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Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.

Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.

Glucokinase activators increase insulin release from pancreatic beta-cells and hepatic glucose utilization by modifying the activity of glucokinase, a key enzyme in glucose-sensing and glycemic regulation. Sulfonylureas are antihyperglycemic agents that stimulate insulin secretion via a glucose-independent mechanism that is vulnerable to secondary failure through beta-cell desensitization. The present study determined whether glucokinase activator treatment retains its glucose-lowering efficacy in male, adult, non-diabetic Sprague-Dawley rats desensitized to sulfonylurea treatment and whether glucose-lowering during chronic glucokinase activator treatment is subject to secondary failure. Animals were given food containing either glimepiride (a sulfonylurea), Compound B (3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide, an experimental glucokinase activator), or no drug for up to 5 weeks. Food containing 0.04% of either drug produced acute (within 4-8 h) and significant (P

We describe design, syntheses and structure-activity relationships of a novel class of 4,6-disubstituted quinazoline glucokinase activators. Prototype quinazoline leads (4 and 5) were designed based on the X-ray analyses of the previous 2-aminobenzamide lead classes. Modifications of the quinazoline leads led to the identification of a potent GK activator (21d).

The optimization of a series of benzimidazole glucokinase activators is described. We identified a novel and potent achiral benzimidazole derivative as an allosteric GK activator. This activator was designed and synthesized via removal of the chiral center of the lead compound, 6-(N-acylpyrrolidin-2-yl)benzimidazole. The activator exhibited good PK profiles in rats and dogs, and significant hypoglycemic efficacy at 1 mg/kg po dosing in a rat OGTT model. The binding site and binding mode of the benzimidazole class of GKA with GK protein was confirmed by X-ray crystallographic analysis.

The synthesis and structure-activity-relationships (SARs) of novel 2-(pyridine-2-yl)-1H-benzimidazole glucokinase activators are described. Systematic modification of benzimidazole lead 5a identified from a high-throughput screening led to the discovery of a potent and metabolically stable glucokinase activator 16p(R) with greater structural diversity from GKAs reported to date. The compound also demonstrated acute oral glucose lowering efficacy in rat OGTT model.

The optimization of our lead GK activator 2a to 3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide (6g), a potent GK activator with good oral availability, is described, including to uncouple the relationship between potency and hydrophobicity. Following oral administration, this compound exhibited robust glucose lowering in diabetic model rodents.

Identification and synthesis of novel 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as glucokinase activators are described. Removal of an aniline structure of the prototype lead (2a) and incorporation of an alkoxy or phenoxy substituent led to the identification of 3-Isopropoxy-5-[4-(methylsulfonyl)phenoxy]-N-(4-methyl-1,3-thiazol-2-yl)benzamide (27e) as a novel, potent, and orally bioavailable GK activator. Rat oral glucose tolerance test indicated that 27e exhibited a glucose-lowering effect after 10 mg/kg oral administration.

The identification and structure-activity-relationships (SARs) of novel 2-amino benzamide glucokinase activators are described. Compounds in this series were developed to be potent GK activators, and their binding mode to the GK protein was determined by crystal structure analysis. In vivo pharmacokinetic and acute in vivo efficacy studies of compound 18 are also described.

We compared features of the precipitation associated with subsynoptic-scale Baiu frontal depression simulated by an atmospheric general circulation model (AGCM; T106L56: a spectral primitive-equation model with 56 σ levels and triangular spectral truncation at zonal wavenumber 106) with the features had been described in observational studies. The 21-year model integration from 1979 to 1999 was constrained by observed sea-surface temperature and sea-ice distribution. As typical examples, this paper examines simulation cases for June 1991.Comparisons with past observational results showed that the AGCM properly simulated the Baiu front and the Baiu frontal precipitation in the averaged elds for a 15-day period in June 1991. However, the area of the largest 1-hour precipitation is simulated at about 500 km northeastward from the area of the largest averaged precipitation. We also found signicant differences between the simulations and the ob servations when we examined the daily precipitation and the maximum 1-hour precipitation for each day simulated by the model. While precipitation associated with subsynoptic-scale Baiu frontal depressions was relatively well simulated, intense precipitation in the trailing portion of these depressions was signi cantly underestimated.The result of the present study indicates that the ability of the AGCM to reproduce such extreme pre cipitation events must be examined in detail by comparing simulated daily and hourly precipitation with observational studies as well as by statistical analyses.

Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.

To test the hypothesis that glucokinase is a critical regulator of neuronal glucosensing, glucokinase activity was increased, using a glucokinase activator drug, or decreased, using RNA interference combined with calcium imaging in freshly dissociated ventromedial hypothalamic nucleus (VMN) neurons or primary ventromedial hypothalamus (VMH; VMN plus arcuate nucleus) cultures. To assess the validity of our approach, we first showed that glucose-induced (0.5-2.5 mmol/l) changes in intracellular Ca(2+) concentration ([Ca(2+)](i)) oscillations, using fura-2 and changes in membrane potential (using a membrane potential-sensitive dye), were highly correlated in both glucose-excited and -inhibited neurons. Also, glucose-excited neurons increased (half-maximal effective concentration [EC(50)] = 0.54 mmol/l) and glucose-inhibited neurons decreased (half-maximal inhibitory concentration [IC(50)] = 1.12 mmol/l) [Ca(2+)](i) oscillations to incremental changes in glucose from 0.3 to 5 mmol/l. In untreated primary VMH neuronal cultures, the expression of glucokinase mRNA and the number of demonstrable glucosensing neurons fell spontaneously by half over 12-96 h without loss of viable neurons. Transfection of neurons with small interfering glucokinase RNA did not affect survival but did reduce glucokinase mRNA by 90% in association with loss of all demonstrable glucose-excited neurons and a 99% reduction in glucose-inhibited neurons. A pharmacological glucokinase activator produced a dose-related increase in [Ca(2+)](i) oscillations in glucose-excited neurons (EC(50) = 0.98 mmol/l) and a decrease in glucose-inhibited neurons (IC(50) = 0.025 micromol/l) held at 0.5 mmol/l glucose. Together, these data support a critical role for glucokinase in neuronal glucosensing.

The present report studies features of the polar-air outbreak and the associated air-mass transformation over the east coast of Asia simulated in an AGCM (T106L52: a primitive equation spectral model, which has 52 σ-levels and triangular spectral truncation at wave-number 106) that used climatological SST in comparison with the features described in several observational studies.The large-scale circulations are properly reproduced for January Y07 (the 7th year after the spin up integration). A typical case of polar-air outbreak simulated in January is studied in detail. During the polar-air outbreak, cyclonic northwesterly polar-air streams over the Sea of Japan and the northwestern Pacific, and anticyclonic northeasterly polar-air streams over the East China Sea and the South China Sea are reasonably simulated. During the polar-air outbreak, the sensible and latent heat fluxes simulated over the Sea of Japan reach to ∼150 and ∼250 W m−2, while those over the East China Sea reach to ∼75 and ∼250 W m−2, respectively. These simulated fluxes agree with the fluxes evaluated in observational studies. The multi-layer structure of the transformed air-mass, including the unstable surface layer, the subcloud layer, and the cloud layer capped by the stable layer, simulated over the coastal areas of Asia is consistent with the observations for the cases of typical polar-air outbreak.However, the precipitation over the coastal areas of Japan simulated during the polar-air outbreak is significantly small as compared with the observation. This is due to the insufficient horizontal resolution of the T106L52 to simulate mesoscale circulation systems which induce snowfalls. In addition, the duration of the polar-air outbreak simulated in the AGCM is relatively short as compared with that in the real atmosphere, since the anticyclone over the continent tends to extend eastward in the model.

