Acetylated sesterterpenes from the Great Barrier Reef sponge Luffariella variabilis

Chemical investigation of the sponge Luffariella variabilis collected from the Palm Island group of the Great Barrier Reef, Australia, yielded three new acetylated compounds, 25-acetoxyluffariellin A (1), 25-acetoxyluffariellin B (2), and 25-acetoxyseco-manoalide (3). The structures of the new compounds were elucidated on the basis of interpretation of their spectroscopic data. The known metabolites manoalide (4), seco-manoalide (5), luffariellin A (8), and manoalide monoacetate (10) were also isolated. The new acetylated compounds (1-3) were labile in the sponge tissue when samples were allowed to thaw prior to extraction, but were stable once isolated. Sponge samples that were completely thawed contained only hydroxylated compounds (alcohols). This finding supported the deduction that the acetylated compounds are being enzymatically transformed and/or degraded.     

Cytotoxic dihydroagarofuranoid sesquiterpenes from the seeds of Celastrus orbiculatus

A chemical study on the seeds of Celastrus orbiculatus has led to the isolation of nine new (1- 9) and 13 known dihydro-beta-agarofuran derivatives. The identification and structural elucidation of the new compounds were based on spectroscopic data analysis, and the absolute configurations of compounds 1- 6, 8-10, and 16, as well as derivatives 2a and 6a, were determined by CD studies or by chemical methods. All compounds isolated were evaluated for cytotoxic activity against HL-60 human leukemia cells.     

Hydroxylation of yohimbine in superacidic media: one-step access to human metabolites 10 and 11-hydroxyyohimbine.

Two major human metabolites of yohimbine (1), 10- and 11-hydroxyyohimbine (2 and 3), were prepared by direct hydroxylation of 1 under superacidic conditions. In this medium, the four positions of the benzene part of yohimbine were hydroxylated and the corresponding monohydroxylated compounds (2-5) were isolated. The structures of 2-5 were elucidated by spectroscopic methods including 1D and 2D NMR techniques.     

Dammarane-type triterpenes from the Brazilian medicinal plant Cordia multispicata

From the Brazilian medicinal plant Carucaá (Cordia multispicata), oleanane- and ursane-type triterpenoids were previously reported as anti-androgenic constituents of the plant. In this study, purification of the polar elements of the EtOAc-soluble fraction of the plant revealed nine novel dammarane-type triterpenes, named cordianols A-I (1-9) along with the known compound cordialin A (10). The structures of these new compounds were elucidated by means of spectral methods including HRFABMS, (1)H NMR, (13)C NMR, and 2D NMR (HMQC, HMBC, NOESY). Absolute configuration at C-23 of compound 7 was determined by an excitone chirality method. Some of these new compounds revealed a hemiketal structure on the A ring and a hydroxylated or epoxidated 20(22)-(E)-ene side chain and showed weak anti-androgenic activity.     

Synthesis of A-seco derivatives of betulinic acid with cytotoxic activity

In this study, the relationships between the chemical structure and cytotoxic activity of betulinic acid (1) derivatives were investigated. Eight lupane derivatives (1-8), one of them new (6), five diosphenols (9-13), four of them new (10-13), two new norderivatives (14 and 15), five seco derivatives (16-20), four of them new (16, 17, 19, and 20), and three new seco-anhydrides (21-23) were synthesized from 1, and their activities were compared with the activities of known compounds. The effects of substitution on the A-ring and esterification of the carboxyl group in position 28 on cytotoxicity were of special interest. Significant cytotoxic activity against the T-lymphoblastic leukemia cell line CEM was found in diosphenols 9 and 13 (TCS(50) 4 and 5 micromol/L) and seco-anhydrides 22 and 23 (TCS(50) 7 and 6 micromol/L). All compounds were also tested on cancer cell lines HT 29, K562, K562 Tax, and PC-3, and these confirmed activity of diosphenols 9, 10, and 11 and anhydride 22. Diosphenols, as the most promising group of derivatives, were further tested on four more lines (A 549, DU 145, MCF 7, SK-Mel2).     

Antibacterial anthraquinone derivatives from a sea anemone-derived fungus Nigrospora sp

Chemical investigation of a marine-derived fungus Nigrospora sp., isolated from an unidentified sea anemone, yielded two new hydroanthraquinone analogues, 4a-epi-9α-methoxydihydrodeoxybostrycin (1) and 10-deoxybostrycin (2), together with seven known anthraquinone derivatives (3-9). The structures of the two new compounds were established through extensive NMR spectroscopy as well as a single-crystal X-ray diffraction analysis using Cu Kα radiation. The antibacterial activities of compounds 1-9 and 10 acetyl derivatives (6a, 7a, 8a-8g, 9a) were evaluated in vitro. Compound 6a, the acetylated derivative of 6, exhibited promising activity against Bacillus cereus with an MIC value of 48.8 nM, which was stronger than that of the positive control ciprofloxacin (MIC = 1250 nM). Analysis of the antibacterial screening data for the metabolites and their acetyl derivatives revealed the key structural features required for this activity.     

