New ψ-Santonin Derivatives from Crossostephium chinense and Their Anti-Proliferative Activities against Leishmania major and Human Cancer Cells A549.

Previously, we reported two cytotoxic ψ-santonin-amino acid conjugates isolated from the EtOAc layer of Crossostephium chinense. However, a further phytochemical investigation seems to be required because of the few reports of similar derivatives. In this study, we targeted the 1-BuOH layer, which resulted in the isolation of seven new ψ-santonin derivatives (1-7) together with ten known compounds (8-17). The structures of 1-7 were elucidated based on spectroscopic methods, including 1D and 2D NMR experiments (1H, 13C, DEPT, COSY, HSQC, and HMBC), IR spectrum, and high-resolution electrospray ionization-mass spectrometry (HR-ESI-MS). The stereochemistry of new compounds was confirmed by NOESY and ECD calculations. All isolated compounds were evaluated by in vitro experiments for their anti-proliferative activities against Leishmania major, human lung cancer cell line A549, and Vero cells. As a result, most of the ψ-santonin derivatives, especially 1-5, showed significant cytotoxicity against L. major with a lower IC50 than the positive control we used (miltefosine).

Two New Cytotoxic Sesquiterpene-Amino Acid Conjugates and a Coumarin-Glucoside from Crossostephium chinense.

The Asteraceae family is a promising source of bioactive compounds, such as the famous Asteraceae plants Tanacetum cinerariifolium (pyrethrin) and Artemisia annua (artemisinin). As a result of our series of phytochemical studies of the subtropical plants, two novel sesquiterpenes, named crossoseamines A and B in this study (1 and 2, respectively), one undescribed coumarin-glucoside (3), and eighteen known compounds (4-21) were isolated from the aerial part of Crossostephium chinense (Asteraceae). The structures of isolated compounds were elucidated by spectroscopic methods, including 1D and 2D NMR experiments (1H, 13C, DEPT, COSY, HSQC, HMBC, and NOESY), IR spectrum, circular dichroism spectrum (CD), and high-resolution electrospray ionization-mass spectrometry (HR-ESI-MS). All isolated compounds were evaluated for their cytotoxic activities against Leishmania major, Plasmodium falciparum, Trypanosoma brucei (gambiense and rhodesiense), and human lung cancer cell line A549 because of the high demand for the discovery of new drug leads to overcome the present side effects and emerging drug-resistant strains. As a result, the new compounds (1 and 2) showed significant activities against A549 (IC50, 1: 3.3 ± 0.3; 2: 12.3 ± 1.0 µg/mL), L. major (IC50, 1: 6.9 ± 0.6; 2: 24.9 ± 2.2 µg/mL), and P. falciparum (IC50, 1: 12.1 ± 1.1; 2: 15.6 ± 1.2 µg/mL).

Pregnane Steroids from the Leaves of Melia Azedarach and Apoptotic Activity against T47D Cells.

OBJECTIVE: Nature has provided us with many pharmaceutical resources so far. Breast cancer shows an increasing trend in the world for the last decade and becomes one of five leading causes of death. Among the plants, Melia azedarach L. has been used widely in traditional medicine for many ailments including breast cancer. Following our previous findings that the ethyl acetate fraction was the most active cytotoxic fraction against T47D cells, we aimed to isolate the cytotoxic compounds and further elucidate their apoptotic mechanisms. METHODS: The compounds were isolated through a series of chromatography with cytotoxicity evaluations. Identification of the isolated compounds was achieved by intensive spectroscopic analysis such as NMR, MS, and IR spectra. Cytotoxicity was evaluated by MTT method using doxorubicin as a reference compound. The expression of apoptosis-related factors was quantified by flow cytometry and immunocytochemistry. RESULTS: Two isomers of pregnane steroids with molecular weight 330.2087 (C21H30O3) were isolated from the EtOAc extract. Spectroscopic analysis revealed the structures as 17-ethylene-3,4-dihydroxy-14-methyl-18-norandrostene-16-one (1) and 17-ethylene-3,4-dihydroxy-5-pregnene-16-one (2), respectively. These compounds showed moderate cytotoxicity (IC50 172.9 and 62.2 µg/mL, respectively) comparable to doxorubicin (IC50 3.08 µg/mL). The execution of apoptosis may be related to the increase of the ratio of BAX/bcl-2 of the cells.  Conclusion: The EtOAc fraction of Melia azedarach L. leaves and the isolated 5-pregnene-16-one steroids are promising reagents for breast cancer treatment by introducing apoptosis to tumor cells. However, further researches are required to highlight its safety and usage in vivo.
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Lasianosides A-E: New Iridoid Glucosides from the Leaves of Lasianthus verticillatus (Lour.) Merr. and Their Antioxidant Activity.

