A SmI2-mediated reductive cyclisation reaction using the trifluoroacetamide group as the radical precursor.

A samarium(II)-mediated reductive cyclisation reaction with the aminoketyl radical from the trifluoroacetamide group for synthesising 2-trifluoromethylindolines was developed. This reaction is the first example of using an acyclic amide group, which is considered difficult to react with SmI2, in a reductive cyclisation. Additionally, the conversion of the obtained product into 2-trifluoromethylindole was achieved.

Regioselective SmI2-Mediated Radical ipso-Substitution Cyclization for the Construction of Pyrrolophenanthridinone Skeletons: The Synthesis of Amaryllidaceae Alkaloids.

Here, we report a regioselective, samarium(II) diiodide mediated intramolecular radical ipso-substitution cyclization. Through the use of a methoxy group as a leaving group, it was possible to regulate the regioselectivity of the reaction by changing the temperature and additives. We applied the developed reaction to the synthesis of four Amaryllidaceae alkaloids and have shown that the present reaction successfully overcomes regioselectivity issues encountered with other cyclization methods.

Synthesis of Acetogenin Analogs Comprising Pyrimidine Moieties Linked by Amine Bonds and Their Inhibitory Activity against Human Cancer Cell Lines.

Here, we synthesized three acetogenin analogs containing pyrimidine moieties linked by amine bonds, which represent the skeleton structure of pyrimidifen, a mitochondrial complex I-inhibiting insecticide. Replacing the pyrimidine moiety linked by the amine bond remarkably enhanced growth-inhibitory activity of the analogs against several human cancer cell lines. Moreover, these analogs selectively and potently inhibited the growth of these human cancer cell lines regardless of the pyrimidine substituents. Furthermore, COMPARE analyses suggested that these analogs inhibited cancer growth by inhibiting mitochondrial complex I. Our study provides insights into the design of acetogenin analogs as novel antitumor agents.

Structure-Activity Relationships of Thiophene Carboxamide Annonaceous Acetogenin Analogs: Shortening the Alkyl Chain in the Tail Part Significantly Affects Their Growth Inhibitory Activity against Human Cancer Cell Lines.

In a previous study, we found that the thiophene carboxamide solamin analog, which is a mono-tetrahydrofuran annonaceous acetogenin, showed potent antitumor activity through the inhibition of mitochondrial complex I. In this study, we synthesized analogs with short alkyl chains instead of the n-dodecyl group in the tail part. We evaluated their growth inhibitory activities against human cancer cell lines. We found that the alkyl chain in the tail part plays an essential role in their activity.

Reaction of 3-Oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate with Dimethylsulfoxonium Methylide.

We have been interested in the reactivities of small-ring compounds and have reported reactions that proceed through cyclopropane intermediates starting from coumarin derivatives bearing an electron-withdrawing group at the 3-position or 2-oxo-2H-pyran-3-carboxylate derivatives and dimethylsulfoxonium methylide. This time, the reaction between 3-oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate and dimethylsulfoxonium methylide has been investigated. 3a,4,5,7a-Tetrahydro-7-hydroxybenzofuran-6-carboxylate and/or 2-hydroxybicyclo[4.1.0]hept-2-ene-3-carboxylate were obtained. The compounds were characterized using various spectral and X-ray crystallographic techniques. A plausible reaction mechanism has been discussed. This reaction was applied to some 3-oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate derivatives to clarify the generality.

Construction of Acyclic All-Carbon Quaternary Stereocenter Based on Asymmetric Michael Addition of Chiral Amine.

Acyclic asymmetric quaternary stereocenters, which are composed of four carbon-carbon bonds, were finely constructed by utilizing a face-selective alkylation of enolate intermediates derived from an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted (E)-α,ß-unsaturated esters. The present face-selective alkylation was able to employ diverse alkyl halides as an electrophile to afford various Michael adducts having an all-carbon quaternary stereocenter. With regard to the deprotection of the chiral auxiliary, N-iodosuccinimide used in our previous study did not work in the present cases; however, we found that pyridine iodine monochloride in the presence of H2O was effective to remove the bornyl group and the benzyl group on the amino group to provide the ß-amino ester derivative.

Syntheses of C2'-Fluorinated Analogs of Solamin.