A robust synthetic method for 2-alkylamino-6-carboxy-5,7-diarylcyclopenteno[1,2-b]pyridines via acylamination at the alpha position of the functionalized pyridine system has been developed. The key step in this method was achieved by treatment of the corresponding pyridine N-oxides with 2.5 equiv of imidoyl chlorides in the presence of triethylamine, thus producing the desired 2-acylaminopyridines in good yields (74–96%).

Simulations of the Northern Hemisphere ice sheet at the Last Glacial Maximum (LGM; 21 kyr BP) are performed using a high-resolution atmospheric general circulation model (AGCM) in order to re-evaluate the conventional surface temperature- or elevation-based parameterization. The influence of precipitation change on the steady-state topography of the Laurentide ice sheet at the LGM is estimated using an AGCM with a horizontal resolution of ∼1° and a three-dimensional thermomechanically coupled ice-sheet model. The ice volume estimated by the AGCM simulation is much larger than that indicated by the conventional parameterization. Through sensitivity analysis of the AGCM and ice-sheet model, it is found that the rate of precipitation change depends on the location of the ice sheet, and that the rate of precipitation change due to surface elevation change is higher than the rate unrelated to surface elevation change on the Laurentide ice sheet. The rate of precipitation is also shown to exhibit seasonality and regionality due to effects such as interior desertification and the concentration of storm tracks.

Glucokinase is a monomeric enzyme that displays a low affinity for glucose and a sigmoidal saturation curve for its substrate, two properties that are important for its playing the role of a glucose sensor in pancreas and liver. The molecular basis for these two properties is not well understood. Herein we report the crystal structures of glucokinase in its active and inactive forms, which demonstrate that global conformational change, including domain reorganization, is induced by glucose binding. This suggests that the positive cooperativity of monomeric glucokinase obeys the “mnemonical mechanism” rather than the well-known concerted model. These structures also revealed an allosteric site through which small molecules may modulate the kinetic properties of the enzyme. This finding provided the mechanistic basis for activation of glucokinase as a potential therapeutic approach for treating type 2 diabetes mellitus.

A polar mesoscale cyclone (PMC) developed over the east coast of Asia in an atmospheric general circulation model (AGCM) that used seasonally varying climatological sea surface temperatures (SSTs). The AGCM had 52 layers and triangular spectral truncation at wavenumber 106 (T106L52). This study compares the model PMC, which formed in February, 8 years after model spin-up, with observational studies. The simulated PMC formed over the western Sea of Japan under the influence of a short-wave trough propagating around a cold upper low. PMC genesis occurred as a surface trough over the Sea of Japan. The surface trough extended northward from a major cyclone that developed over the western North Pacific south of Japan. Large sensible heat fluxes from the sea surface facilitated PMC genesis by decreasing the vertical stability and maintaining a thermal gradient in the lower troposphere. Significant weakening of the PMC as it passed over Japan suggests that energy supplied from the surface played an important role in the evolution of the PMC. The PMC subsequently developed rapidly over the western North Pacific east of Japan, under the influence of the upper cold low and a short-wave trough. Precipitation, diabatic heating, and energy from the sea surface all increased as the PMC developed. The evolution of the simulated PMC matched the evolution of observed PMCs. Realistic formation of synoptic-scale circulation systems, such as the upper cold low, short-wave troughs, and a major cyclone in the model, are crucial if PMCs are to be simulated realistically in the AGCM.

The present paper studies features of the Baiu front and associated precipitation systems simulated in the climatological SST run by an AGCM T106L52 (primitive equation spectral model, the maximum wave-number of 106, with 52 vertical levels) in comparison with the features found in observational studies. The Baiu front is properly simulated in 1-20 June Y07 (the 7th year after the spin-up integration). In this “Baiu phase”, the large-scale circulation systems, such as the upper cold lows and blocking ridge in the northern latitudes, westward extending Pacific subtropical anticyclone, monsoon westerly, and subtropical jet stream, are simultaneously maintained. Under this condition, the synoptic- and meso-ascale variations of the Baiu front are simulated. The southward shift of the front occurs when a synopticscale cyclone develops in association with a westerly trough. When westerly troughs are inactive, weak subsynoptic-scale depression is formed in the frontal zone. A few meso-α-scale precipitation systems are generated in the trailing portion of the preceding depression, and form a “Baiu precipitation system family” with a length of∼2000 km. This indicates that the simulation of the realistic Baiu front depends on the maintenance of proper large- and synoptic-scale circulation systems. However, the Baiu precipitation zone disappears in the early July, as the west-east elongating barotropic anticyclone, which is usually seen over Japan in August in the real atmosphere, is situated over ∼37°N.

