Cuceolatins A–D: New Bioactive Diterpenoids from the Leaves of Cunninghamia lanceolata

Four new diterpenoids named cuceolatins A–D, including three labdane‐type ( 1 – 3 ) and one abietane‐type ( 4 ) as well as three known labdane analogs ( 5 – 7 ), were reported from the leaves of Cunninghamia lanceolata. Structural assignments for these compounds were conducted by analyses of spectroscopic data, and their absolute configurations were determined by time‐dependent density functional theory (TD‐DFT) based electronic circular dichroism (ECD) calculations. Among them, the abietane‐type diterpenoid (11‐hydroxy‐12‐methoxyabieta‐8,11,13‐trien‐3‐one ( 4 )) showed significant cytotoxicity against human MDA‐MB‐231, MCF‐7, and HeLa tumor cell lines with IC₅₀ measurements of 4.3, 2.8 and 4.5 μm , respectively, while the labdane‐type diterpenoids with a 4α‐carboxy group ( 1 – 3 and 5 ) exhibited moderate antibacterial activity towards Bacillus subtilis and Staphylococcus aureus with IC₅₀ values all below 25 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.     

Four New Diterpenoids from the Roots of Euphorbia pekinensis

Three new isopimarane diterpenoids ( 1 – 3 ) and one new abietane diterpenoid ( 4 ) were isolated and identified from the roots of Euphorbia pekinensis, together with four known diterpenoids. Their structures were elucidated on the basis of extensive spectroscopic methods (IR, MS, NMR, and CD), and their cytotoxicities and anticomplement activities were evaluated.     

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.     

2,5‐Diketopiperazines from the Marine‐Derived Fungus Aspergillus fumigatus YK‐7

Five new diketopiperazines, prenylcyclotryprostatin B ( 1 ), 20‐hydroxycyclotryprostatin B ( 2 ), 9‐hydroxyfumitremorgin C ( 3 ), 6‐hydroxytryprostatin B ( 4 ), and spirogliotoxin ( 5 ), were isolated from the marine‐derived fungus Aspergillus fumigatus YK‐7, along with nine known compounds, 6 – 14 . Their structures were elucidated by spectroscopic methods, and their antiproliferative effects on human leukemic monocyte lymphoma U937 and human prostate cancer PC‐3 cell lines were assessed in vitro. Compounds 10, 12 , and 13 exhibited significant cell growth‐inhibitory activities against U937 cell line, with the IC₅₀ values of 1.8, 0.2, and 0.5 μM , respectively.     

Bioactive Tyrosine‐Derived Cytochalasins from Fungus Eutypella sp. D‐1

Three new cytochalasins Z₂₄, Z₂₅, Z₂₆ ( 1 – 3 , resp.) and one known compound, scoparasin B ( 4 ), were isolated from the fungus Eutypella sp. D‐1 isolated from the soil of high latitude of the Arctic. The structures of 1 – 3 were elucidated from spectroscopic data (NMR, MS). These compounds were evaluated for cytotoxic activities against several human tumor cell lines. Among them, compound 1 exhibited moderate cytotoxicity toward human breast cancer MCF‐7 cell line with IC₅₀ of 9.33 μM .     

Cytotoxic and Melanogenesis‐Inhibitory Activities of Limonoids from the Leaves of Azadirachta indica (Neem)

Seventeen limonoids (tetranortriterpenoids), 1 – 17 , including three new compounds, i.e., 17‐defurano‐17‐(2,5‐dihydro‐2‐oxofuran‐3‐yl)‐28‐deoxonimbolide ( 14 ), 17‐defurano‐17‐(2ξ‐2,5‐dihydro‐2‐hydroxy‐5‐oxofuran‐3‐yl)‐28‐deoxonimbolide ( 15 ), and 17‐defurano‐17‐(5ξ‐2,5‐dihydro‐5‐hydroxy‐2‐oxofuran‐3‐yl)‐2′,3′‐dehydrosalannol ( 17 ), were isolated from an EtOH extract of the leaf of neem (Azadirachta indica). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses and comparison with literature. Upon evaluation of the cytotoxic activities of these compounds against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK‐BR‐3) cancer cell lines, seven compounds, i.e., 1 – 3, 12, 13, 15 , and 16 , exhibited potent cytotoxicities with IC₅₀ values in the range of 0.1–9.9 μM against one or more cell lines. Among these compounds, cytotoxicity of nimonol ( 1 ; IC₅₀ 2.8 μM ) against HL60 cells was demonstrated to be mainly due to the induction of apoptosis by flow cytometry. Western blot analysis suggested that compound 1 induced apoptosis via both the mitochondrial and death receptor‐mediated pathways in HL60 cells. In addition, when compounds 1 – 17 were evaluated for their inhibitory activities against melanogenesis in B16 melanoma cells, induced with α‐melanocyte‐stimulating hormone (α‐MSH), seven compounds, 1, 2, 4 – 6, 15 , and 16 , exhibited inhibitory activities with 31–94% reduction of melanin content at 10 μM concentration with no or low toxicity to the cells (82–112% of cell viability at 10 μM ). All 17 compounds were further evaluated for their inhibitory effects against the Epstein? Barr virus early antigen (EBV‐EA) activation induced by 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) in Raji cells.     

