Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease.

AIM: Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects. METHODS: This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, AUC0-72 h and AUC0-∞ were calculated. Tolerance assessments were conducted throughout the study. RESULTS: ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean tmax of huperzine A was 0.76-0.82 h; the AUC0-72 h and Cmax of huperzine A showed approximately dose-proportional increase over the dose range of 0.5-1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed. CONCLUSION: ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers.

Two new lignans from Celastrus flagellaris Rupr.

Two new lignans (R-biar)-12-angeloyloxy-6,7,8,9-tetrahydro-1,2,3,13,14-pentamethoxy-7,8-dimethyl-7-dibenzo[a,c]cyclooctenol (1) and (R-biar)-12-benzoyloxy-6,7,8,9-tetrahydro-1,2,3,13,14-pentamethoxy-7,8-dimethyl-7-dibenzo[a,c]cyclooctenol (2) were isolated from the stems of Celastrus flagellaris Rupr. Their structures were elucidated on the basis of spectroscopic methods including HR-EI-MS, 1D and 2D NMR, HMQC, NOESY, and CD.

Arylnaphthalene lignan glycosides and other constituents from Phyllanthus reticulatus.

Two new arylnaphthalene lignan glycosides, named reticulatusides A (1) and B (2), together with eight known compounds were isolated from the 95% EtOH extract of the whole plant of Phyllanthus reticulatus. The structures of the new compounds were elucidated by spectroscopic methods.

[Analysis of saponins in Panax notoginseng by UPLC-LTQ-Orbitrap MS/MS].

A method for qualitative analysis of constituents in Panax notoginseng by UPLC-LTQ-Orbitrap mass spectrometry was established. Based on the high-resolution mass information, MS/MS fragmentation behaviors and chemical components from literatures, 43 compounds were identified or tentatively characterized. New type saponin aglycone, combined with malonyl-substituted and acetyl-substituted saponins were discovered and plausibly identified in this study. This work could be helpful for the quality control and further phytochemical studies of Panax notoginseng, and provided a good example for the analysis of chemical constituents in traditional Chinese medicine.

[Study on chemical constituents of the ethyl acetate extract from Blumea aromatica].

OBJECTIVE: To study the chemical constituents of the ethyl acetate extract from Blumea aromatica. METHODS: Column chromatographic techniques were used for the isolation and purification. Spectroscopic techniques were used for the identification of structures. RESULTS: Seven compounds were isolated from the ethyl acetate extract of 80% alcohol extract of the whole plant, and their structures were identified as xanthoxylin(1), dibutyl phthalate(2), luteolin-3',4',7-trimethyl ether(3), rubiadin(4), eriodictyol(5), kaempherol(6), luteolin 7,3'-dimethyl ether(7). CONCLUSION: All the compounds are isolated from this plant for the first time. Among them, compounds 2,4 and 7 are isolated from this genus for the first time.

Tryptamine derivatives as novel non-nucleosidic inhibitors against hepatitis B virus.

A series of tryptamine derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in the HepG2.2.15 cell line. The preliminary SAR was discussed. Compounds 2e and 4a showed potent antiviral activity (IC(50)=0.4 and <1 µM, respectively) and low cytotoxicity (CC(50)=40.6 and >25 µM, respectively).

Minor dammarane saponins from the hongshen extract of Shenmai injection.

A new dammarane-type triterpenoid saponin, (20R)-ginsenoside ST(2) (1), along with five known saponins was isolated from the hongshen extract of Shenmai injection. The structure of 1 was elucidated to be (20R)-dammar-23(E)-ene-3ß,6α,12ß,20,25-pentol 6-O-ß-D-glucopyranoside by means of spectroscopic methods.

Chemical constituents from the leaves of Aglaia perviridis.

A new cinnamic acid-derived bisamide 1 and a new oplopanone-type sesquiterpenoid diglycoside 2, together with 11 known compounds, were isolated from the 95% ethanolic extract of the leaves of Aglaia perviridis. Their structures were elucidated by chemical and spectroscopic methods.

Lycopodium alkaloids from Huperzia serrata.

A new lycopodane-type Lycopodium alkaloid, 6α-hydroxy-5,15-oxide-lycopodane (1), and seven known alkaloids were isolated from the whole plants of Huperzia serrata. Their structures were elucidated by means of spectroscopic methods. 12-Deoxyhuperzine O (2) was reported as a naturally occurring alkaloid for the first time, and showed an antagonist effect on the N-methyl-d-aspartate receptor with an IC(50) value of 0.92 µM.

