Synthesis of long-chain fatty acid derivatives as a novel anti-Alzheimer's agent.

In order to develop new drugs for Alzheimer's disease, we prepared 17 fatty acid derivatives with different chain lengths and different numbers and positions of double bonds by using Wittig reaction and stereospecific hydrogenation of triple bonds as key reactions. Among them, (4Z,15Z)-octadecadienoic acid (10) and (23Z,34Z)-heptatriacontadienoic acid (16) showed the most potent neurite outgrowth activities on Aß(25-35)-treated rat cortical neurons, which activities were comparable to that of a positive control, NGF. Both fatty acids 10 and 16 possess two (Z)-double bonds at the n-3 and n-14 positions, which might be important for the neurite outgrowth activity.

Muchimangins G-J, fully substituted xanthones with a diphenylmethyl substituent, from Securidaca longepedunculata.

Four highly oxygenated xanthones, muchimangins G-J (1-4), have been isolated from the roots of Securidaca longepedunculata collected in Democratic Republic of Congo. Their structures were elucidated by analyses of spectroscopic data to be fully substituted xanthones with a diphenylmethyl substituent at C-2.

Heptaoxygenated xanthones as anti-austerity agents from Securidaca longepedunculata.

In a course of our search for anticancer agent based on a novel anti-austerity strategy, we found that the CHCl3 extract of the roots of Securidaca longepedunculata (Polygalaceae), collected at Democratic Republic of Congo, killed PANC-1 human pancreatic cancer cells preferentially in nutrient-deprived medium (NDM). Phytochemical investigation on the CHCl3 extract led to the isolation of 28 compounds including five new polymethoxylated xanthones [1,6,8-trihydroxy-2,3,4,5-tetramethoxyxanthone (1), 1,6-dihydroxy-2,3,4,5,8-pentamethoxyxanthone (2), 8-hydroxy-1,4,5,6-tetramethoxy-2,3-methylenedioxyxanthone (3), 4,6,8-trihydroxy-1,2,3,5-tetramethoxyxanthone (4), 4,8-dihydroxy-1,2,3,5,6-pentamethoxyxanthone (5)] and a new benzyl benzoate [benzyl 3-hydroxy-2-methoxybenzoate (6)]. Among them, 1,6,8-trihydroxy-2,3,4,5-tetramethoxyxanthone (1) and 1,6-dihydroxy-2,3,4,5,8-pentamethoxyxanthone (2) displayed the potent preferential cytotoxicity with PC50 of 22.8 and 17.4 µM, respectively. They triggered apoptosis-like PANC-1 cell death in NDM with a glucose-sensitive mode.

Sesquiterpenes from the rhizomes of Curcuma heyneana.

Four new germacranes [heyneanones A-D (1-4)], three new guaianes [4,10-epizedoarondiol (5), 15-hydroxyprocurcumenol (6), 12-hydroxycurcumenol (7)], and two new spirolactones [curcumanolides C (8) and D (9)] were isolated from the rhizomes of Curcuma heyneana together with 13 known sesquiterpenes and two known labdane-type diterpenes. Among the isolated compounds, heyneanone A (1), heyneanone C (3), 4,10-epizedoarondiol (5), procurcumenol (16), aerugidiol (17), zerumin A (23), and (E)-15,16-bisnorlabda-8(17),11-dien-13-one (24) inhibited protein tyrosine phosphatase 1B (PTP1B) with IC(50) values of 42.5, 35.2, 35.1, 45.6, 35.7, 10.4, and 14.7 µM, respectively.

Dipasperoside A, a novel pyridine alkaloid-coupled iridoid glucoside from the roots of Dipsacus asper.

A new pyridine alkaloid-coupled iridoid glucoside, dipasperoside A (1), and 20 known compounds (2­21) were isolated from a water extract of Dipsacus asper roots. Compound 1 possessed a unique structural feature with a nicotinic acid nucleus coupled through C-5 with C-7 of a secoiridoid/iridoid glucoside dimer, and esterified with a C-7 hydroxyl group of an iridoid glucoside monomer. All isolates were evaluated for their inhibitory activity against nitric oxide (NO) production in a lipopolysaccharide (LPS)-activated murine macrophage cell line, RAW264.7.

[Stump recurrence after pulmonary metastasectomy from colorectal cancer].

