Chaephilones A and B,Two New Azaphilone Derivatives Isolated from Chaetomium globosum

Two new azaphilone derivatives, chaephilones A ( 1 ) and B ( 2 ), were isolated from the fungus Chaetomium globosum, together with four structurally related analogs 3  –  6 . The structures of 1 and 2 were elucidated by comprehensive spectroscopic analyses including HR‐ESI‐MS and NMR. The known compounds were identified as chaetomugilin Q ( 3 ), chaetomugilin D ( 4 ), 11‐epichaetomugilin A ( 5 ), and chaetomugilin S ( 6 ) by comparing their NMR data and optical rotation values with those reported. Compound 2 represents the first example of azaphilone with an open furan ring. Compounds 1 and 2 were evaluated for cytotoxic activities against five human cancer cell lines (HL‐60, SMMC‐7721, A‐549, MCF‐7, and SW480) by the MTS method.     

Sesquiterpenes from the Leaves of Magnolia delavayi Franch. and Their Cytotoxic Activities

Thirteen sesquiterpenes including eight new ones, magnodelavins A?H ( 1 – 8 ), were obtained from the 95 % ethanolic extract of the leaves of Magnolia delavayi Franch . The structures of the new compounds were determined by exhaustive ¹H‐, ¹³C‐, 2D‐NMR, UV, IR, and HR‐ESI‐MS data, as well as X‐ray crystallographic analysis. Compounds 9 and 10 showed potent cytotoxic activities against HL‐60, A‐549, SMMC‐7721, MCF‐7, and SW480 human cancer cell lines in vitro using MTS assay.     

Daphnane‐Type Diterpenoid Glucosides and Further Constituents of Euphorbia pilosa

Phytochemical investigation of whole plants of Euphorbia pilosa led to the isolation and identification of two new daphnane‐diterpenoid glucosides, euphopilosides A and B ( 1 and 2 , resp.), and a new ent‐abietane, euphopilolide ( 3 ), together with eight known compounds. Compounds 1 and 2 are the first daphnane‐type diterpenoid glycosides. Their structures were elucidated by a combination of 1D‐ and 2D‐NMR, and MS analyses, and acid hydrolysis. Compounds 1 – 9 were evaluated for their in vitro cytotoxicities against five human tumor cell lines, HL‐60, SMMC‐7721, A‐549, MCF‐7, and SW‐480. Compound 7 showed moderate inhibitory activity against all five cell lines.     

Penicamedine A,a Highly Oxygenated Hexacyclic Indole Alkaloid from Penicillium camemberti

A highly oxygenated hexacyclic indole alkaloid, penicamedine A ( 1 ), bearing a rare furan ring, was isolated from the culture broth of Penicillium camemberti, together with two known analogs, iso‐α‐cyclopiazonic acid ( 2 ) and cyclopiazonic acid ( 3 ). The structure of 1 was elucidated by comprehensive spectroscopic analyses including NMR and HR‐ESI‐MS. Its absolute configuration was further confirmed unambiguously by single‐crystal X‐ray diffraction analysis. Compound 1 was evaluated for anti‐HIV activity with p24 assays and tested for cytotoxic activities against five human cancer cell lines, including HL‐60, SMMC‐7721, A‐549, MCF‐7, SW480, and the immortalized non‐cancerous human pulmonary epithelial cell line BEAS‐2B by MTS method.     

New Cytotoxic Alkylated Chalcones from Fatoua villosa

Three new alkylated chalcones, villosins A – C ( 1  –  3 ), five known analogues, together with ten known coumarins, were isolated from Fatoua villosa. The structures of the new compounds were elucidated by extensive spectroscopic analysis, including 1D‐, 2D‐NMR, and MS data. Compounds 1  –  3 showed cytotoxicity against five kinds of human tumor cell lines (NB4, A549, SHSY5Y, PC3, and MCF7) with IC₅₀ values ranging from 1.4 ± 0.1 to 5.7 ± 0.3 μm .     