The details of the total syntheses of C2'-fluorinated analogs of solamin, an antitumor annonaceous acetogenin, are described. Fluorine was enantioselectively introduced at the C2'-position by organocatalytic α-fluorination of the aldehyde according to a previously reported method. C2'-fluorinated solamin and its C2'-diastereomer were synthesized by the Sonogashira coupling of a tetrahydrofuran fragment and fluorine-containing γ-lactone fragments.

Cytological tumour cell characteristics and reactive small lymphocytes influence patient prognosis in acute and lymphoma type adult T-cell leukaemia/lymphoma.

OBJECTIVE: Acute and lymphoma type adult T-cell leukaemia/lymphoma (ATLL) patients show an aggressive clinical course. While some clinical signs indicate good prognosis, definitive cytohistological prognostic factors have yet to be described. METHODS: We classified 65 ATLL patients into three groups by tumour cell size and nuclear pleomorphism on fine-needle aspiration and tumour touch smear samples. Semi-quantitative analysis of background small lymphocytes, reactive CD20-positive B cells and CD8-positive T cells was performed. RESULTS: Thirty-one patients had pleomorphic lymphoma with predominantly medium-sized cells and coarse granular nuclei. Another 24 patients showed pleomorphic large cell lymphoma with stippled chromatin. The remaining 10 demonstrated monomorphic large lymphoma cells with fine granular chromatin. Patients with pleomorphic lymphoma with medium-sized cells showed significantly higher serum lactate dehydrogenase and lower CD30 and C-MYC expression in lymphoma cells than the other two groups (P = .0216, P < 0.01, respectively). Patients with pleomorphic medium-sized ATLL had few usual small lymphocytes observed on routine morphological examination and showed less concurrent detection of CD20-positive B cells and CD8-positive T cells, both of which were lower than in the other two groups (P = .006, P = .019, respectively). Furthermore, ATLL patients with predominantly medium-sized lymphocytes exhibited a worse prognosis than patients with pleomorphic large cells (P = .0197). Background small lymphocytes and concurrent detection of CD20-positive B cells and CD8-positive T cells may thus be good prognostic factors (P = .011, P = .021, respectively). CONCLUSIONS: Morphological features, size of neoplastic cells and background non-neoplastic lymphocyte (B cells and CD8-positive T cells) volume appear to influence the prognosis of patients with aggressive-type ATLL.

A Facile and Convenient Synthesis of Trisubstituted (E)-α,ß-Unsaturated Esters by Tandem Acetylation-E1cB Reaction.

A facile and convenient synthesis of trisubstituted (E)-α,ß-unsaturated esters was developed by improving our previously established method. The new method circumvented the separation of the intermediates, which have an activating group of the hydroxyl group in ß-hydroxy esters, furnishing α,ß-unsaturated esters in shorter steps than the previous method: an acetylation of ß-hydroxy group and subsequent E1cB reaction proceeded in tandem. In addition, the new method can not only employ a diastereomeric mixture of the substrate for the E1cB reaction, it has a wide substrate scope as well, which would enable the synthesis of various trisubstituted (E)-α,ß-unsaturated esters.

Vicenistatin induces early endosome-derived vacuole formation in mammalian cells.

Homotypic fusion of early endosomes is important for efficient protein trafficking and sorting. The key controller of this process is Rab5 which regulates several effectors and PtdInsPs levels, but whose mechanisms are largely unknown. Here, we report that vicenistatin, a natural product, enhanced homotypic fusion of early endosomes and induced the formation of large vacuole-like structures in mammalian cells. Unlike YM201636, another early endosome vacuolating compound, vicenistatin did not inhibit PIKfyve activity in vitro but activated Rab5-PAS pathway in cells. Furthermore, vicenistatin increased the membrane surface fluidity of cholesterol-containing liposomes in vitro, and cholesterol deprivation from the plasma membrane stimulated vicenistatin-induced vacuolation in cells. These results suggest that vicenistatin is a novel compound that induces the formation of vacuole-like structures by activating Rab5-PAS pathway and increasing membrane fluidity.

Reaction of 2a,8b-Dihydrobenzo[b]cyclobute[d]pyran-3-ones with Dimethylsulfoxonium Methylide.

Using dimethylsulfoxonium methylide as the methylene transfer reagent, 2a,8b-dihydrobenzo[b]cyclobute[d]pyran-3-ones were converted into 2,2'-biphenol derivatives as major products and dihydrodibenzofurans as minor products. The reaction mechanism was extrapolated from a deuteration experiment with CD2=S(O)(CD3)2.

