Chemical constituents from Astilbe chinensis

A new compound, 11-O-(3′-O-methylgalloyl)-bergenin (1), along with 11 known compounds (2–12), has been isolated from the rhizome of Astilbe chinensis. The chemical structure of compound 1 was determined by IR, MS, and NMR spectral data. All compounds were evaluated for the cytotoxic activity in vitro, and compound 4 showed a moderate cytotoxic activity against HepG2 cells.     

Synthesis and anti-HIV activity of 2-, 3-, and 4-substituted analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)

Several analogues of a new lead for anti-HIV-1 agents, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), in which the C-2, N-3, or C-4 position was modified were synthesized. These involve 2-thiothymine (11), 2-thiouracil (12), 4-thiothymine (17), 4-thiouracil (18), 5-methylcytosine (27), and cytosine (28) derivatives. Preparation of N-3-substituted derivatives (29 and 30) of HEPT was also carried out. Among these analogues, compound 11 exhibited excellent activity against HIV-1 HTLV-IIIB strain with an EC50 value of 0.98 microM, which is 7-fold more potent than that of HEPT. Removal of the 5-methyl group in compound 11 results in total loss of activity. Other compounds did not show any anti-HIV-1 activity. The 4-thio derivatives 17 and 18 were found to be rather cytotoxic. When compound 11 was evaluated for its inhibitory effects on another HIV-1 strain, HTLV-IIIRE, and two HIV-2 strains, LAV-2ROD and LAV-2EHO, it proved equally inhibitory to HTLV-IIIRF, whereas both HIV-2 strains were insensitive to the compound.     

Sesquiterpene lactone glycosides,eudesmanolides, and other constituents from Carpesium macrocephalum

Two new sesquiterpene lactone glycosides and two new eudesmanolides, along with twelve known compounds were isolated from seeds of Carpesium macrocephalum. The structures of these new compounds were elucidated as 2alpha- O-beta- D-glucopyranosyl-5alpha, 11alpha H-eudesma-4(15)-en-12,8beta-olide ( 1), 2alpha- O-beta- D-glucopyranosyl-5alpha H-eudesma-4(15),11(13)-dien-12,8beta-olide ( 2), 2alpha-acetoxy-5alpha-hydroxy-11alpha H-eudesma-4(15)-en-12,8beta-olide ( 3) and 2alpha,5alpha-dihydroxy-11alphaH-eudesma-4(15)-en-12,8beta-olide ( 4) by spectroscopic methods including 2D NMR techniques ( (1)H- (1)H COSY, (1)H- (1)H NOESY, HMQC, HMBC) and chemical transformations. Compounds 1, 6, 8, 9 and 10 exhibited moderate antibacterial activity, while compound 4 showed appreciable cytotoxic activity against cultured SMMC-7721 (human hepatoma cell).     

New flavonol glycosides and new xanthone from Polygala japonica

Three new flavonol glycosides and a new xanthone were isolated from Polygala japonica HOUTT. with eight known compounds. Their structures were identified as 1,7-dihydroxy-3,4-dimethoxy-xanthone (1), kaempferol-7,4'-dimethyl ether (2), physcion (3), guazijinxanthone (4), rhamnetin (5), polygalin A (6), 3,5,7-trihydroxy-4'-methoxy-flavone-3-O-beta-d-galactopyranoside (7), 3,5,3'-trihydoxy-7,4'-dimethoxy-flavone-3-O-beta-d-galactopyranoside (8), 3,5,3',4'-tetrahydroxy-7-methoxy-flavone-3-O-beta-d-galactopyranoside (9), 3,5,3',4'-tetrahydroxy-7-methoxy-flavone-3-O-beta-d-glucopyranoside (10), polygalin B (11), polygalin C (12). Among them, compound 4 is a new xanthone, and 6, 11 and 12 are new flavonol glycosides. Compounds 1, 4, 7 and 8 were tested for cytotoxic activity with MTT assays on five human tumor cell lines, K562, A549, PC-3M, HCT-8 and SHG-44. Compound 4 showed cytotoxic activity against all the five cell lines.     