Diterpenoids from Acanthopanax brachypus Harms

Four diterpenoids, including two new ones, namely noracanthopanin A ( 1 ) and acanthopanolide B ( 2 ), and two known ones, ent‐pimara‐9(11),15‐dien‐19‐oic acid ( 3 ) and ent‐kaur‐16‐en‐19‐oic acid ( 4 ), were isolated from the stem bark of Acanthopanax brachypus Harms . Their structures were elucidated by physicochemical and spectroscopic analyses. Compound 1 and 2 exhibited moderate cytotoxicities against HO‐8910 cells with IC₅₀ values of 65.21±0.23 and 31.43±1.01 μg/ml, respectively, and 2 showed selective weak cytotoxicity against SMMC‐7721 cells (IC₅₀ 89.67±2.54 μg/ml).     

Triterpenoid Alkaloids from Buxus microphylla

Two new triterpenoid alkaloids, buxmicrophyllines J and K ( 1 and 2 , resp.), together with four analogues, 3 – 6 , were isolated from the leaves and stems of Buxus microphylla. The structures of the new compounds were elucidated by NMR and MS spectroscopic analyses. The partial assignments of the NMR spectra of 3 were also revised. Compounds 1 and 3 – 6 were evaluated for their growth inhibitory activity against human cell lines HL‐60, SMMC‐7721, A‐549, SK‐BR‐3, and PANC‐1. Compound 6 showed significant cytotoxicity against HL‐60, SK‐BR‐3, and PANC‐1 cell lines, with IC₅₀ values of 6.46, 19.61, and 28.57 μM , respectively.     

Cytotoxic Triterpenoids from the Barks of Betula platyphylla var. japonica

Phytochemical investigation on the barks of Betula platyphylla var. japonica (Betulaceae) was carried out, resulting in the isolation and identification of three new triterpenoids, 27‐O‐cis‐caffeoylcylicodiscic acid ( 1 ), 27‐O‐cis‐feruloylcylicodiscic acid ( 2 ), and 27‐O‐cis‐caffeoylmyricerol ( 3 ), along with six known triterpenoids, obtusilinin ( 4 ), winchic acid ( 5 ), 27‐O‐trans‐caffeoylcylicodiscic acid ( 6 ), uncarinic acid E ( 7 ), myriceric acid B ( 8 ), and 3‐O‐trans‐caffeoyloleanolic acid ( 9 ). The structures of the new compounds were elucidated by extensive spectroscopic methods, including 1D‐ and 2D‐NMR, and HR‐ESI‐MS. All of the isolated compounds were evaluated for cytotoxicity against four human tumor cell lines (A549, SK‐OV‐3, SK‐MEL‐2, and Bt549). Compounds 2 , 6 , 8 , and 9 exhibited potent cytotoxicity against all of the tumor cells tested (IC₅₀ < 10.0 μm ), while compounds 3 , 4 , 5 , and 7 showed moderate cytotoxicity against all of the tumor cells tested (IC₅₀ < 20.0 μm ).     

The ROS‐induced cytotoxicity of ascorbate is attenuated by hypoxia and HIF‐1alpha in the NCI60 cancer cell lines