Synthesis of dansyl-labeled probe of thiophene analogue of annonaceous acetogenins for visualization of cell distribution and growth inhibitory activity toward human cancer cell lines.

The convergent synthesis of the dansyl-labeled probe of the thiophene-3-carboxamide analogue of annonaceous acetogenins, which shows potent antitumor activity, was accomplished by two asymmetric alkynylations of the 2,5-diformyl THF equivalent with an alkyne having a thiophene moiety and another alkyne tagged with a dansyl group. The growth inhibitory profiles toward 39 human cancer cell lines revealed that the probe retained the biological function of its mother compound, and would be useful for studying cellular activity.

Susceptibility-weighted imaging in acute-stage pediatric convulsive disorders.

BACKGROUND: The aim of this preliminary study was to investigate the clinical use of acute-stage susceptibility-weighted imaging (SWI) in children with prolonged convulsive disorder. METHODS: Ten children with prolonged convulsive disorder who underwent SWI within 2 h after termination of seizure (acute-stage SWI group) and 15 control children who underwent SWI > 2 h after their seizures terminated or for other purposes were enrolled. The cerebral venous vasculature was compared between the groups. The acute-stage SWI group was further divided into three subgroups: normal group, those with regional low signals in the cerebral veins (regional group) and those with diffuse low signals in the cerebral veins (generalized group). Inter-ictal electroencephalography (EEG) and venous blood gas findings during seizure activity were compared between these subgroups. RESULTS: All patients in the acute-stage SWI group had low cerebral vein signal. Four patients were assigned to the regional group and six patients to the generalized group. Decrease of venous pH and the increase of venous pCO2 during seizure activity was more prominent in the regional group than in the generalized group. In the regional group, low-signal areas in the cerebral veins were consistent with abnormal areas on EEG; these low-signal areas resolved completely in all patients on follow-up SWI. Ten patients in the control group had normal SWI, and five had a generalized low signal. CONCLUSIONS: Acute-stage SWI may be a useful alternative for identifying lateralization of seizures in children with prolonged convulsive disorder.

Indole synthesis from N-allenyl-2-iodoanilines under mild conditions mediated by samarium(II) diiodide.

A novel method for indole skeleton synthesis under mild conditions mediated by samarium(ii) diiodide has been developed. The reaction of N-allenyl-2-iodoaniline derivatives with SmI2 in the presence of HMPA and i-PrOH at 0 °C afforded indole derivatives in high yields.

Prevalence and symptom of ossification of posterior longitudinal ligaments in the Japanese general population.

BACKGROUND: Ossification of the posterior longitudinal ligaments (OPLL) causes myelopathy with progression or trauma. Most OPLL patients visit the hospital after severe symptoms occur, and surgery did not supply complete relief in severe symptoms related to OPLL. While it is necessary to diagnose OPLL early and observe carefully, the nature of symptoms and asymptomatic OPLL have been unclear. The purposes of this study were to investigate the prevalence and symptoms of ossification of the posterior longitudinal ligaments (OPLL) of the cervical spine in the general population. METHODS: The subjects were 1291 Japanese general residents. Radiographic OPLL was detected by lateral view of the cervical spine, and subjects were classified into OPLL and non-OPLL groups. Visual analog scales of neck stiffness, neck pain, arm pain, and the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire were examined. Neck and arm symptoms were compared among the presence of OPLL, and among subtypes (continuous, segmental, and mixed types) statistically. RESULTS: Prevalence of OPLL was 3.7 % in overall participants, 3.9 % in symptomatic participants, and 2.2 % in asymptomatic participants. While 86.7 % of participants with OPLL had symptoms, the consultation rate was only 6.7 %. The female OPLL group had higher neck pain than the non-OPLL group, and neck function of JOACMEQ in the continuous type of OPLL was significantly restricted compared to those without OPLL and with the mixed type of OPLL. CONCLUSIONS: Prevalence of OPLL was 3.7 %, and most of them had neck and arm symptoms; however, they did not visit hospitals. Asymptomatic OPLL had the potential risk for spinal cord injury and myelopathy. Early detection and careful observation would prevent the severe symptoms induced by OPLL.

Association between roentgenographic findings of the cervical spine and neck symptoms in a Japanese community population.