Cytotoxic agents from Terminalia arjuna

Although a number of chemicals have been isolated from Terminalia arjuna, only a few have been evaluated for their biological significance. As a part of our drug discovery programme for cytotoxic agents from Indian medicinal plants, four novel cytotoxic agents arjunic acid (1), arjungenin (2), arjunetin (3) and arjunoglucoside I (4) were isolated from the bark of T. ARJUNA. Out of the four compounds, arjunic acid (1) was significantly active against the human oral (KB), ovarian (PA 1) and liver (HepG-2 & WRL-68) cancer cell lines. Further, the most active compound arjunic acid was converted into seven semi-synthetic ester derivatives 5 - 11. 2-O-Palmitoyl arjunic acid (6) showed two times more activity, while 2, 3-di-O-acetyl-, 2-O-p-anisoyl-, 2, 3-di-O-benzoyl- and 2, 3-di-O-p-nitrobenzoyl arjunic acid (7 - 10) showed 1.7 - 2.3 times less activity than the cytotoxic drug vinblastine against the liver cancer cell lines HepG-2 and WRL-68 respectively.     

Synthesis and antiviral and cytotoxic activity of iodohydrin and iodomethoxy derivatives of 5-vinyl-2'-deoxyuridines, 2'-fluoro-2'-deoxyuridine, and uridine

A series of new 5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine and uridine compounds (11, 16) was synthesized by the regiospecific addition of HOI to the vinyl substituent of 5-vinyl-2'-deoxyuridine (10a), 5-vinyl-2'-fluoro-2'-deoxyuridine (10b), 5-vinyluridine (10c), and (E)-5-(2-iodovinyl)-2'-deoxyuridine (4b). Treatment of the iodohydrins 11a-c with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-iodoethyl) derivatives (12a-c). In contrast, reaction of 5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine (11a) with sodium carbonate in methanol afforded a mixture of 5-(1-hydroxy-2-methoxyethyl)-2'-deoxyuridine (13) and 2,3-dihydro-3-hydroxy-5-(2'-deoxy-beta-D-ribofuranosyl)- furano[2,3-d]pyrimidin-6(5H)-one (14). The most active compound, 5-(1-methoxy-2-iodoethyl)-2'-deoxyuridine (12a, ID50 = 0.1 micrograms/mL), which exhibited antiviral activity (HSV-1) 100-fold higher than that of the 5-(1-hydroxy-2-iodoethyl) analogue (11a), was less active than IVDU or acyclovir (ID50 = 0.01-0.1 micrograms/mL range). The C-5 substituent in the 2'-deoxyuridine series was a determinant of cytotoxic activity, as determined in the in vitro L1210 screen, where the relative activity order was CH(OH)CHI2 (16) greater than CH(OMe)CH2I (12a) greater than CH(OH)CH2I (11a) congruent to CH(OH)CH2OMe (13). The 2'-substituent was also a determinant of cytotoxic activity in the 5-(1-hydroxy-2-iodoethyl) (11a-c) and 5-(1-methoxy-2-iodoethyl) series of compounds, where the relative activity profile was 2'-deoxyuridine greater than 2'-fluoro-2'-deoxyuridine greater than uridine (11a greater than 11b greater than or equal to 11c; 12a greater than 12b greater than 12c). The most active cytotoxic agent (16), possessing a 5-(1-hydroxy-2,2-diiodoethyl) substituent (ED50 = 0.77 micrograms/mL), exhibited an activity approaching that of melphalan (ED50 = 0.15 micrograms/mL). All compounds tested, except for 13 and 14, exhibited high affinity (Ki = 0.035-0.22 mM range relative to deoxyuridine, Ki = 0.125) for the murine NBMPR-sensitive erythrocyte nucleoside transport system, suggesting that these iodohydrins are good permeants of cell membranes.     