Intravenous application of high‐dose ascorbate is used in complementary palliative medicine to treat cancer patients. Pharmacological doses of ascorbate in the mM range induce cytotoxicity in cancer cells mediated by reactive oxygen species (ROS), namely hydrogen peroxide and ascorbyl radicals. However, little is known about intrinsic or extrinsic factors modulating this ascorbate‐mediated cytotoxicity. Under normoxia and hypoxia, ascorbate IC₅₀ values were determined on the NCI60 cancer cells. The cell cycle, the influence of cobalt chloride‐induced hypoxia‐inducible factor‐1α (HIF‐1α) and the glucose transporter 1 (GLUT‐1) expression (a pro‐survival HIF‐1α‐downstream‐target) were analysed after ascorbate exposure under normoxic and hypoxic conditions. The amount of ascorbyl radicals increased with rising serum concentrations. Hypoxia (0.1% O₂) globally increased the IC₅₀ of ascorbate in the 60 cancer cell lines from 4.5 ± 3.6 mM to 10.1 ± 5.9 mM (2.2‐fold increase, P < 0.001, Mann–Whitney t‐test), thus inducing cellular resistance towards ascorbate. This ascorbate resistance depended on HIF‐1α‐signalling, but did not correlate with cell line‐specific expression of the ascorbate transporter GLUT‐1. However, under normoxic and hypoxic conditions, ascorbate treatment at the individual IC₅₀ reduced the expression of GLUT‐1 in the cancer cells. Our data show a ROS‐induced, HIF‐1α‐ and O₂‐dependent cytotoxicity of ascorbate on 60 different cancer cells. This suggests that for clinical application, cancer patients should additionally be oxygenized to increase the cytotoxic efficacy of ascorbate.     

民族药四数九里香的化学成分及其细胞毒活性研究

为了阐明民族药四数九里香Murraya tetramera Huang的药效物质基础,课题组使用色谱技术从其醇提取物中分离得14个化合物;运用~1H NMR、¹³C NMR波谱方法和文献数据对比鉴定为正24烷酸(1)、9,13,17,21-tetramethyl-5-docosenoic acid(2)、3-O-β-D-吡喃葡萄糖基-山奈酚甙(3)、补骨脂素(4)、紫苏醛(5)、槲皮素(6)、methyl salicylate glucoside(7)、(9S,10R,11E,13R,15Z)-9,10,13-trihydroxyoctadeca-11,15-dienoic Acid(8)、2-isopropyl-5-methylphenol(9)、β-胡萝卜甘(10)、7-羟基香豆素(11)、七叶内酯(12)、β-谷甾醇醋酸酯(13)、山奈酚(14)。除了化合物4、6外,其他化合物为首次从该植物中分离得到。同时,研究各化合物对5株肿瘤细胞的体外生长抑制作用。与阳性对照组比较,结果表明:化合物3、4、5、6、7、8、10、11、12、13、14对白血病HL60显现良好的细胞毒活性;化合物1～14对肺腺癌A549的的细胞毒活性低于阳性对照组;化合物6、13、14对肝癌SMMC7721显现良好的细胞毒活性;化合物1、2、3、6、7、9、11、12对乳腺癌MCF7显现良好的细胞毒活性;化合物1～14对结肠癌SW480的细胞毒活性低于阳性对照组。     

Two New Dolabrane Diterpenes from the Chinese Mangrove Ceriops tagal

Two new dolabrane diterpenes, tagalenes J and K ( 1 and 2 ), together with eleven known analogues ( 3 – 13 ), were isolated from the ethanolic extract of the Chinese mangrove Ceriops tagal. The structures of these compounds were determined by extensive spectroscopic analysis, including 1D‐, 2D‐NMR and HR‐ESI‐MS, as well as the comparison with data in the literatures. Cytotoxicities of isolated compounds against MCF‐7, SW480, HepG2, HeLa, PANC‐1, and A2058 cancer cell lines were also evaluated. Compound 4 exhibited weak cytotoxic activity against SW480, HeLa, and PANC‐1 cell lines with IC₅₀ values of 27.7, 22.2, and 17.6 μm , respectively.     

Synthesis and Cytotoxicity Evaluation of Panaxadiol Derivatives

In this study, 13 panaxadiol (PD) derivatives were synthesized via reactions with aromatic compounds and amino acids. Following this, the cytotoxicity of these compounds was evaluated against four cancer cell lines (human hepatoma cells HepG‐2, human lung cancer cells A549, human breast cancer cells MCF‐7, and human colon cancer cells HCT‐116) and one normal cell lines (human gastric epithelial cells GES‐1). The results showed that the panaxadiol derivatives 3 , 12 , and 13 showed significant inhibition of cellular proliferation against cancer cells compared with PD, and the panaxadiol derivative 12 had the lowest IC₅₀ value for A549 (IC₅₀=18.91±1.03 μm ). For MCF‐7 cells, most compounds exhibited good inhibition of cellular proliferation, and the panaxadiol derivative 13 showed the strongest inhibitory effect (IC₅₀=8.62±0.23 μm ), which significantly increased the cytotoxicity of PD and was stronger than the positive control (mitomycin). For normal cells, all compounds exhibited low or no toxic effects; thus, these derivatives can be used to develop novel antiproliferative agents.     