The genus Lasianthus (Rubiaceae) consists of approximately 180 species, of which the greatest species diversity is found in tropical Asia. Some of the Lasianthus species have been used in folk medicine to treat tinnitus, arthritis, fever, and bleeding. Lasianthus verticillatus (Lour.) Merr. (Syn. Lasianthus trichophlebus auct. non Hemsl.) is a shrub, branchlets terete about 1.5-3 m in height. This paper studies the chemical composition of the leaves of L. verticillatus for the first time, which resulted in the isolation of five undescribed iridoid glucosides, lasianosides A-E (1-5), together with three known compounds (6-8). The undescribed structures of isolated compounds (1-5) were characterized by physical and spectroscopic data analyses, including one-dimensional (1D) and two-dimensional (2D) NMR, IR, UV, and high-resolution electrospray ionization mass spectra (HR-ESI-MS). Furthermore, the electronic circular dichroism data determined the absolute configurations of the new compounds. The free radical scavenging properties of isolated compounds was assessed by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, and their cytotoxicity was assessed toward human lung cancer cell line A549 by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Among the isolated compounds, 3 and 4 displayed potent radical scavenging activities with IC50 values of 30.2 ± 1.8 and 32.0 ± 1.2 µM, which were comparable to that of Trolox (29.2 ± 0.39 µM), respectively, while 5 possessed moderate activity with an IC50 value of 46.4 ± 2.3 µM. None of the isolated compounds exerted cytotoxicity against human cell line A549. As a result, lasianosides C, D, and E have the potential to be non-toxic safe antioxidant agents.

Significance of N-isopropyl-[123I] p-iodoamphetamine single-photon emission computed tomography in detection of responsible hypoperfusion in hemichorea.

Hemichorea is relatively an uncommon clinical presentation while its known etiology are vascular, metabolic, neoplastic, infectious, autoimmune, and inherited disorders. In the acquired case of hemichorea, the most common cause is the cerebrovascular insult, which is often diagnosed by the magnetic resonance (MR) imaging. An 84-year-old woman reported a one-week history of involuntary movements in the left side of her face and left limbs. Blood tests were normal and brain MR imaging showed no responsible hyperintense lesion on T1-, FLAIR, and diffusion-weighted imaging. N-isopropyl-[123I] p-iodoamphetamine single-photon emission computed tomography (SPECT) detected hypoperfusion in the right thalamus. Further three-dimensional tomography clearly detected the hypoperfusion in the right subthalamic nucleus. The hypoperfused lesion was MR-negative and remained unchanged in SPECT one year after the onset. After the treatment with 0.35 mg of oral haloperidol was initiated, the hemichorea was gradually decreased and completely disappeared in 9 months. Because the three-dimensional analysis performs voxel-by-voxel analysis, it possibly detects the precise hypoperfusion in a specific region. In conclusion, evaluation of cerebral blood flow using SPECT on patients presenting with acute hemichorea can lead to the detection of responsible lesion when the routine examinations are negative.

Isolation of Sesquiterpene-Amino Acid Conjugates, Onopornoids A-D, and a Flavonoid Glucoside from Onopordum alexandrinum.