Two new casbane diterpenoids from the roots of Euphorbia pekinensis

From the roots of Euphorbia pekinensis, two new casbane diterpenoids, named pekinenins A (1) and B (2), were isolated. Their structures were elucidated as 18-hydroxy-1βH,2αH-casba-3E,7E,11E-trien-5-one (1), 5α-methoxy-1βH,2αH-casba-3Z,7E,11E-trien-18-oic acid (2) by a combination of 1D and 2D NMR spectroscopy and mass spectrometry. In the cytotoxicity assay of the two new compounds against Hela, MCF-7, and C6 human cancer cell lines, compound 1 showed moderate cytotoxic activity against two human cancer cell lines, Hela and C6, with IC(50) values of 42.97 and 50.00?μM, respectively.     

A novel degraded sesquiterpene from the fresh stem of Aquilaria sinensis

A novel degraded sesquiterpene, named aquilarin B (1), together with two known compounds (2 and 3), was isolated from the EtOH extract of the fresh stem of Aquilaria sinensis (Lour.) Gilg. Their structures were elucidated by spectroscopic methods including 1D and 2D NMR (HMQC, (1)H-(1)H COSY, HMBC, and ROESY). The cytotoxic activities of the three compounds against three human tumor cell lines K562, SMMC-7721, and SGC-7901 were evaluated, and compound 3 exhibited obvious cytotoxic activity.     

Synthesis of some novel quinolines and pyrimido [4,5-b] quinolines bearing A sulfonamide moiety as potential anticancer and radioprotective agents

Some novel 4-(quinolin-1-yl)-benzenesulfonamide and 4-(pyrimido[4,5-b]quinolin-10-yl)-benzenesulfonamide derivatives have been synthesized. All the newly synthesized target compounds were subjected to in vitro cytotoxic screening to be evaluated for their anticancer activity against Ehrlich ascites carcinoma cells. Among these new compounds, compounds 9a, 11, 12b, 18 and, in particular, 19 showed promising in vitro cytotoxic activity compared with doxorubicin (CAS 23214-92-8) as a reference drug. Moreover, compound 8 exhibited in vivo radioprotective activity against gamma-irradiation in mice.     

Bioactivity of compounds isolated from the leaves of the Lantana camara Linn plant

Two compounds with different bioactivitieswere isolated from the leaves of the Lantana camara Linn plant. Compound 1wastriterpenoid (Lantadene B)(22β-dimethylacroyloxy-3-oxoolean-12-en-28-oic-acid, C₃₅H₅₂O₅), which was isolatedfrom n-hexane fraction and obtained as white solid (amorphous). Compound 2was glycosideflavonoid (5-hydroxy-6,4′-dimethoxyflavon-7-O-glucopyranose, C₂₃H₂₄O₁₁), which was isolated from ethyl acetate and obtained as pale yellow solid (amorphous). Extraction was performed withmaceration method using methanol solvent. Subsequently, fractionation was carried out using n-hexane and ethyl acetate solvents. Isolation and purification of both fractions were conductedusing chromatography method. The structure of the isolated compounds was determined throughspectralanalyses of ultraviolet (UV), infrared (IR), and nuclear magnetic resonance (¹H NMR and ¹³C NMR), distortionless enhancement by polarization transfer (DEPT), heteronuclear multiple bond connectivity (HMBC), heteronuclear single quantum correlation (HSQC), and H-H COSY (¹H-¹H homonuclear correlatedspectroscopy). The cytotoxic activity of compound 1 was tested against MCF-7 breast cancer cellsin vitro using MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), showing very strong cytotoxic activity in inhibiting the growth of MCF-7 breast cancer cells, and the IC₅₀ value was 1.1336 µM. The antioxidant activity of compound 2 was tested using DPPH assay (1,1-diphenyl-2-picrylhydrazyl), showing strong activity in inhibiting free radicals, and its IC₅₀ value was 71.03 mg/L.     