Synthesis and antitumor activity of biotinylated camptothecin derivatives as potent cytotoxic agents

A series of biotinylated camptothecin derivatives were designed and synthesized. The key to the synthesis was achieved by employing an esterification reaction and click chemistry. All of the new derivatives were tested for cytotoxicity against five human tumor cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480 with IC₅₀ values ranging from 0.13 to 21.53?μM. Most of the derivatives exhibited potent cytotoxicity, especially compound 17 (IC₅₀?=?0.13–3.31?μM) and compound 18 (IC₅₀?=?0.23–1.48?μM), which exhibited the highest potencies. The structure-activity relationships (SARs) of the biotinylated camptothecin derivatives were discussed for exploring novel anticancer agents.     

Melanogenesis‐Inhibitory and Cytotoxic Activities of Limonoids,Alkaloids, and Phenolic Compounds from Phellodendron amurense Bark

Four limonoids, 1  –  4 , five alkaloids, 5  –  9 , and four phenolic compounds, 10  –  13 , were isolated from a MeOH extract of the bark of Phellodendron amurense (Rutaceae). Among these, compound 13 was new, and its structure was established as rel‐(1R,2R,3R)‐5‐hydroxy‐3‐(4‐hydroxy‐3‐methoxyphenyl)‐6‐methoxy‐1‐(methoxycarbonylmethyl)indane‐2‐carboxylic acid methyl ester (γ‐di(methyl ferulate)) based on the spectrometric analysis. Upon evaluation of compounds 1  –  13 against the melanogenesis in the B16 melanoma cells induced with α‐melanocyte‐stimulating hormone (α‐MSH), four compounds, limonin ( 1 ), noroxyhydrastinine ( 6 ), haplopine ( 7 ), and 4‐methoxy‐1‐methylquinolin‐2(1H)‐one ( 8 ), exhibited potent melanogenesis‐inhibitory activities with almost no toxicity to the cells. Western blot analysis revealed that compound 6 inhibited melanogenesis, at least in part, by inhibiting the expression of protein levels of tyrosinase, TRP‐1, and TRP‐2 in α‐MSH‐stimulated B16 melanoma cells. In addition, when compounds 1  –  13 were evaluated for their cytotoxic activities against leukemia (HL60), lung (A549), duodenum (AZ521), and breast (SK‐BR‐3) cancer cell lines, five compounds, berberine ( 5 ), 8 , canthin‐6‐one ( 9 ), α‐di‐(methyl ferulate) ( 12 ), and 13 , exhibited cytotoxicities against one or more cancer cell lines with IC₅₀ values in the range of 2.6 – 90.0 μm . In particular, compound 5 exhibited strong cytotoxicity against AZ521 (IC₅₀ 2.6 μm ) which was superior to that of the reference cisplatin (IC₅₀ 9.5 μm ).     

Salvisertin A,a New Hexacyclic Triterpenoid,and Other Bioactive Terpenes from Salvia deserta Root