This report shows genesis of a polar low by an AGCM without specialized initial condition. A case of polar low genesis over the eastern coast of the Asian Continent, simulated in the seasonally varying climatological SST run by an AGCM (T42L52, primitive equation spectral model with 42 wave-number and 52 layers), is presented. A polar low simulated in January 22-23 of the fourth year (Y04) integration after the 10-year period of the spin-up is studied in comparison with polar lows described in several observational studies. In January Y04, large-scale circulation systems, such as Asian winter monsoon, extratropical cyclones and upper cold lows are reasonably simulated. A typical polar low is formed in January 22 over the coastal sea area ∼1500 km west of the major extratropical cyclone that developed over the Northwestern Pacific Ocean, under the influence of a short wave trough, which propagates along the rim of an upper cold low. The polar low genesis takes place first in connection with a deepening of the surface trough, which extends westward from the major cyclone. The deepening of the surface trough in the zone of strong low-level thermal gradient over the coastal sea area suggests the important role of the low-level baroclinicity for the polar low genesis. The strong heating due to the energy supply from the sea surface contributes for the genesis of the polar low through the decreasing of the vertical stability, and the sustaining thermal gradient. Meanwhile, the heating around 700 hPa associated with the precipitation concentrated within the polar low indicates the influence of the condensation heating for the development of the polar low. Aforementioned various processes contribute together to generate and develop the polar low. The structure and the evolution process of the simulated polar low are consistent with those of the observed polar lows. It is concluded that the realistic polar low genesis takes place in the model, when the large-scale phenomena such as the upper cold low, the short-wave trough, parent major cyclone and polar air outbreak are reasonably simulated. The present study is significant in presenting an AGCM simulation of a polar low for the first time.

A new indolocarbazole compound, NB-506 (1), modified at the glucose group yielded a beta-D-glucopyranoside, J-107,088 (2), which showed potent anticancer activity. A beta-D-ribofuranoside, J-109,534 (3), was found to be 6 times more potent than J-107,088 at inhibiting topoisomerase I.

In the course of a study of 6-N-amino-substituted analogues of NB-506 (1), a more potent anticancer drug, J-109,404 (2), in which the formyl group of NB-506 was replaced with a 1,3-dihydroxypropane group, was reported. A study of further modification in the positions of two hydroxyl groups at the indole rings of 2 resulted in the discovery of a 2,10-dihydroxy analogue, J-107,088 (3), which is a promising anticancer agent with a broader therapeutic window than J-109,404.

A novel method for the synthesis of N-glycosylated dissymmetric indolo[2,3-a]pyrrolo-[3,4-c]carbazole derivatives was developed by applying the Mitsunobu reaction to the N-glycosylation reaction of substituted indole substrates. © 1997 Elsevier Science Ltd.

陸面数値モデル(LSP)は大気数値モデルなどに組み込まれて地表面での水とエネルギーの交換を表現している.全球土壌水分プロジェクト(GSWP)において,いつかのLSPにより1987年および1988年の水収支が,共通の降水量や放射強度に対して算定された.ここでは,全球1度グリッドメッシュで作成された河川流路網情報(TRIP)を利用し,河川流量データによってそれらLSPによる年水収支算定値を検証した.その結果,充分な降水観測(雨量計密度≧30個/l06km2)に基づいて入力降水量が算定されている領域ではLSPは適切に年流出高を算定していることがわかった.