1, 2, 4-Triazine N-oxide derivatives: studies as potential hypoxic cytotoxins. Part III

New 5-(2-arylethenyl)-1, 2, 4-triazine N-oxide and N, N'-dioxide derivatives were synthesized in order to obtain compounds as selective hypoxic cell cytotoxins. The desired products were obtained when the 5-methyl heterocycle reacted with the corresponding iminium electrophiles. The new compounds were tested for their cytotoxicity in oxia and hypoxia. Some of them proved to be less active in hypoxic conditions than Tirapazamine, 3-aminobenzo[1, 2-e]1, 2, 4-triazine N(1), N(4)-dioxide. Derivative 11, 6-methyl-5-[2-(5-nitrofuryl)ethenyl)-1, 2, 4-triazine N(4)-oxide, was the most cytotoxic compound, but it was non-selective. Some derivatives were studied as DNA-binding agents in oxic conditions showing poor affinity for this biomolecule. This result showed that the cytotoxic activity in oxia is DNA damage not dependent. Electrochemical and ESR spectroscopy studies were performed in order to determine the ability of compounds to produce radicals and the relation of these in the mechanism of cytotoxicity.     

Combined effect of platination and intercalation upon DNA binding of novel cytotoxic Pt-bis(naphthalimide) complexes

The reaction of platinum salts with bis(naphthalimide), compound 1, yielded two Pt-bis(naphthalimide) complexes, compounds 2 and 3 which differ from each other in their leaving groups being 1,1-cyclobutane dicarboxylate or chloride, respectively. The testing of the cytotoxic activity of compounds 2 and 3 against several tumor cell lines indicated that both compounds may be endowed with important antineoplastic properties since they circumvent cisplatin resistance. At similar rates of DNA platination (r(b) = 0.025), compounds 2 and 3 unwind supercoiled pUC8 DNA by (48 +/- 2) degrees. Altogether, these data suggest (i) that the cytotoxic activity of compounds 2 and 3 may be due to a combined effect of platination and intercalation and (ii) that the bis(naphthalimide) ligand is a suitable "carrier" that favors DNA targeting by cis-Pt(II) centers.     

Phenanthroindolizidine alkaloids as cytotoxic substances in a Danaid butterfly, Ideopsis similis, against human cancer cells

We previously reported the presence of cytotoxic substances in extracts of the Danaid butterfly, Ideopsis similis. In the present study, we isolated cytotoxic substances against a human gastric cancer cell line, TMK-1, in I. similis pupae, with an activity similar to that of the adult butterfly. The basic fraction, prepared from a methanol extract, accounted for 83% of the cytotoxic activity. Two major cytotoxic substances were purified by HPLC, and one was determined to be a new phenanthroindolizidine alkaloid, trans-(+)-3,14alpha-dihydroxy-6,7-dimethoxyphenanthroindolizidine (1), and the other a known compound, trans-(+)-3,14alpha-dihydroxy-4,6,7-trimethoxyphenanthroindolizidine (2). The IC(50) values for TMK-1 cells were 0.5 ng/mL and 0.7 ng/mL, respectively. These two compounds showed similar cytotoxic potential with four other cancer cell lines including cervical, lung, and colon carcinomas and leukemia. Quantitative analyses indicated the presence of each of the two phenanthroindolizidine alkaloids at levels of 11-74 microg in each larva, pupa, or adult of I. similis. However, 1 was not detected in the leaves of Tylophora tanakae, a host plant for larvae of I. similis, and the level of 2 (2 microg per gram of leaves) was far less than that in the larvae. Since the leaves of T. tanakae are known to contain various phenanthroindolizidines, compounds 1 and 2 are presumably metabolically converted from such alkaloids in larvae of I. similis.     