Antimycobacterial serratamolides and diacyl peptoglucosamine derivatives from Serratia sp

The cyclodepsipeptide serratamolide A ( 1) and five closely related compounds together with three new glucosamine derivatives were isolated by bioactivity-guided chromatography from the XAD adsorber resin extract of a Serratia sp. The structures of the compounds were elucidated by 2D NMR and MS analyses. In addition to the known serratamolide A ( 1) with two C 10 alkyl chains, its derivatives always contained one C 10 chain combined with either C 12:1, C 12, C 11, C 9, or C 8 chains. The glucosamine derivatives contained a common core consisting of an N-butyl-alpha-glucopyranosylamide, which was acylated at the C-1 oxygen with valine. The differences between the derivatives arise from the nature of the acyl groups attached to the N-terminus of valine, which were identified as the linear fatty acid moieties C 16:1, C 15, or C 14. Each compound was present in two isomeric forms arising from racemization of the valine moiety. All compounds showed antibiotic activity against Mycobacterium diernhoferi and other rapidly growing mycobacteria.     

Natural and synthetic 2,2-dimethylpyranocoumarins with antibacterial activity

A new efficient synthetic approach to the natural coumarins 5-hydroxyseselin (5), 5-methoxyseselin (3), and (+/-) cis-grandmarin (9) is described as well as the synthesis of some new derivatives in the 5-methoxyseselin series (10-15). The natural coumarins 7-hydroxyalloxanthyletin (6), alloxanthoxyletin (8), and dipetalolactone (7) have also been obtained as secondary products. The type of fusion of the pyrano ring in all cases has been established by 2D NMR spectroscopy. The compounds have been studied for their in vitro antibacterial activity, which has been compared with that of some previously synthesized seselin derivatives. The most active compounds were 3, 7, 8, 11, and 14. Some structure-activity relationships are discussed.     

Melophlins C-O,thirteen novel tetramic acids from the marine sponge Melophlus sarassinorum

Thirteen new metabolites, melophlins C-O (1-13), were identified from the marine sponge Melophlus sarassinorum. Compounds 1-13 represent tetramic acid derivatives that differ with regard to the nature of their alkyl side chains. The structures of the new compounds were elucidated on the basis of comprehensive spectral analysis (1H, 13C, 1H-1H COSY, HMQC, and HMBC NMR, as well as low- and high-resolution ESIMS and EIMS). The absolute configurations of 1, 8, 10, 11, 12, and 13 were determined by ESI LC/MS analysis of chiral derivatives obtained upon oxidation and hydrolysis of the respective parent compounds. Melophlin C (1) displayed pronounced antibacterial activity against Bacillus subtilisand Staphylococcus aureus, together with antifungal activity against Candida albicans.     

Nigerapyrones A-H, α-pyrone derivatives from the marine mangrove-derived endophytic fungus Aspergillus niger MA-132

Eight new α-pyrone derivatives, namely, nigerapyrones A-E (1-5) and nigerapyrones F-H (8-10), along with two known congeners, asnipyrones B (6) and A (7), were isolated from Aspergillus niger MA-132, an endophytic fungus obtained from the fresh tissue of the marine mangrove plant Avicennia marina. The structures of these compounds were elucidated on the basis of spectroscopic analysis. The undescribed geometries of the trisubstituted double bonds (C-9 and C-11) for asnipyrone B (6) have now been explicitly determined, while the incorrect placement of the methyl group at C-5 of asnipyrone A (7) has now been revised at C-3. The cytotoxic activities of the isolated α-pyrone derivatives against eight tumor cell lines as well as antimicrobial activities against two bacteria and four plant-pathogenic fungi of these compounds were evaluated. Compounds 2, 4, 5, and 7 showed weak cytotoxicity against some of the tested tumor cell lines.     

6-�л�-3-����-7H-����[3,2-b]-1,2,4-���-7-ͪ�໯����ĺϳɼ�������������ø���ƻ���

??OBJECTIVE To explore the synthesis and acetylcholinesterase inhibitory activity of 6-benzyl-3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives. METHODS Benzaldehyde and acetylglycine were used as raw materials and underwent Erlenmeyer-Pl??chl reaction, condensation reaction, hydrolysis reaction, condensation reaction to obtain 6-benzyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-ones derivatives. The derivatives reacted with substituted ??-phenacyl chlorides to generate 6-benzyl-3-(hydroxylaryl)-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones derivatives. Then, Williamson reaction was used to yield 6-benzyl-3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones as target compounds. RESULTS Nine 6-benzyl-3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones were prepared as target compounds. All target compounds exhibited inhibitory activities against human AChE in vitro, five of which had inhibitory rates above 50% at 10 ??mol??L^-1. CONCLUSION Based on the screening results of AChE inhibitory activity in vitro and docking studies, there are some interactions between 6-benzyl-3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives and the anionic binding site and PAS zones of AChE, and the target compounds have exhibited AChE inhibitory activities.     