A practical method for the synthesis of an indolo[2,3-a]pyrrolo[3,4-c]carbazole ring system is described. The method involves two key processes: a coupling reaction between indole and substituted methylmaleimide portions using lithium hexamethyldisilazide (LiHMDS) as a base, and the oxidative cyclization of bisindolylmaleimide with palladium (II) chloride. We applied this method to the synthesis of arcyriaflavin B ( 5 ), C ( 6 ) and D (7).

Glucokinase activators (GKAs) are small-molecule agents that enhance glucose sensing by pancreatic β cells and glucose metabolism by hepatocytes. There is strong interest in these agents as potential therapies for type 2 diabetes. Here, we report key pharmacokinetic and pharmacodynamic findings from preclinical studies of the GKA 3-[[6-(ethylsulfonyl)-3-pyridinyl]oxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (MK-0941). Incubated in vitro with recombinant human glucokinase, 1 μM MK-0941 lowered the S(0.5) of this enzyme for glucose from 6.9 to 1.4 mM and increased the maximum velocity of glucose phosphorylation by 1.5-fold. In 2.5 and 10 mM glucose, the EC(50) values for activation of GK by MK-0941 were 0.240 and 0.065 μM, respectively. Treatment of isolated rat islets of Langerhans and hepatocytes with 10 μM MK-0941 increased insulin secretion by 17-fold and glucose uptake up to 18-fold, respectively. MK-0941 exhibited strong glucose-lowering activity in C57BL/6J mice maintained on a high-fat diet (HFD), db/db mice, HFD plus low-dose streptozotocin-treated mice, and nondiabetic dogs. In both mice and dogs, oral doses of MK-0941 were rapidly absorbed and rapidly cleared from the blood; plasma levels reached maximum within 1 h and fell thereafter with a half-life of ~2 h. During oral glucose tolerance testing in dogs, MK-0941 reduced total area-under-the-curve postchallenge (0-2 h) plasma glucose levels by up to 48% compared with vehicle-treated controls. When administered twice daily to mice for 16 days, and once daily to the dog for 4 days, MK-0941 remained efficacious on successive days. These findings support further investigation of MK-0941 as a potential therapeutic agent for treatment of type 2 diabetes.

Acyltrialkylgermanes 4 have been obtained in good yields by the Swern oxidation of trialkyl(1-hydroxyalkyl)germanes 3 which were prepared from aldehydes 1 and trialkylgermyllithium 2. Reaction of 4 with butyllithium 5, tert-butyl lithioacetate 7 or 2-lithiopropionitrile 9 gave the respective 1,2-addition products 6, 8 and 10. However, reaction with 1-lithioethyl phenyl sulfone 11 gave α-(trialkylgermyl) ketones 12, and with the lithium enolate of tert-butyl bromoacetate 14 gave (trialkylgermyl)oxiranes 15 as the main products, respectively. The results of the treatment of 15 with Lewis acids are also discussed.

A practical method for the synthesis of an indolo[2,3-a]pyrrolo[3,4-c]carbazole ring system is described. The method involves two key processes: a coupling reaction between indole and substituted methylmaleimide portions using lithium hexamethyldisilazide (LiHMDS) as a base, and the oxidative cyclization of bisindolylmaleimide with palladium (II) chloride. We applied this method to the synthesis of arcyriaflavin B ( 5 ), C ( 6 ) and D (7).

A novel method for the synthesis of N-glycosylated dissymmetric indolo[2,3-a]pyrrolo-[3,4-c]carbazole derivatives was developed by applying the Mitsunobu reaction to the N-glycosylation reaction of substituted indole substrates. © 1997 Elsevier Science Ltd.

In the course of a study of 6-N-amino-substituted analogues of NB-506 (1), a more potent anticancer drug, J-109,404 (2), in which the formyl group of NB-506 was replaced with a 1,3-dihydroxypropane group, was reported. A study of further modification in the positions of two hydroxyl groups at the indole rings of 2 resulted in the discovery of a 2,10-dihydroxy analogue, J-107,088 (3), which is a promising anticancer agent with a broader therapeutic window than J-109,404.