Cytotoxic activity of polyacetylenes and polyenes isolated from roots of Echinacea pallida

BACKGROUND AND PURPOSE: The n-hexane extracts of the roots of three medicinally used Echinacea species exhibited cytotoxic activity on human cancer cell lines, with Echinacea pallida found to be the most cytotoxic. Acetylenes are present in E. pallida lipophilic extracts but essentially absent in extracts from the other two species. In the present study, the cytotoxic effects of five compounds, two polyacetylenes (namely, 8-hydroxy-pentadeca-(9E)-ene-11,13-diyn-2-one (1) and pentadeca-(9E)-ene-11,13-diyne-2,8-dione (3)) and three polyenes (namely, 8-hydroxy-pentadeca-(9E,13Z)-dien-11-yn-2-one (2), pentadeca-(9E,13Z)-dien-11-yne-2,8-dione (4) and pentadeca-(8Z,13Z)-dien-11-yn-2-one (5)), isolated from the n-hexane extract of E. pallida roots by bioassay-guided fractionation, were investigated and the potential bioavailability of these compounds in the extract was studied. EXPERIMENTAL APPROACH: Cytotoxic effects were assessed on human pancreatic MIA PaCa-2 and colonic COLO320 cancer cell lines. Cell viability was evaluated by the WST-1 assay and apoptotic cell death by the cytosolic internucleosomal DNA enrichment and the caspase 3/7 activity tests. Caco-2 cell monolayers were used to assess the potential bioavailability of the acetylenes. KEY RESULTS: The five compounds exhibited concentration-dependent cytotoxicity in both cell types, with a greater potency in the colonic cancer cells. Apoptotic cell death was found to be involved in the cytotoxic effect of the most active, compound 5. Compounds 2 and 5 were found to cross the Caco-2 monolayer with apparent permeabilities above 10 x 10(-6) cm s(-1). CONCLUSIONS AND IMPLICATIONS: Compounds isolated from n-hexane extracts of E. pallida roots have a direct cytotoxicity on cancer cells and good potential for absorption in humans when taken orally.     

海洋真菌Aspergillus sp.HH-3中1个新的抗肿瘤硫代二酮哌嗪类化合物

目的 研究海泥真菌Aspergillus sp.HH-3的次级代谢产物及其抗肿瘤活性。方法 使用硅胶色谱柱、LH-20凝胶色谱等对代谢粗提物进行分离纯化;运用核磁共振、质谱等方法并结合文献报道数据确定化合物的结构;采用CCK-8法评价化合物对三种肿瘤细胞(A549、HepG2、Hela)的抑制活性。结果 从Aspergillus sp.HH-3中分离获得六个化合物,包括一个新的硫代二酮哌嗪类化合物aspersin(1)与五个已知化合物dehydroxymethylbis(dethio)bis(methylthio)gliotoxin(2)、trypacidin(3)、monomethylsubchrin(4)、verruculogen(5)及chaetominine(6)。化合物1、2和6显示有一定的肿瘤细胞抑制活性。结论 化合物1为新的硫代二酮哌嗪类化合物;化合物1、2和4具有肿瘤细胞毒活性。     

New eremophilenolides from Cacalia pilgeriana

Five new eremophilenolides and a known sesquiterpene were isolated from the methanol extract of the roots of Cacalia pilgeriana. Their structures were identified as 1 beta-hydroxy-2 beta-methyl-senecioyloxyeremophil-7(11)-en-8 beta(12)-olide (1), 1 beta-hydroxy-2 beta-methylsenecioyloxy-8 alpha-methoxyeremophil-7(11)-en- 8 beta(12)-olide, 2 beta-hydroxy-3 beta-methylsenecioyloxyeremophil-7(11)-en-8 alpha(12)-olide ( 3), 2 beta,8 beta-dihydroxy-3 beta-methylsenecioyloxyeremophil-7(11)-en-8 alpha(12)-olide and 1 beta,8 beta-dihydroxy-2 beta,3 alpha-diangeloyloxyeremophil-7(11)-en-8 alpha(12)-olide ( 5) and caryolane-1,9 beta-diol by spectroscopic methods including 2D-NMR techniques ( (1)H- (1)H COSY, HMQC, HMBC) and HR-ESI-MS. The structure and relative stereochemistry of compound 1 were unequivocally established by X-ray diffraction analysis. Bioassays showed compounds 3 and 5 to possess strong cytotoxic activity in vitro against human leukemia cells (HL-60) (IC (50) < 15 microg mL (-1)). The structure-activity relationship is discussed.     