Using various chromatographic methods, a new hexacyclic triterpenoid, 2β,3β,24β‐trihydroxy‐12,13‐cyclotaraxer‐l4‐en‐28oic acid ( 1 ), together with ten known compounds, 2α,3α,23‐trihydroxyurs‐12,20(30)‐dien‐28oic acid ( 2 ), 6,7‐dehydroroyleanone ( 3 ), horminone ( 4 ), 7‐O‐methylhorminone ( 5 ), sugiol ( 6 ), demethylcryptojaponol ( 7 ), 14‐deoxycoleon U ( 8 ), 5,6‐didehydro‐7‐hydroxy‐taxodone ( 9 ), ferruginol ( 10 ), and dichroanone ( 11 ), were isolated from the roots of Salvia deserta. Their structures were identified on the basis of spectroscopic analysis and comparison with the reported data. The individual compounds ( 1 , 3  –  8 ) were screened for cytotoxic activity, using the sulforhodamine B bioassay (SRB) method. As the results, Compounds 3 , 5 , and 8 showed cytotoxic potency against A549, MDA‐MB‐231, KB, KB‐VIN, and MCF7 cell lines with IC₅₀ values ranging from 6.5 to 10.2 μm .     

Composition,Antioxidant, and Cytotoxic Activities of the Essential Oils from Fresh and Air‐Dried Aerial Parts of Pallenis spinosa

This study was performed to determine the chemical composition, antioxidant and cytotoxic effects of essential oils extracted from the aerial parts of fresh (F‐PSEO) and air‐dried (D‐PSEO) Pallenis spinosa. The composition of the oils was analyzed by gas chromatography (GC) and GC/mass spectrometry, the antioxidant activity by free radical scavenging and metal chelating assays, and their cytotoxicity by a flow cytometry analysis. The primary components in both oils were sesquiterpene hydrocarbons and oxygentated sesquiterpenes. F‐PSEO contained 36 different compounds; α‐cadinol (16.48%), germacra‐1(10),5‐diene‐3,4‐diol (14.45%), γ‐cadinene (12.03%), and α‐muurolol (9.89%) were the principal components. D‐PSEO contained 53 molecules; α‐cadinol (19.26%), δ‐cadinene (13.93%), α‐muurolol (12.88%), and germacra‐1(10),5‐diene‐3,4‐diol (8.41%) constituted the highest percentages. Although both oils exhibited a weak radical scavenging and chelating activity, compared to α‐tocopherol and ascorbic acid, D‐PSEO showed a 2‐fold greater antioxidant activity than F‐PSEO. Furthermore, low doses of F‐PSEO were able to inhibit the growth of leukemic (HL‐60, K562, and Jurkat) and solid tumor cells (MCF‐7, HepG2, HT‐1080, and Caco‐2) with an IC₅₀ range of 0.25 – 0.66 μg/ml and 0.50 – 2.35 μg/ml, respectively. F‐PSEO showed a ca. 2 – 3‐fold stronger cytotoxicity against the tested cells than D‐PSEO. The potent growth inhibitory effect of the plant essential oil encourages further studies to characterize the molecular mechanisms of its cytotoxicity.     

Synthesis and biological activity of new bisbenzofuran-imidazolium salts

A series of novel bisbenzofuran-imidazolium salts were designed and prepared. The in vitro antitumor activity of these derivatives was evaluated against a panel of human tumor cell lines (A549, HL-60, MCF-7, SMMC-7721 and SW480). Results demonstrated that 2-methyl-benzimidazole ring and substitution of the imidazolyl-3-position with a 4-methoxyphenacyl or 2-naphthylacyl substituent were important for promoting cytotoxic activity. Notably, compound 23 was found to be the most potent compound with IC₅₀ values of 0.64–1.47 μM against five human tumor cell lines, and exhibited higher selectivity to MCF-7 and SW-480 cell lines with IC₅₀ values 15.3-fold and 9.1-fold lower than DDP.     