Pulmonary metastasectomy with wedge resection is an ideal procedure in terms of less invasiveness and preservation of respiratory function, while local recurrence is a major problem. The goal of this study was to verify risk factors of stump recurrence after pulmonary metastasectomy from colorectal cancer. Pulmonary metastasectomies including 112 operations for 131 lesions in 85 patients with colorectal cancer were performed in our department since March, 2005 until the end of 2010. In our cases, stump recurrence significantly occurred in patients who underwent wedge resection than segmentectomy or lobectomy. Stump recurrence developed in 14 operations among 62 wedge resections (recurrence rate: 23%). Diameter more than 10 mm and distance between pleura and deepest end of the tumor (depth value) more than 14 mm were risk factors as stump recurrence. Tumor diameter and depth value can be a decisional factor for wedge resection in pulmonary metastasectomy in the colorectal cancer patients.

Protein tyrosine phosphatase 1B (PTP1B)-inhibiting constituents from the leaves of Syzygium polyanthum.

A methanol extract of the leaves of Syzygium polyanthum (Wight) Walp. afforded four new acylbenzene derivatives (1-4) together with seven known compounds (5-11). The structures of 1-11 were elucidated by extensive spectroscopic methods and comparison with the literature data. The new compounds 1-3 and a known compound, campest-4-en-3-one (10), exhibited a significant protein tyrosine phosphatase 1B inhibitory activity with IC50 values of 13.1 ± 0.1, 5.77 ± 0.15, 4.01 ± 0.26, and 10.4 ± 0.5 µM, respectively. The inhibitory potency of the new compounds 2 and 3 was comparable to that of a positive control RK-682 (IC50, 5.51 ± 0.04 µM).

Anti-austerity agents from Rhizoma et Radix Notopterygii (Qianghuo).

During a search for potent anticancer agents from natural products based on an anti-austerity strategy, we found that a CHCl3 extract of Rhizoma et Radix Notopterygii (Qianghuo), a Chinese crude drug, exhibited strong cytotoxicity against PANC-1 human pancreatic cancer cells, with a PC50 value of 17.5 µg/mL. Further fractionation and purification of this bioactive extract led to the isolation of 19 known compounds. The in vitro preferential cytotoxicity of the isolates was evaluated against two human pancreatic cancer cell lines, PANC-1 and PSN-1. Among the compounds isolated, ostruthin displayed the most potent activity against both PANC-1 (PC50, 7.2 µM) and PSN-1 (PC50, 7.8 µM) cells in nutrient-deprived medium (NDM) and may have induced necrotic nutrient-deprived PANC-1 cell death.

Damnacanthal from the Congolese medicinal plant Garcinia huillensis has a potent preferential cytotoxicity against human pancreatic cancer PANC-1 cells.

Screening of eight Congolese medicinal plants showed that the CHCl(3) and MeOH extracts of Aframomum melegueta (PC(50) = 47.8 µg/mL and 13.8 µg/mL, respectively) and CHCl(3) extracts of Garcinia huillensis (PC(50) = 17.8 µg/mL) and Securidaca longepedunculata (PC(50) = 23.4 µg/mL) had preferential cytotoxicity against human pancreatic cancer PANC-1 cells under nutrient-deprived conditions. The active constituents of the CHCl(3) extract of G. huillensis were examined and 12 known anthraquinones were identified. Among them, damnacanthal (1) caused preferential necrotic cell death of PANC-1 and PSN-1 cells under nutrient-deprived and serum-sensitive conditions (PC(50) = 4.46 µm and 3.77 µm, respectively).

[Clinicopathological study of small lung cancer (diameter of 2 cm or less) by uptake value of 18F-fluorodeoxyglucose].

18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) for lung cancer may be a biomarker for malignancy as well as a useful tool for detection of nodal involvement and distant metastasis. The goal of this study was to clarify a relationship between clinicopathological findings and maximum standardized uptake value( SUVmax) obtained by preoperative PET in patients with non-small cell lung cancer in diameter of 2 cm or less. Between January 2008 and April 2011, 124 patients( 54 men and 70 women) with non-small cell lung cancer in diameter of 2 cm or less undergoing lobectomy or segmentectomy were enrolled. The relationship between SUVmax and clinicopathological findings as tumor diameter, histological type, pleural invasion, vascular invasion, lymphatic permeation and nodal involvement were analyzed. Correlation between SUVmax and findings such as vascular invasion and lymphatic permeation showed relatively strong in the patients with adenocarcinoma, on the contrary to the correlation in the patients with non-adenocarcinoma. No tumor showing SUVmax of 2 or less showed vascular invasion and/or lymphatic permeation as well as nodal involvement in any patients with adenocarcinoma. SUVmax of the primary tumor in diameter of 2 cm or less, can be a useful biomarker which indicates a surgical candidate for sublobar pulmonary resection as well as mediastinal nodal dissection, especially in patients with adenocarcinoma.

[Clinical outcome after video-assisted thoracic surgery (VATS) for clinical stage I lung cancer with pathologically nodal involvement].