Sesquiterpene and xanthone derivatives from the sea fan-derived fungus Aspergillus sydowii PSU-F154

Three new sesquiterpenes, named aspergillusenes A and B and (+)-(7S)-7-O-methylsydonic acid, and two new hydrogenated xanthone derivatives, named aspergillusones A and B, were isolated from the sea fan-derived fungus Aspergillus sydowii PSU-F154 together with 10 known compounds. Their structures were identified on the basis of spectroscopic data. The isolated compounds were evaluated for their antioxidant activity.     

Antioxidative meroterpenoids from the brown alga Cystoseira crinita

Six new tetraprenyltoluquinol derivatives (1-6), two new triprenyltoluquinol derivatives (7 and 8), and two new tetraprenyltoluquinone derivatives (9 and 10) were isolated from the brown alga Cystoseira crinita Duby together with four known tetraprenyltoluquinol derivatives (11-14). All structures were elucidated by employing spectroscopic techniques (NMR, MS, UV, and IR). Each compound was evaluated for its antioxidative properties in the TBARS and DPPH assay, and compounds 1, 2, 6, and 10-14 were additionally assessed in the TEAC and PCL assay. Hydroquinones were found to have powerful antioxidant activity.     

New lamellarin alkaloids from the australian ascidian, didemnum chartaceum

Five novel lamellarin-class alkaloids have been isolated from a Great Barrier Reef ascidian, Didemnum chartaceum. The structures of the 20-sulfated derivatives of lamellarins B, C, and L (1-3); the 8-sulfated derivative of lamellarin G (4), plus a nonsulfated compound, lamellarin Z (5), were identified by interpretation of spectroscopic data. Lamellarin G 8-sulfate (4) is the first example of this class of compounds sulfated at the C-8 position, while lamellarin Z (5) is the first example of a dimethoxylated lamellarin. The known lamellarins A, B, C, E, G, and L (6-11), plus the triacetate derivatives of lamellarins D (12) and N (13), were also isolated. An aberration in the integration of signals in the 1H NMR spectra of the 20-sulfated derivatives of lamellarins B, C, and L (1-3) led to NMR relaxation studies. T1 values were calculated for all protons in the sulfated lamellarins (1-4) and their corresponding nonsulfated derivatives (7, 8, 10, 11). Interestingly, the protons ortho to the sulfate group in compounds (1-4) had T1 values up to five times larger than the corresponding protons in their nonsulfated derivatives (7, 8, 10, 11).     

Synthesis and biological evaluation of a natural ester sintenin and its synthetic analogues

Synthesis of 3-(3,4-dimethoxyphenyl)propyl-3-(3,4-dimethoxyphenyl) propanoate (18), a cytotoxic natural ester, was carried out by a convenient synthetic path with a total yield of 49%. Sixteen of its analogues (19-34) were also prepared. Seventeen unsaturated derivatives of 18, compounds 1-17, were also synthesized to examine the structure-activity relationship of this type of ester. All of the synthetic compounds were passed through the cytotoxicity screenings on human tumor cell lines, such as PC-3, Hela, A549, BEL7404, CNE, and KB. Some of the esters exhibited moderate inhibitory effects on these tumor cell lines. The phenolic derivatives exhibited the highest cytotoxicity among these derivatives, while the unsaturated esters were more cytotoxic than the saturated analogues. Some of the compounds also exhibited inhibition on alpha-glucosidase.     

Synthesis and evaluation of hydroxylated flavones and related compounds as potential inhibitors of the protein-tyrosine kinase p56lck.

An array of hydroxylated flavones and related compounds was synthesized and evaluated for inhibition of the in vitro protein-tyrosine kinase activity of p56lck, an enzyme that is thought to play a key role in mediating signal transduction from the CD4 receptor during lymphocyte activation. In general, the most active compounds had hydroxyl groups on both the A and C rings. At least two hydroxyl groups were required for good inhibitory activity, and the relative positions of these groups played an important role in determining potency. Compounds without hydroxyl groups were inactive as inhibitors.     

