COX‐2 proteins in a concentration‐dependent manner. Furthermore, compounds 5, 6, 13 , and 18 – 20 exhibited potent inhibitory effects (IC₅₀ 299–381 molar ratio/32 pmol TPA) against Epstein? Barr virus early antigen (EBV‐EA) activation induced by 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) in Raji cell line.     

neo-Clerodane Diterpenoids from the Aerial Parts of Scutellaria barbata with Anti-Inflammatory Activity

The bioactivity-guided isolation on the Scutellaria barbata extract resulted in the purification of four undescribed neo-clerodane diterpenoids, scuttenlines A–D ( 1 – 4 ), alone with 20 known diterpenoids ( 5 – 24 ). The chemical structures of them were elaborated by extensive spectroscopic means, including 1D, 2D-NMR and HR-MS. The anti-inflammatory potential ability of 1 – 24 was screened in lipopolysaccharide-stimulated mouse RAW 264.7 cells. Scuttenline C (IC₅₀=1.9 μM) and 18 (IC₅₀=3.7 μM) exhibited potent activity to inhibit NO production.     

Cytotoxic ent‐Kaurane Diterpenoids from Isodon nervosus

Four new ent‐kaurane diterpenoids, rabdonervosins G–J ( 1 – 4 , resp.), were isolated from the leaves and stems of Isodon nervosus. Their structures were elucidated by extensive spectroscopic analyses, including 1D‐, 2D‐NMR and HR mass spectra. Compound 2 showed potent cytotoxicity against the HepG2 and PC‐9/ZD cell lines with IC₅₀ values of 2.36 and 6.07 μM , respectively, and compound 3 exhibited cytotoxicity against the HepG2 and CNE2 cell lines with IC₅₀ values of 8.64 and 9.77 μM , respectively.     

Sesquiterpene Lactones with COX‐2 Inhibition Activity from Artemisia lavandulaefolia

Two new sesquiterpene lactones, artelavanolides A ( 1 ) and B ( 2 ), and four known sesquiterpene lactones ( 3 – 6 ) were isolated from the leaves of Artemisia lavandulaefolia. Their structures were elucidated based on the analysis of spectroscopic data (1D, 2D‐NMR and HR‐ESI‐MS). The absolute configuration of 1 was determined by the analysis of single‐crystal X‐ray diffraction data. Artelavanolide A ( 1 ) is a rare sesquiterpene lactone possessing an unusual skeleton with the linkage of Me(14)–C(1) that is probably formed through a rearrangement of the guaiane‐type sesquiterpenoids. Artelavanolide B ( 2 ) is a new highly unsaturated guaianolide. Compounds 1 – 6 were tested for activities on the inhibition of COX‐2 enzyme in vitro. All of compounds exhibited inhibitory activity against COX‐2 with IC₅₀ values ranging from 43.29 to 287.07 μm compared with the positive control, celecoxib (IC₅₀ = 18.10 μm ). Among them, 3 showed the best COX‐2 inhibitory activity with an IC₅₀ value of 43.29 μm .     

Quinazolin‐4(3H)‐one‐Based Hydroxamic Acids: Design,Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity

The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin‐4(3H)‐ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC‐3, prostate; NCI?H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N‐hydroxy‐7‐(7‐methyl‐4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5b ) and N‐hydroxy‐7‐(6‐methyl‐4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5c ) (IC₅₀ values, 0.10–0.16 μm ) were found to be approximately 30‐fold more cytotoxic than SAHA (IC₅₀ values of 3.29–3.67 μm ). N‐Hydroxy‐7‐(4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5a ; IC₅₀ values of 0.21–0.38 μm ) was approximately 10‐ to 15‐fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC₅₀ values in sub‐micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c , strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.     

New Rosane Diterpenoids and Their Analogs from Euphorbia ebracteolata Hayata

Phytochemical investigation of the roots of Euphorbia ebracteolata Hayata resulted in the isolation of three new rosane diterpenoids, euphebracteolatins C–E ( 1 – 3 ), along with fourteen known analogs ( 4 – 17 ). Their structures were determined on the basis of extensive spectroscopic analysis including HR-ESI-MS, 1D and 2D NMR. Euphebracteolatin C ( 1 ) contains a C-1/C-10 double bond and a keto group at C-7, and euphebracteolatins D and E ( 2 – 3 ) possess an aromatic ring-A in their skeleton. The plausible biogenetic pathways of all the isolates were also proposed. Furthermore, compounds 1 and 9 showed selective cytotoxicity against HepG2 cells with IC₅₀ values of 14.29 and 12.33 μM, respectively, and 2 – 3 displayed moderate cytotoxicity against three human cancer lines, with IC₅₀ values ranging from 23.69 to 39.25 μM.     

A New Aromatic Amide from the Roots of Zanthoxylum tessmannii (Rutaceae)

Phytochemical investigation of the methanolic extract of the roots of Zanthoxylum tessmannii Zepernick and Timler (Rutaceae) led to the isolation and characterization of one new aromatic amide named tessmamide ( 1 ) along with twelve known compounds, N‐benzoyltyramine methyl ether ( 2 ), 7,8,9‐trimethoxycoumarin ( 3 ), 7,8‐dimethoxycoumarin ( 4 ), integrifoliodiol ( 5 ), robustin ( 6 ), skimmianine ( 7 ), lupeol ( 8 ), lupenone ( 9 ), a mixture of stigmasterol and β‐sitosterol, and a mixture of their glucosides. The structures of all compounds were determined by comprehensive spectroscopic analyses (1D‐ and 2D‐NMR, EI‐MS, and ESI‐MS) and comparison with known analogs. The determination of the radical scavenging activity using the 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) assay gave moderate antioxidant values for the crude extracts of the roots of Zanthoxylum tessmannii (IC₅₀ 0.8 mg/mL), tessmamide ( 1 ; IC₅₀ 31.8 μm ), and 7,8,9‐trimethoxycoumarin ( 3 ; IC₅₀ 29.3 μm ), compared to the standard ascorbic acid (IC₅₀ 11.6 μm ).     

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.