The lymph node dissection with video-assisted thoracic surgery( VATS) was technically feasible and the remnant lymph nodes and tissues were 2% to 3%, which seems acceptable for clinical stage I lung cancer. Surgical outcome after VATS for clinical stage I lung cancer with pathologically nodal involvement, however, remains unclear. Medical records of 72 patients who had clinical stage I non small cell lung cancer with pathologically nodal involvement( pN1:21 patients, pN2:51 patients) and underwent VATS lobectomy or segmentectomy with mediastinal dissection between January 2005 and December 2010, were retrospectively reviewed. Postoperative recurrence and survival were studied. Remnant nodal recurrence occurred in 8 patients with pN1 (recurrence rate 38%) and 15 patients with pN2 (recurrence rate 29%). The 1- and 3-year disease free survival rate was 87% and 68%. The 1- and 3-year survival rate was 100% and 79%. This study suggested that VATS is acceptable for patients with clinical stage I lung in terms of survival rate, cancer with pN1. In a view point of remnant nodal recurrence, a more skillful dissection procedure is required.

Cytochrome P450 3A4 inhibitory constituents of the wood of Taxus yunnanensis.

From the aqueous extract of the wood of Taxus yunnanensis, which showed cytochrome P450 3A4 (CYP3A4) inhibition, a new isoflavan [(3S,4R)-4'-hydroxy-6,3'-dimethoxyisoflavan-4-ol (1)], a new degraded lignan [2,3-bis(hydroxymethyl)-7-hydroxy-6-methoxy-1-tetralone (2)], and a new lignan [(7R)-7-hydroxytaxiresinol (3)] were isolated, together with nine known lignans. Among the isolates obtained, α-conidendrin (12) showed strong CYP3A4 inhibition with an IC(50) value of 0.2 µM.

Protective Effects of Rosa damascena and Its Active Constituent on Aß(25-35)-Induced Neuritic Atrophy.

Dementia is a clinical syndrome characterized by multiple cognitive deficits and causes progressive neurodegeneration leading eventually to death. The incidence of dementia is increasing worldwide with the increase in ageing population. However, no effective treatment is available yet. It has been hypothesized that drugs activating neurite outgrowth might induce neuronal reconstruction and help in the recovery of brain function. Working on this hypothesis, we recently observed that the chloroform extract of the Rosa damascena significantly induced the neurite outgrowth activity and inhibited the Aß(25-35)-induced atrophy and cell death. Further workup led the isolation of a very long polyunsaturated fatty acid having molecular formula C(37)H(64)O(2) as an active constituent. The structure of this compound was established by extensive analysis of fragmentations observed in EI-MS mode. The isolated compound protected Aß(25-35)-induced atrophy and displayed strong neurite outgrowth activity. The length of dendrite in the cells treated with this compound were comparable to those of nerve growth factor (NGF) treated cells.

Identification of chrysoplenetin from Vitex negundo as a potential cytotoxic agent against PANC-1 and a panel of 39 human cancer cell lines (JFCR-39).

Human pancreatic cancer is known to be the most deadly disease with the lowest 5-year survival rate and is resistant to well known conventional chemotherapeutic drugs in clinical use. Screening of medicinal plants from Myanmar utilizing antiausterity strategy led to the identification of Vitex negundo as one of the medicinal plants having potent preferential cytotoxic activity against PANC-1 human pancreatic cancer cells. Bioactivity-guided phytochemical investigation led to the isolation of chrysoplenetin (1) and chrysosplenol D (2) as the active constituents with a PC(50) value of 3.4 µg/mL and 4.6 µg/mL, respectively, against PANC-1 cells. Both these compounds induced apoptosis-like morphological changes in PANC-1 cells. Chrysoplenetin was further tested against a panel of 39 human cancer cell lines (JFCR-39) at the Japanese Foundation for Cancer Research, and 25 cell lines belonging to lung, breast, CNS, colon, melanoma, ovarian, prostate cancer and stomach cancer cell lines were found to be highly sensitive to chrysoplenetin at a submicromolar range. In the JFCR-39 panel, lung NCI-H522, ovarian OVCAR-3 and prostate PC-3 cells were found to be most sensitive with GI(50) of 0.12, 0.18 and 0.17 µm, respectively. The COMPARE analysis suggested that the molecular mode of action of chrysoplenetin was unique compared with the existing anticancer drugs.

Two new cytotoxic phenylallylflavanones from Mexican propolis.

Two new phenylallylflavanones, (2R,3R)-6-[1-(4'-hydroxy-3'-methoxyphenyl)prop-2-en-1-yl]pinobanksin (1) and (2R,3R)-6-[1-(4'-hydroxy-3'-methoxyphenyl)prop-2-en-1-yl]pinobanksin 3-acetate (2) were isolated from a methanolic extract of Mexican propolis. Their structures were elucidated with spectroscopic analysis. Both compounds (1, 2) exhibited preferential cytotoxic activity against PANC-1 human pancreatic cancer cells in a nutrient-deprived medium with the concentration at which 50% cells died preferentially in NDM (PC50) values of 17.9 µM and 9.1 µM, respectively.