Synthesis and antibacterial evaluation of certain quinolone derivatives.

A number of 7-substituted quinolone derivatives were synthesized and evaluated for antibacterial and cytotoxic activities. Preliminary results indicated that most compounds tested in this study demonstrated better activity against methicillin-resistant Staphylococcus aureus than norfloxacin. Among them, 1-(4-amino-2-fluorophenyl)-6-fluoro-1,4-dihydro-7-[4-[2-(4-methoxyphenyl)-2-hydroxyiminoethyl]-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid (11d) and its ketone precursor 10d exhibited significant activities against Klebsiella pneumoniae, methicillin-resistant S. aureus, erythromycin- and ampicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus faecalis. Due to strong cytotoxicities of 11d (a mean log GI(50) of -5.40), compound 10d, with good antibacterial activities and low cytotoxicities (a mean log GI(50) of -4.67), is a more potential drug candidate.     

A novel isoflavonoid from Millettia puguensis

From the roots of Millettia puguensis (Leguminosae), a novel isoflavonoid (5), 2'-methoxy-4',5'-methylenedioxy-7,8-[2-(1-methylethenyl)furo]isoflavone, and four known compounds, i. e., lupeol (1), (-)-maackiain (2), 6,7-dimethoxy-3',4'-methylenedioxyisoflavone (3) and 7,2'-dimethoxy-4',5'-methylenedioxyisoflavone (4) were isolated and identified by 1H-, 13C-NMR and mass spectroscopy. All compounds were evaluated for their antiprotozoal and cytotoxic activities, but only a moderate antileishmanial activity was observed for compound 3 (IC50 = 32 microM against Leishmania infantum), and a moderate cytotoxicity for compound 2 (IC50 = 43 microM on MRC-5 cells).     

Cytotoxic triterpene and sesquiterpene lactones from Elephantopus mollis and induction of apoptosis in neuroblastoma cells

Activity-guided fractionation of root and leaf extracts from Elephantopus mollis led to the isolation of a new triterpene (1) and a new sesquiterpene lactone (2) together with five known sesquiterpene lactones (3-7). The structures of compounds 1 and 2 were determined based on their spectroscopic data. The cytotoxic activity of the isolated compounds was evaluated against neuroblastoma B104 cells. The sesquiterpene lactone-type compounds 2-7 were highly cytotoxic. Among these, compound (5) was the most cytotoxic and induced apoptosis of neuroblastoma B104 cells in a dose- and time-dependent manner. No significant difference was observed for cytotoxicity of compound 5 towards all 3 cell lines tested.     

New 8-substituted xanthiene derivatives as potent bronchodilators

The synthesis and structure determination of 8-aryl /alkyl aryl 1, 3-dimethyl-3, 7-dihydropurin-2, 6-dione derivatives (1-13), was carried out in this study. Bronchodilator activity is investigated using isolated guinea-pig tracheal strips, pre-contracted by acetylcholine and histamine. Spasmolytic activity of the compounds was compared to theophylline. Synthesized compounds (1-13) did not inhibit the acetylcholine-induced pre-contractions except compound (8) at 10(-5) M concentration. In contrast, some of the compounds, especially (7), (11), (12) at 10(-5) M and (3), (4), (9) and (11) in 10(-4) M displayed inhibitory activity on the tracheal strips pre-contracted by histamine. The potency of the compounds at human adenosine receptors was evaluated using radioligand binding assay and a cyclic AMP functional assay in CHO cells expressing these receptors. Compound (11) displayed the greatest activity against radioligand binding of specific agonists to A2A and A2B receptors. The compounds were relatively selective for both A2A and A2B compared with A1 and A3 receptors. All compounds were also tested for the inhibition of NECA-induced cAMP accumulation mediated by the A2B adenosine receptor and compound (11) was found to be the most effective. Our results showed that these compounds are acting as selective adenosine antagonists, especially for adenosine A2B receptors, and are promising as potent anti-inflammatory agents rather than bronchodilator for the treatment of asthma.