[Isolation and identification of chemical constituents from peels of Citrus changshan-huyou Y.B. Chang].

OBJECTIVE: To study the chemical constituents of the peels collected from Citrus changshan-huyou Y. B. Chang, and further screen the bioactive components as the lead structures. METHODS: These compounds were isolated by repeated flash column chromatography on silica gel and Sephadex LH-20. The structures of isolated compounds were elucidated by using IR, EIMS, and NMR analyses. RESULTS: One novel compound along with nine known compounds were obtained and identified as huyoujiasu(I), 3-hydroxy-4-methoxybenzoic acid(II), 3, 4-dihydroxybenzoic acid(III), fatty acid(IV), glyceride(V), 6, 7-dimethoxycoumarin(VI), 6', 7'-dihydroxybergamottin(VII), daucossterol A(VIII), daucossterol B(IX) and huyou-triterpenoid(X). CONCLUSION: One new compound, Huyoujiasu, was obtained from these peels by repeated column chromatography, and the other known compounds were isolated from this fruit for the first time as well.

Vascular effects of different lipophilic components of "Danshen", a traditional Chinese medicine, in the isolated porcine coronary artery.

"Danshen" has been used for the treatment of various cardiovascular diseases in the People's Republic of China for many years. Two different forms of "Danshen" exist, with the roots of Salvia miltiorrhiza being the traditional form and the roots of Salvia przewalskii being a surrogate used in the western areas of mainland China. The most abundant lipophilic diterpene quinones present in S. miltiorrhiza and S. przewalskii roots, tanshinone IIA (1) and cryptotanshinone (2), inhibited contraction of the isolated porcine coronary artery to the thromboxane A(2) analogue, U46619. Przewaquinone A (3), a lipophilic diterpene quinone present only in S. przewalskii, induced a similar but greater inhibitory action on vascular contraction than 1 and 2. This effect of 3 was endothelium-independent and reversible. The present results suggest that 3 is more potent than 1 and 2 and may contribute to a great extent to the ability of S. przewalskii roots to inhibit vascular contractions.

A novel compound isolated from the peels of Citrus changshan-huyou.

Five compounds, huyouyisu (1), vomifoliol (2), isoferulic acid (3), 1,2,3-trihydroxyphenol (4) and p-hydroxy-phenol (5), were isolated from the peels of Citrus changshan-huyou Y. B. Chang for the first time by utilizing repeated column chromatography on silica gel. Among them, huyouyisu (1) is a new compound. The structure was elucidated by using 1D and 2D spectra.

[Effects of microbes on rooting and on several physiological and biochemical indexes of cuttings of Huperzia serrata].

OBJECTIVE: To study the effects of soil microbes of habitats, endophytic fungi and root surface fungi of Huperzia serrata on rooting rate of the cuttings and on several physiological and biochemical indexes. METHOD: The cuttings of H. serrata were planted on soil I of primary habitat, the soil II had been inoculated endophytic fungi and root surface fungi, the soil III had been auto-claved, rooting rate was examined, and soluble protein and soluble sugar contents, activities of PPO and POD, flavonoids and huperzine A contents were determined. RESULT: Compared with the H. serrata that were planted on soil III, soil I and soil II were found to increase the rooting rate by 10% and 16%, soil II increased the soluble protein contents of stem of H. serrata (P < 0.05), Soil I increased the soluble sugar contents of leaves and stem of H. serrata (P < 0.05), soil I and Soil II increased the flavonoids contents of H. serrata (P < 0.05). CONCLUSION: Soil microbes from primary habitat, endophytic fungi and root surface fungi promote rooting, they also increase plant metabolism level of H. serrata.

[Studies on phenylpropanoids from herbs of Eriophyton wallichii].

OBJECTIVE: To study the chemical constituents of Eriophyton wallichii. METHOD: Compounds were separated and purified by column chromatographic methods, and their structures were elucidated by spectroscopic methods. RESULT: Eight phenylpropanoids were isolated and identified as martynoside (1), leucosceptoside A (2), citrusin B (3), (+)-dehydrodiconiferyl alcohol-4, 9-beta-D-glucopyranoside (4), liriodendrin (5), velutinoside 11[ (6), jionoside B, (7), stachysoside D (8), respectively. CONCLUSION: The eight compounds were firstly isolated from E. wallichii.

Fibrarecisin, a novel triterpenoid from Fibraurea recisa with antitumor activity.

Fibrarecisin (1), a novel triterpenoid, was isolated from chloroform extract of the stem bark of Fibraurea recisa Pierre. Its structure was elucidated by spectroscopic methods. Compound 1 exhibited significant antitumor activity in vitro against A-549 cancer cell at 10 microM by SRB and MTT methods.