BACKGROUND: Radiographic findings may provide clues to the underlying cause of neck symptoms. However, these associations remain controversial. This study investigates the association between roentgenographic findings of the cervical spine and neck symptoms in a Japanese community population. METHODS: A total of 762 volunteers participated in this study. Sagittal radiographs of the cervical spine were taken and a questionnaire about the presence of and visual analog scale (VAS) for neck pain or stiff shoulder was completed. The sagittal alignment of the cervical spine (C2-C7) and the degenerative index were measured from lateral aspect radiographs. Three groups based on the sagittal alignment of C2-C7 were defined: straight-spine, lordotic-spine, and kyphotic-spine. The roentgenographic findings were examined in relation to symptoms. RESULTS: The prevalence rate of stiff shoulder on the day of examination was significantly higher in females than males. Although the VAS for neck pain and stiff shoulder on the examination day and for stiff shoulder in the preceding 12 months were not significantly different between females and males, that for neck pain in the preceding 12 months was significantly higher in females than males. Although there was no association between the sagittal alignment of C2-C7 and neck symptoms in males or females, a significant correlation between the degenerative index and VAS for neck pain on the examination day and in the preceding 12 months was seen in females after adjusting for age. The prevalence of and VAS for neck pain and stiff shoulder were not significantly different among the three C2-C7 sagittal alignment groups. CONCLUSION: Although the sagittal alignment of the cervical spine was not associated with neck symptoms, degenerative changes were associated with the severity of neck pain in females.

Critical role of a methyl group on the γ-lactone ring of annonaceous acetogenins in the potent inhibition of mitochondrial complex I.

C34-epi and C34-epi-C35-trifluoro analogues of solamin, a mono-THF annonaceous acetogenin, were synthesized. Their inhibitory activity, along with previously synthesized analogues (C35-fluoro, C35-difluoro, and C35-trifluorosolamins), against bovine mitochondrial NADH-ubiquinone oxidoreductase (complex I) was determined. The present study revealed that the methyl group on the γ-lactone moiety is critical to the potent inhibition of complex I by natural acetogenins.

Influence of a 3-month training program on muscular damage and neutrophil function in male university freshman judoists.

We studied the effects of a high intensity and high frequency 3-month training program on muscle damage and neutrophil function in male judoists. The study included 15 male judoists who started intensive judo training program after a 6-month break. Creatine kinase (CK), neutrophil counts and reactive oxygen species (ROS) production capability as well as phagocytic activity (PA) of neutrophils were measured at 2 stages; entering university (pre-training) and after 3-month training (post-training). At both points, we investigated parameters three times: just before, immediately after and 24 h after a 2-h practice session. Practice-mediated change in CK was lower at post-training than at pre-training. Neutrophil count significantly increased after 2-h practice but recovered 24 h later whereas it showed no subsequent and further increased at 24 h post-practice. Although neutrophil ROS production capability and PA both decreased (breakdown) after practice session, ROS production capability increased and PA decreased (well-adapted) at the post-training. Long-term training strengthened muscular function and improved neutrophil reaction against practice-mediated stress.

Synthesis of (±)-8-deisopropyladunctin B.

(±)-8-Deisopropyladunctin B, the deisopropyl form of adunctin B, which was isolated from the leaves of Piper aduncum (Piperaceae) collected in Papua New Guinea, was synthesized in 0.77% overall yield in 17 steps from 5,7-dimethoxycoumarin-3-carboxylate. The key step was our original stereoconvergent skeleton transformation from 1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-one to 1,2,4a,9b-tetrahydrodibenzofuran-4-ol with dimethylsulfoxonium methylide.

Structure-antitumor activity relationship of hybrid acetogenins focusing on connecting groups between heterocycles and the linker moiety.

We studied hybrid molecules of annonaceous acetogenins and mitochondrial complex I-inhibiting insecticides to develop a novel anticancer agent. A structure-antitumor activity relationship study focusing on the connecting groups between the heterocycles and the linker moiety bearing the tetrahydrofuran moiety was conducted. Eleven hybrid acetogenins with 1-methylpyrazole instead of γ-lactone were synthesized and their growth inhibitory activities against 39 human cancer cell lines were evaluated. The nitrogen atom at the 2'-position of the linker moiety was essential for inhibiting cancer growth. The 1-methylpyrazole-5-sulfonamide analog showed potent growth inhibition of NCI-H23, a human lung cancer cell line, in a xenograft mouse assay without critical toxicity. Hence, the results of this study may pave the way for the development of novel anticancer agents, with both selective and broad anticancer activities.