Bioactive 9,11‐Secosteroids from Gorgonian Subergorgia suberosa Collected from the South China Sea

Five new 9,11‐secosteroids 1, 2 , and 4 – 6 , and seven known analogs, 3 and 7 – 12 , with the same steroid skeleton, (5αH)‐3β,6α,11‐trihydroxy‐9,11‐secocholest‐7‐en‐9‐one, were isolated from the South China Sea gorgonian Subergorgia suberosa. Among them, 2 / 3 and 4 / 5 are C(24)‐epimeric mixtures, and 6 / 7 is an (E)/(Z) mixture of (C(24)?C(28)). Their structures and relative configurations were elucidated by using comprehensive spectroscopic methods including NOESY spectra. The absolute configuration of the steroidal nucleus was established by the modified Mosher method applied to 10 and on the basis of a common biogenesis for all of these compounds. All isolated compounds, 1 – 12 , and five synthetic acetylated derivatives, 12a – 12e , were evaluated for their cytotoxicities in vitro. Compounds 4 / 5, 11, 12 , and 12b – 12d showed cytotoxic activities against K562 cell line with the IC₅₀ values ranging from 1.09 to 8.12 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 .     

Naphtho‐γ‐pyrones from Endophyte Aspergillus niger Occurring in the Liverwort Heteroscyphus tener (Steph.) Schiffn.

Bioactivity‐guided fractionation of the cytotoxic extract of Aspergillus niger, an endophytic fungus from the Chinese liverwort Heteroscyphus tener (Steph .) Schiffn ., afforded five new naphtho‐γ‐pyrones, rubrofusarin‐6‐O‐α‐D ‐ribofuranoside ( 1 ), (R)‐10‐(3‐succinimidyl)‐TMC‐256A1 ( 2 ), asperpyrone E ( 3 ), isoaurasperone A ( 4 ), and isoaurasperone F ( 5 ), as well as four known ones, dianhydroaurasperone C ( 6 ), aurasperone D ( 7 ), asperpyrone D ( 8 ), and asperpyrone A ( 9 ), together with a cytotoxic cyclic pentapeptide, malformin A₁ ( 10 ). Their structures were determined by extensive spectroscopic analysis. The absolute configurations of dimeric naphtho‐γ‐pyrones 3 – 9 were also determined by analysis of their respective CD spectra.     

Melanogenesis‐Inhibitory Activities of Isomeric C‐seco Limonoids and Deesterified Limonoids

Treatment of eight C‐seco limonoids including six of salannin‐type, 1 – 6 , and two of nimbin‐type, 7 and 8 , with a combination of BF₃ · Et₂O and iodide ion yielded the isomeric C‐seco derivatives, i.e., six isosalannins, 1a – 6a , and two isonimbins, 7a and 8a , respectively. Ohchinin ( 1 ) was further subjected to LiAlH₄ reduction which yielded a deesterified trihydroxy limonoid, nimbidinol ( 9 ). In addition, ten limonoids including seven of azadirone‐type, 10 – 16 , and three of gedunin‐type, 17 – 19 , all of which possess no ester functionality in the molecule, were obtained from the neutral fraction of Azadirachta indica seed extract after alkaline hydrolysis. Among the above, twelve compounds, i.e., 1a – 4a , 6a , 9 , 13 – 16 , 18 , and 19 , were new compounds, and their structures were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. Upon evaluation of all these limonoids for their inhibitory activities against melanogenesis in B16 melanoma cells induced with α‐melanocyte‐stimulating hormone (α‐MSH), five structurally modified limonoids, 3‐deacetyl‐28‐oxosalannin ( 6a ), 9 , 17‐epi‐17‐hydroxynimbocinol ( 14 ), 17‐epi‐17‐hydroxy‐15‐methoxynimbocinol ( 15 ), and 7‐deacetyl‐17‐epinimolicinol ( 18 ), in addition to a natural limonoid, 1 , exhibited potent inhibitory activities with 26 – 66% reduction of melanin content at 100 μm concentration with almost no or low toxicity to the B16 melanoma cells (70 – 99% cell viability at 100 μm ).     