Previous phytochemical investigations have revealed the presence of a variety of compounds such as pyrrolidine derivatives, flavonoids, and megastigmanes in Egyptian plants. Onopordum alexandrinum has been traditionally used by the natives for treatment of skin cancers and leprosy. In this paper the isolation of four new sesquiterpene-amino acid conjugates, onopornoids A-D (1-4), i.e., three elemanes and one germacrane, and a new acylated flavonoid glucoside (5) along with nine known compounds (6-14) from the whole aerial parts of the title plant is discussed. The structures were elucidated based on chemical and spectroscopic/spectrometric data.

Eight ent-Kaurane Diterpenoid Glycosides Named Diosmariosides A-H from the Leaves of Diospyros maritima and Their Cytotoxic Activity.

From the leaves of Diospyros maritima, collected from Okinawa Island, eight new glycosides based on ent-kaurane-type diterpenoids, entitled diosmariosides A-H, were isolated. The absolute structure of diosmarioside E (5) was determined by X-ray crystallographic analysis. The structure of diosmarioside H was elucidated to be a dimeric compound between diosmarioside A and a sugeroside through a ketal bond. An assay of cytotoxicity towards the lung adenocarcinoma (A549) cell line was performed. Among the compounds isolated, only diosmarioside D (4) and sugeroside 9 showed strong activity. The anti-microbial activity toward multi-drug resistant strains was also determined, but no activity was observed.

Dianthosaponins G-I, triterpene saponins, an anthranilic acid amide glucoside and a flavonoid glycoside from the aerial parts of Dianthus japonicus and their cytotoxicity.

Extensive isolation work on the 1-BuOH-soluble fraction of a MeOH extract of the aerial parts of Dianthus japonicus afforded three further triterpene glycosyl estsers, termed dianthosaponins G-I, an anthranilic acid amide glucoside and a C-glycosyl flavonoid along with one known triterpene saponin. Their structures were elucidated from spectroscopic evidence. The cytotoxicity of the isolated compounds toward A549 cells was evaluated.

New Isolinariins C, D and E, Flavonoid Glycosides from Linaria japonica.

Three new flavonoid glycosides named isolinariins C, D and E (1-3), two known flavonoid glycosides (4, 5) and three known flavonoids (6-8) were isolated from the whole plant of Linaria japonica. The structures of these compounds were determined mainly by spectroscopic analyses. The bioactivities of these isolated compounds were evaluated for their inhibitory activities against human cell line A549, collagenase, and advanced glycation end product (AGE) formation. Among the isolated compounds, isolinariins C, D and E (1, 2 and 3) showed inhibition toward AGE formation (IC50 values of 34.8, 35.0 and 19.5 µM, respectively). And linariin (4), pectolinarin (5) and luteolin (8) were found to be active against collagenase with IC50 values of 79.4, 78.6 and 40.5 µM, respectively, without significant cytotoxicity at these concentrations.

Effects of Hepatoprotective Compounds from the Leaves of Lumnitzera racemosa on Acetaminophen-Induced Liver Damage in Vitro.

Phytochemical investigation of the n-BuOH fraction of the mangrove plant Lumnitzera racemosa WILLD. (Combretaceae) led to the isolation of one new flavonoid glycoside; myrcetin 3-O-methyl glucuronate (1), one new phenolic glycoside; lumniracemoside (2) and one new aliphatic alcohol glycoside; n-hexanol 1-O-rutinoside (3), in addition to seven known compounds (4-10). The structures of these compounds were determined by spectroscopic analyses (UV, IR, high resolution-electrospray ionization (HR-ESI)-MS, one- and two-dimensional (1D- and 2D)-NMR). Compound 7 showed the highest hepatoprotective activity against acetaminophen-induced hepatotoxicity using human HepG2 cells at protection % value of 34.2±3.1%, while compounds 1, 2, 3, 6, and 9 showed weak to moderate hepatoprotective activity (11.6-18.9%). Almost all of these compounds showed stronger 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity compared with the standard Trolox. These results suggest the usefulness of this plant extract and the isolated compounds as promising hepatoprotective agents.

Officinalioside, a new lignan glucoside from Borago officinalis L.