Chemical constituents from the roots of Homonoia riparia.

A new compound and twelve known compounds were isolated from the ethyl acetate extract of the roots of Homonoia riparia Lour, which are used in folk medicine for treatment of hepatitis, bellyache and scald, by the method of silica gel column chromatography repeatedly with a gradient of PE-EtOAc, PE-Me2CO, CHCl3-Me2CO, CHCl3-MeOH. Their structures were identified as a new compound 1-oxo-aleuritolic acid (1), and twelve known compounds aleuritolic acid (2), 3-acetoxy-aleuritolic acid (3), taraxerone (4), taraxerol (5), methyl 3-acetoxy-12-oleanen-28-oate (6), 3-acetoxy-12-oleanen-28-ol (7), ursolic acid (8), lupenol (9), 3beta-acetoxy-lupenol (10), cleomiscosin A (11), chrysophanol (12), and gallic acid (13), which were obtained from this plant for the first time, by the spectroscopic techniques of NMR, HMBC, IR and MS, separately. Among the cytotoxicities evaluation of compounds 1 -3 towards AGZY 83-a (human lung cancer cells) and SMMC-7721 (human liver cancer cells) tumor cells was assayed by MTT methods with cis-dichlorodiamminoplatinum (DDP) used as positive control. Compound 2 exerted weak activity against AGZY 83-a with the IC50 value of 33.055 microg x mL(-1), while 1 and 3 showed no activity to these two cell lines.

[Mechanism of effects of soil microbes on cuttings rooting of Huperzia serrata].

OBJECTIVE: To study the effects of soil microbes of habitats on the cuttings rooting of Huperzia serrata and its mechanism. METHOD: The cuttings of H. serrata were planted on the primary habitat soil and on the soil autoclaved, rooting rates were examined respectively. Changes of contents of phenolic compounds (catechin, quercetin, chlorogenic acid, ferulic acid) and indoleacetic acid (IAA) , and changes of activities of polyphenoloxidase (PPO) and peroxydase (POD) during the cuttings rooting were determined. RESULT: Soil microbes of primary habitat could increase the rooting rate and the number of roots, could increase contents of catechin, chlorogenic acid, ferulic acid and IAA during rooting, and could affect activities of PPO and POD. CONCLUSION: During the rooting higher contents of catechin, chlorogenic, ferulic acid and IAA caused by soil microbes of primary habitat are important factor for rooting rate.

Sensitized photooxidation of furanoeremophilane with singlet oxygen and their biogenetic relationship.

In an attempt to explore the biogenetic relationship of furanoeremophilane derivatives and eremophilan-8alpha,12-olides, produced in Ligularia and their structure-activity relationship, we studied the photosensitized oxidation of furanoeremophilane-type sesquiterpenes. Under the condition of several solvents solution Irradiation with a 200 W incandescent lamp of furanoeremophilan-14beta,6alpha-olide isolated from Ligularia vellerea, in various solutions with methylene blue, rose bengal, toluidine blue and safranine T gave several products. The products were isolated by chromatographic procedure and their structures were elucidated as eremophilan-14beta,6alpha,8alpha,12-diolide derivatives by NMR, IR and MS methods. A reaction mechanism has been proposed.

A novel bieremophilanolide from Ligularia lapathifolia.

A new bieremophilanolide was isolated from the roots and rhizomes of Ligularia lapathifolia. Its structure was established as 8,8'-bi-3beta-angeloyloxy-eremophil-7(11)-en-12,8alpha(14beta,6alpha)-diolide (1) by IR, MS, 1D, and 2D NMR experiments.

A novel bis-furan derivative, two new natural furan derivatives from Rehmannia glutinosa and their bioactivity.

A novel bis-furan derivative and two new natural furan derivatives were isolated from the CHCl3 extracts of the dried roots of Rehmannia glutinosa (Gaerth) Lilosch. Their structures were identified as 1,5-bis(5-methoxymethyl)furan-2-yl-penta-1,4-dien-3-one 1, (E)-4-(5-(methoxymethyl)furan-2-yl)but-3-en-2-one 2 and (E)-4-(5-(hydroxymethyl)furan-2-yl)but-3-en-2-one 3 on the basis of spectral data. Moreover, biological assay showed that 1 (10 microg/mL) and 3 (10 microg/mL) can promote immune activity, 2 (100 microg/mL) and 3 (100 microg/mL) inhibit immune activity and 1 can inhibit blood platelet aggregation.