Diterpenoids and Flavonoids from the Twigs of Cephalotaxus fortunei var. alpina

Three new diterpenoids (a cephalotane, an abietane and a 9(10→20)‐abeo‐abietane) and one new flavonoid, together with 11 known compounds, were isolated from the twigs of Cephalotaxus fortunei var. alpina. The new compounds were identified by comprehensive spectroscopic (including 1D and 2D‐NMR and HR‐ESI‐MS) analysis. Anti‐inflammatory, immunosuppressive and cytotoxic activities of three new compounds were evaluated. 3β,20‐epoxyabieta‐8,11,13‐triene‐3α,12‐diol showed weak cytotoxicity against tumor cell lines NCI?H1975, HepG2, MCF‐7, while fortalpinoid R and 3‐acetonyl‐3,5,7,4′‐tetrahydroxy‐2‐methoxyflavanone were not active at 80 μM. None of these compounds showed anti‐inflammatory and immunosuppressive activities.     

Abietane Diterpenes from Hyptis suaveolens

Investigation of the constituents of the whole plant of Hyptis suaveolens led to the isolation of three new abietane diterpenes, isosuaveolic acid ( 1 ), 8α,9α‐epoxysuaveolic acid ( 2 ), and 14‐O‐methylsuaveolic acid ( 3 ), together with eleven known compounds. The structures of 1 – 3 were established by spectroscopic methods and chemical correlations. Some isolates were tested for their antimycobacterial and cytotoxic activities.     

Terpenoids from Rhizomes of Alpinia japonica Inhibiting Nitric Oxide Production

A new sesquiterpenoid, 1 , and three new diterpenoids, 3 – 5 , along with five known compounds, 2 and 6 – 9 , were isolated from rhizomes of Alpinia japonica. The structures of the new compounds were determined as (1R,4R,6S,7S,9S)‐4α‐hydroxy‐1,9‐peroxybisabola‐2,10‐diene ( 1 ), methyl (12E)‐16‐oxolabda‐8(17),12‐dien‐15‐oate ( 3 ), (12R)‐15‐ethoxy‐12‐hydroxylabda‐8(17),13(14)‐dien‐16,15‐olide ( 4 ), and methyl (11E)‐14,15,16‐trinorlabda‐8(17),11‐dien‐13‐oate ( 5 ) by means of spectroscopic data. The absolute configurations at C(4) in 1 and C(12) in 4 were deduced from the circular dichroism (CD) data of the in situ‐formed [Rh₂(CF₃COO)₄] complexes. Inhibitory effects of the isolates on NO production in lipopolysaccharide‐induced RAW264.7 macrophages were evaluated, and 2 – 4, 6 , and 7 were found to exhibit inhibitory activities with IC₅₀ values between 14.6 and 34.3 μM .     

Julichrome Monomers from Marine Gastropod Mollusk‐Associated Streptomyces and Stereochemical Revision of Julichromes Q3 ⋅ 5 and Q3 ⋅ 3

Two julichrome monomers, julichromes Q₁₁ ( 1 ) and Q₁₂ ( 2 ), along with five known julichromes (Q₁₀, Q_{3 ? 5}, Q_{3 ? 3}, Q_{6 ? 6}, Q₆, 3 – 7 ) and four known anthraquinones (chrysophanol, 4‐acetylchrysophanol, islandicin, huanglongmycin A, 8 – 11 ), were isolated from the marine gastropod mollusk Batillaria zonalis‐associated Streptomyces sampsonii SCSIO 054. This is the first report of julichromes isolated from a marine source. Extensive dissection of 1D and 2D NMR datasets combined with X‐ray crystallography enabled rigorous elucidation of the previously reported configurations of julichrome Q_{3 ? 5} ( 4 ) and related julichrome Q_{3 ? 3} ( 5 ); both of the configuration at C(9) needs to be revised. In addition, julichrome Q₁₂ ( 2 ) was found to display antibacterial activity against Micrococcus luteus and Bacillus subtilis with MICs of 2.0 and 8.0 μg mL^?1; four compounds ( 1 , 3 , 6 , 7 ) also showed inhibitory activities against an array of methicillin‐resistant Staphylococcus aureus, S. aureus and S. simulans AKA1 with MIC values ranging from 8 to 64 μg mL^?1.     

Antibacterial Δ1‐3‐Ketosteroids from the South China Sea Gorgonian Coral Subergorgia rubra

Three new Δ¹‐3‐ketosteroids characterized with a 9‐OH, subergosterones A–C ( 1 – 3 ), together with five known analogs 4 – 8 , were obtained from the gorgonian coral Subergorgia rubra collected from the South China Sea. The structures of 1 – 3 , including their absolute configurations, were determined by comprehensive spectroscopic methods and electronic circular dichroism (ECD) experiments. Compounds 2 and 3 exhibited inhibitory antibacterial activities against Bacillus cereus with MIC values of 1.56 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 .     

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).