A new lignan glucoside, officinalioside (1), was isolated from n-BuOH fraction of the aerial parts of Borago officinalis L., together with four known compounds: actinidioionoside (2), roseoside (3), crotalionoside C (4) and kaempferol 3-O-ß-D-galactopyranoside (5). The structure of the new compound was established by means of spectroscopic and chemical analyses. Compounds 1 and 2 showed a moderate DPPH radical scavenging activity (IC50: 52.6 ± 1.70 and 41.3 ± 0.25 µM, respectively) comparable with that of the standard trolox (16.6 ± 2.2 µM) without any significant cytotoxicity towards human cell line A549 (IC50 > 100 µM).

[Left atrial giant myxoma incidentally discovered during endoscopic ultrasonography; report of a case].

A 49-year-old female patient with a symptom of dysphagia underwent endoscopic ultrasonography (EUS) of the upper gastrointestinal tract, which incidentally revealed a tumor compressing the esophagus from outside. Transthoracic echocardiography performed after EUS showed a giant tumor in the left atrium. The tumor, measuring 75×68×43 mm, weighing 105 g was successfully removed, and pathologically diagnosed as myxoma. Her symptom disappeared completely. When performing clinical studies, it is important to pay every attention not to miss any abnormal findings beyond the scope of targeted areas. We also mentioned an ambiguity of the term," giant" regarding the size and weight of myxoma.

Taxiphyllin 6'-O-gallate, actinidioionoside 6'-O-gallate and myricetrin 2″-O-sulfate from the leaves of Syzygium samarangense and their biological activities.

Three new compounds were isolated from a MeOH extract of the leaves of Syzygium samarangense, one new cyanogenic glucoside, taxiphyllin 6'-O-gallate (1), one new megastigmane glucoside, actinidioionoside 6'-O-gallate (2), and one new sulfated flavonoid rhamnoside, myricetrin 2″-O-sulfate (3), together with 14 known compounds, lupeol (4), demethoxymatteucinol (5), cryptostrobin (6), betulinic acid (7), ß-sitosterol glucoside (8), 2R-prunasin (9), myrciaphenone A (10), 1-feruloyl-ß-D-glucopyranoside (11), (3S,5R,6R,7E,9S)-3,5,6,9-tetrahydroxymegastigman-7-ene (12), guaijaverin (13), myricetin 4'-methyl ether 3-O-α-L-rhamnopyranoside (14), myricetrin (15), gallic acid (16) and actinidioionoside (17). The structures of the new compounds were determined through a combination of spectroscopic, HPLC and chemical analyses.

Grevillosides J-Q, arbutin derivatives from the leaves of Grevillea robusta and their melanogenesis inhibitory activity.

From the 1-BuOH-soluble fraction of a MeOH extract of the leaves of Grevillea robusta, new arbutin derivatives and related compounds, named grevillosides J-Q (1-8), together with eight known compounds (9-18) were isolated. Various kind of acyl groups were attached to ß-D-glucose at the 6-position through an ester linkage. Their structures were mainly elucidated from one- and two-dimensional NMR spectroscopic data. For exploitation as skin-lightening and anti-chloasma agents, the inhibitory activities of the isolated compounds as well as ones isolated in previous experiments (19-31) toward tyrosinase and melanin-producing B16 cells were assayed. Several compounds showed promising activity.

3,4-seco-24-homo-28-nor-Cycloartane and drimane-type sesquiterpenes and their lactams from the EtOAc-soluble fraction of a leaf extract of Cinnamosma fragrans and their biological activity.

From the EtOAc-soluble fraction of a MeOH extract of leaves of Cinnamosma fragrans, seven new compounds, including 3,4-seco-24-homo-28-nor-cycloartane, drimane-type sesquiterpenes and their lactams, and two known compounds were isolated. Their structures were elucidated by extensive analyses of spectroscopic data. The cytotoxicity, anti-multidrug resistance activity, and anti-Leishmania activity of a cycloartane derivative and drimane-type sesquiterpene derivatives were assayed. The cycloartane derivative showed strong cytotoxicity, and some drimanes and drimane lactam showed moderate anti-multidrug resistance and anti-Leishmania activity.