Constituents of the bark and twigs of Artocarpus dadah with cyclooxygenase inhibitory activity

Fractionation of an ethyl acetate-soluble extract of the bark of Artocarpus dadah has led to the isolation of three new prenylated stilbenoid derivatives, 3-(gamma,gamma-dimethylallyl)resveratrol (1), 5-(gamma,gamma-dimethylallyl)oxyresveratrol (2), 3-(2,3-dihydroxy-3-methylbutyl)resveratrol (3), and a new benzofuran derivative, 3-(gamma,gamma-dimethylpropenyl)moracin M (4), along with six known compounds, oxyresveratrol, (+)-catechin, afzelechin-3-O-alpha-L-rhamnopyranoside, (-)-epiafzelechin, dihydromorin, and epiafzelechin-(4beta-->8)-epicatechin. From an ethyl acetate-soluble extract of the twigs of the same plant were isolated compound 4 and two new neolignan derivatives, dadahols A (5) and B (6), as well as 10 known compounds, oxyresveratrol, (+)-catechin, afzelechin-3-O-alpha-L-rhamnopyranoside, resveratrol, steppogenin, moracin M, isogemichalcone B, gemichalcone B, norartocarpetin, and engeletin. The structures of compounds 1-6 were determined using spectroscopic and chemical methods. Isolates were evaluated for their inhibitory effects against both cyclooxygenase-1 (COX-1) and -2 (COX-2) and in a mouse mammary organ culture assay.     

neo-Clerodane diterpenoids from Ajuga bracteosa

Different neo-clerodane diterpenoids were isolated from a dichloromethane extract of Ajuga bracteosa depending on the isolation procedure used, owing to the labile nature of these tetrahydrofurofuran derivatives. Under "hydroxyl-free" purification conditions, both clerodin- and dihydroclerodin-type diterpenes were obtained [four new compounds, ajubractins A-D (1-4), along with clerodin (5), 3-epi-caryoptin (6), ajugapitin (7), 14,15-dihydroclerodin (8), 3-epi-14,15-dihydrocaryoptin (9), ivain II (10), and 14,15-dihydroajugapitin (11)]. When methanol-water mixtures were used for a C18 reversed-phase prepurification procedure and for semipreparative HPLC, the new ajubractin E (12) was also isolated along with 3 and 8-11, as previously, but 7 was the only tetrahydrofurofuran derivative obtained. Epimeric (15R and 15S) mixtures were obtained instead of 14-hydro-15-hydroxyclerodin derivatives [15-hydroxyajubractin C (13), 14-hydro-15-hydroxyajugachin A (14), and 14-hydro-15-hydroxyajugapitin (15)], along with 15-epi-lupulin B (16). The structures of the new compounds were elucidated by NMR and MS data analysis and by comparison with values previously reported. Antifeedant activity against Spodoptera littoralis larvae was evaluated for the compounds obtained.     

Xanthone and sesquiterpene derivatives from the fruits of Garcinia scortechinii

The fruits of Garcinia scortechinii afforded 10 new compounds: four caged-tetraprenylated xanthones (scortechinones Q-T, 1-4), four rearranged xanthones (scortechinones U-X, 5-8), and two sesquiterpene derivatives (scortechterpenes A, B, 9, 10), together with 14 known compounds: one sesquiterpene, two biflavonoids, and 11 caged-polyprenylated xanthones. Their structures were elucidated by analysis of spectroscopic data and comparison of the NMR data with those reported previously. All xanthone derivatives were evaluated for antibacterial activity against methicillin-resistant Staphylococcus aureus.     

Antitumor agents. 289. Design, synthesis, and anti-breast cancer activity in vivo of 4-amino-2H-benzo[h]chromen-2-one and 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one analogues with improved water solubility

Previously, we reported that 4-amino-2H-benzo[h]chromen-2-one (ABO) and 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one (ATBO) analogues, which were developed from the lead natural product neo-tanshinlactone, are potent cytotoxic agents. In order to improve on their water solubility, the diamino analogues and related salts were designed. All synthesized compounds were assayed for cytotoxicity, and selected compounds were evaluated for in vivo anti-mammary epithelial proliferation activity in wild-type mice and mice predisposed for mammary tumors due to Brca1/p53 mutations. The new derivatives 10, 16 (ABO), 22, and 27 (ATBO) were the most active analogues, with IC(50) values of 0.038-0.085 μM in the cytotoxicity assay. Analogue 10 showed around 50-fold improved water solubility compared with the prior lead ABO compound 4-[(4'-methoxyphenyl)amino]-2H-benzo[h]chromen-2-one (3). Compounds 3, 4, 10, and 22 significantly reduced overall numbers of mammary cells, as indicated by the reduction of mammary gland branching in mutant mice. A one-week treatment with 10 resulted in 80% reduction in BrdU-positive cells in the cancer prone mammary gland. These four compounds had differential effects on cellular proliferation and apoptosis in wild-type mouse and a mouse model of human breast cancers. Compound 10 merits further development as a promising anticancer clinical trial candidate.