Synthesis of Lanostane‐Type Triterpenoid N‐Glycosides and Their Cytotoxicity against Human Cancer Cell Lines

Seventeen lanostane‐type triterpenoid derivatives ( 2 – 18 ), including 11N‐glycosides ( 8 – 18 ), were synthesized from the natural triterpenoid, lanosterol ( 1 ), and were evaluated for their cytotoxicity against the human cancer cell lines, HL‐60, A549, and MKN45, as well as the normal human lung cells, WI‐38. Among them, N‐β‐d ‐2‐acetamido‐2‐deoxyglucoside ( 10 ) showed cytotoxicity against HL‐60, A549, MKN45, and WI‐38 cells (IC₅₀ 0.0078 – 2.8 μm ). However, N‐β‐d ‐galactoside ( 12 ) showed cytotoxicity against HL‐60 and MKN45 cells (IC₅₀ 0.0021 – 4.0 μm ), but not the normal WI‐38 cells. Furthermore, Western blot analysis suggested that 12 induces apoptosis by activation of caspases‐3, 8, and 9. These results will be useful for the synthesis of other tetracyclic triterpenoids or steroid N‐glycosides to increase their cytotoxicity and apoptosis‐inducing activities.     

Chemical Characterization and Biological Activities of Phenolic‐Rich Fraction from Cauline Leaves of Isatis tinctoria L. (Brassicaceae) Growing in Sicily,Italy

The present work focused on the evaluation of the antioxidant and cytotoxic activities of the phenolic‐rich fraction (ItJ‐EAF) obtained from cauline leaves collected in January from Isatis tinctoria L. (Brassicaceae) growing wild around Acireale (Sicily, Italy). The total phenolic, flavonoid, and condensed tannin contents of the fraction were determined spectrophotometrically, whereas the phenolic profile was assessed by HPLC‐PDA/ESI‐MS analysis. A total of 20 compounds were positively identified and twelve out of them were never previously reported in I. tinctoria leaves. The fraction exhibited good radical scavenging activity in DPPH test (IC₅₀ = 0.6657 ± 0.0024 mg/ml) and reducing power (3.87 ± 0.71 ASE/ml), whereas, it neither showed chelating activity nor was able to counteract H₂O₂ induced oxidative stress damage in Escherichia coli. The antiproliferative effect was evaluated in vitro on two human anaplastic thyroid carcinoma cell lines (CAL‐62 and 8505C) by MTT assay. At the highest tested concentration ItJ‐EAF significantly reduced (80%) the growth of CAL‐62 cells. No cytotoxicity against Artemia salina was observed. It can be concluded that I. tinctoria cauline leaves represent a source of phenolic compounds which could be potentially used as chemopreventive or adjuvant agents against cancer.     

Biological Activities of Triterpenoids and Phenolic Compounds from Myrica cerifera Bark

Seven triterpenoids, 1  –  7 , two diarylheptanoids, 8 and 9 , four phenolic compounds, 10  –  13 , and three other compounds, 14  –  16 , were isolated from the hexane and MeOH extracts of the bark of Myrica cerifera L. (Myricaceae). Among these compounds, betulin ( 1 ), ursolic acid ( 3 ), and myricanol ( 8 ) exhibited cytotoxic activities against HL60 (leukemia), A549 (lung), and SK‐BR‐3 (breast) human cancer cell lines (IC₅₀ 3.1 – 24.2 μm ). Compound 8 induced apoptotic cell death in HL60 cells (IC₅₀ 5.3 μm ) upon evaluation of the apoptosis‐inducing activity by flow cytometric analysis and by Hoechst 33342 staining method. Western blot analysis on HL60 cells revealed that 8 activated caspases‐3, ‐8, and ‐9 suggesting that 8 induced apoptosis via both mitochondrial and death receptor pathways in HL60. Upon evaluation of the melanogenesis‐inhibitory activity in B16 melanoma cells induced with α‐melanocyte‐stimulating hormone (α‐MSH), erythrodiol ( 7 ), 4‐hydroxy‐2‐methoxyphenyl β‐d ‐glucopyranoside ( 13 ), and butyl quinate ( 15 ) exhibited inhibitory effects (65.4 – 86.0% melanin content) with no, or almost no, toxicity to the cells (85.9 – 107.4% cell viability) at 100 μm concentration. In addition, 8 , myricanone ( 9 ), myricitrin ( 10 ), protocatechuic acid ( 11 ), and gallic acid ( 12 ) revealed potent DPPH radical‐scavenging activities (IC₅₀ 6.9 – 20.5 μm ).