Tareciliosides N-S: further cycloartane saponins from the leaves of Tarenna gracilipes, and cytotoxicity of saponins and triterpenes.

Six cycloartane glycosides, named tareciliosides N-S, and a known iridoid glucoside, ixoroside, were isolated in further extensive studies on the 1-BuOH-soluble fraction of a MeOH extract of the leaves of Tarenna gracilipes. From the EtOAc-soluble fraction, three known triterpenes were isolated. Their toxicities toward A549 and Leishmania major trypanosome protozoa were assayed. Triterpenes were selectively active in the two organisms.

Glucosylated sesquiterpene alcohols from Fraxinus griffithii.

Phytochemical investigation of the leaves of Fraxinus griffithii has led to the isolation of two new glucosylated acyclic sesquiterpene alcohols, griffithosides D (1) and E (2), along with iridoid and secoiridoid glycosides. The molecular structures of these compounds were elucidated using NMR, MS and other spectroscopic techniques, as well as comparison with literature data. The isolated compounds were tested for radical-scavenging activity and cytotoxicity against A549 human lung adenocarcinoma cells and Leishmania major parasites.

Annonamine, a new aporphine alkaloid from the leaves of Annona muricata.

Atypical Parkinsonism in the Caribbean Island Guadeloupe is thought to be associated with the consumption of plants of the Annonaceae family, especially Annona muricata (soursop). In this study, a new aporphine alkaloid named annonamine (1) was isolated from the leaves of A. muricata L. together with four known benzylisoquinoline alkaloids (2-5). The structures of the isolated compounds were elucidated by the spectroscopic method.

Blocking of CCR5 and CXCR3 suppresses the infiltration of macrophages in acute renal allograft rejection.

BACKGROUND: The chemokine receptors CCR5 and CXCR3 are expressed by T cells and macrophages. We examined effects of a CCR5/CXCR3 antagonist (TAK), with a particular focus on the role of macrophages, in a rat kidney transplant model. METHODS: Dark Agouti rat kidneys were transplanted into Lewis rats. The recipients were treated daily with a 10 mg/kg TAK on posttransplant days 0 to 14 and/or 2 mg/kg of cyclosporine A (CsA) on days 0 to 5. Graft survival, histological changes, and the expression of chemokines and chemokine receptors on T cells and macrophages were studied. RESULTS: Treatment with TAK alone suppressed CD4+T cell infiltration and slightly prolonged graft survival. The expressions of both CCR5 and CXCR3, and activated macrophage-associated cytokines and chemokines, were significantly increased on macrophages that had been separated from rejecting kidneys, compared with those from spleens. However, these upregulations were decreased in macrophages from kidneys that had been treated with TAK. Immunohistochemistry also showed that macrophages infiltrating tubules of rejecting kidney expressed both receptors. In the CsA alone group, macrophages were the dominant infiltrating cells, and all allografts were rejected within 10 days. A combined therapy involving CsA and TAK resulted in decreased macrophage infiltration, and graft survival was substantially prolonged. The levels of activated macrophage-associated cytokines and chemokines were also decreased. CONCLUSION: The dual blocking of CCR5/CXCR3 can be useful in decreasing rejection, with or without CsA. This mechanism acts, not only to block T-cell recruitment to a kidney graft but to suppress the infiltration of macrophages as well.

A new iridoid glycoside and NO production inhibitory activity of compounds isolated from Russelia equisetiformis.

From the 1-BuOH-soluble fraction of a MeOH extract of the leaves of Russelia equisetiformis, one new iridoid glucoside was isolated along with 24 known compounds, comprising iridoids and iridoid glucosides, phenyl propane glucosides, phenyl ethanoids, lignan glucosides, and flavonoid glucosides. The structure of the new compound was elucidated to be 10-O-cinnamoyl sinuatol. Of the 25 compounds isolated, rehmaglutin B exhibited moderate inhibitory activity toward NO production, which was not associated with cytotoxicity.