[Stump consolidation after video-assisted thoracoscopic segmentectomy].

Pulmonary segmentectomy by video-assisted thoracic surgery (VATS) is used for minimally invasive surgery for removal of small lung neoplasms, and stump consolidation is one of the potential postoperative complications. The objective of the present study is to clarify the incidence of stump consolidation and its predictive factors by assessing patients who underwent VATS segmentectomy in our department. Stump consolidation was defined as atelectatic lesions along the surgical stump with >10 mm thickness in horizontal sectional view by computed tomography, at least 3 months after surgery. Between February 2007 and September 2010, 70 patients (38 men and 32 women) with primary lung cancer (43 patients) and metastatic pulmonary tumor (27 patients) underwent VATS segmentectomy. Stump consolidations were seen in 7 patients. Univariate analysis showed the significant difference for the period of performed operation. Left-sided operation, especially segmentectomy of left S(1+2), was another predictive factor, though not significant. Stump consolidation after VATS segmentectomy can be deueloped by conbined workspace for stapling and misidentification of intersegmental plane. When division of the intersegmental plane is difficult, open thoracotomy should be undertaken to prevent such compliance.

α-Linolenic acid in Papilio machaon larvae regurgitant induces a defensive response in Apiaceae.

Papilio machaon hippocrates C. Felder et R. Felder, 1864 (Papilionidae) larvae are pests of plants of the family Apiaceae. It is unclear whether Apiaceae plants show induced defensive responses against P. machaon hippocrates larvae, and if so, how these responses are induced. Comparison of the fatty acid (FA) composition of the leaves of host plants and the regurgitant of P. machaon hippocrates larvae by LC-MS revealed a great increase in α-linolenic acid (α-LA) in the regurgitant compared with the FAs contained in the leaves. However, specific FA amino acid conjugates, known as elicitor compounds, such as volicitin, were not detected. Sterile host plants (Saposhnikovia divaricata (Turcz.) Schischk., Apiaceae) were treated with α-LA to mimic the damage made by P. machaon hippocrates larvae. After α-LA treatment to leaves, induced defensive reactions, i.e., release of volatile compounds such as α- and ß-pinene and camphene (possible induced indirect defense) and the accumulation of specialized metabolites such as (R)-falcarinol and bergapten (possible induced direct defense) were observed. These findings highlight the role of α-LA in the interaction between P. machaon hippocrates larvae and Apiaceae host plants.

Study on the constituents of Mexican propolis and their cytotoxic activity against PANC-1 human pancreatic cancer cells.

Three new flavonoids, (2R,3R)-3,5-dihydroxy-7-methoxyflavanone 3-(2-methyl)butyrate (1), (7''R)-8-[1-(4'-hydroxy-3'-methoxyphenyl)prop-2-en-1-yl]chrysin (2), and (7''R)-8-[1-(4'-hydroxy-3'-methoxyphenyl)prop-2-en-1-yl]galangin (3), together with 41 known compounds (4-44) were isolated from a methanolic extract of Mexican propolis. Compounds 2 and 3 are unique natural flavones containing a 1-phenylallyl moiety. The in vitro preferential cytotoxicity of all the isolates was evaluated against a PANC-1 human pancreatic cell line. Compound 3 displayed the most potent preferential cytotoxicity (PC(50) 4.6 microM) in the nutrient-deprived medium (NDM) and triggered apoptosis-like morphological changes in PANC-1 cells.

Influence of an adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride, on 5-HT2CR mRNA editing in primary cultured cortical cells.

Treatment of primary cultured cortical cells with erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA), an inhibitor of adenosine deaminase (ADAR), for 6 d significantly and concentration-dependently reduced the editing efficacy at sites C and D but not at site A or B of 5-HT2CR mRNA. The treatment failed to affect the editing of ADAR-2 pre-mRNA and a subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor (GluR2) mRNA. These findings suggest that EHNA is useful for clarifying the functional roles of 5-HT2CR mRNA editing at sites C and D.

Efficient enantio- and diastereodivergent synthesis of poison-frog alkaloids 251O and trans-223B.

An efficient and flexible synthesis of poison-frog alkaloids 251O and trans-223B has been achieved by using for both alkaloids an enantiodivergent process starting from the common lactam 1. The relative stereochemistry of 251O and trans-223B was determined to be 7 (R = n-C(7)H(15), R' = n-Pr) and 14 by the present enantioselective synthesis.