A new indolocarbazole compound, NB-506 (1), modified at the glucose group yielded a beta-D-glucopyranoside, J-107,088 (2), which showed potent anticancer activity. A beta-D-ribofuranoside, J-109,534 (3), was found to be 6 times more potent than J-107,088 at inhibiting topoisomerase I.

Glucokinase activators (GKAs) are currently under investigation as potential antidiabetic agents by many pharmaceutical companies. Most of GKAs reported previously possess N-aminothiazol-2-yl amide moiety in their structures because the aminothiazole moiety interacts with glucokinase (GK) and shows strong GK activation. During the development of N-aminothiazol-2-yl amide derivatives, we identified a bioactivation and metabolic liability of 2-aminothizole substructure of GKA 3 by assessing covalent binding, metabolites in liver microsomes and glutathione (GSH) trap assay.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates insulin secretion in a glucose-dependent manner. Selective GLP-1 secretagogue would be one of the potential therapeutic targets for type 2 diabetes. Here, we describe a newly identified small molecule compound (compound A) that stimulates secretion of GLP-1 in murine enteroendocrine cell lines, STC-1 and GLUTag cells, and in primary cultured fetal rat intestinal cells (FRIC). The underlying mechanism by which compound A stimulated GLP-1 secretion was also examined. Compound A stimulated GLP-1 secretion from STC-1 cells in a concentration-dependent manner, and also from GLUTag cells and FRIC. The action of compound A was selective against other tested endocrine functions such as secretion of insulin from rat islets, growth hormone from rat pituitary gland cells, and norepinephrine from rat PC-12 cells. In STC-1 cells, the compound A-stimulated GLP-1 secretion was neither due to cyclic AMP production nor to Ca2+ release from intracellular stores, but to extracellular Ca2+ influx. The response was inhibited by the presence of either L-type Ca2+ channel blockers or K+ ionophore. Perforated-patch clamp study revealed that compound A induces membrane depolarization. These results suggest that neither Gαs- nor Gαq-coupled signaling account for the mechanism of action, but depolarization-coupled Ca2+ influx from extracellular space is the primary cause for the GLP-1 secretion stimulated by compound A. Identifying a specific target molecule for compound A will reveal a selective regulatory pathway that leads to depolarization-mediated GLP-1 secretion.

A novel class of 3,6-disubstituted 2-pyridinecarboxamide derivatives was designed based on X-ray analysis of the 2-aminobenzamide lead class. Subsequent chemical modification led to the discovery of potent GK activators which eliminate potential toxicity concerns associated with an aniline group of the lead structure. Compound 7 demonstrated glucose lowering effect in a rat OGTT model.

Glucokinase (GK) plays a key role in the control of blood glucose homeostasis. We identified a small molecule GK activator, compound A, that increased the glucose affinity and maximal velocity (V(max)) of GK. Compound A augmented insulin secretion from isolated rat islets and enhanced glucose utilization in primary cultured rat hepatocytes. In rat oral glucose tolerance tests, orally administrated compound A lowered plasma glucose elevation with a concomitant increase in plasma insulin and hepatic glycogen. In liver, GK activity is acutely controlled by its association to the glucokinase regulatory protein (GKRP). In order to decipher the molecular aspects of how GK activator affects the shuttling of GK between nucleus and cytoplasm, the effect of compound A on GK-GKRP interaction was further investigated. Compound A increased the level of cytoplasmic GK in both isolated rat primary hepatocytes and the liver tissues from rats. Experiments in a cell-free system revealed that compound A interacted with glucose-bound free GK, thereby impairing the association of GK and GKRP. On the other hand, compound A did not bind to glucose-unbound GK or GKRP-associated GK. Furthermore, we found that glucose-dependent GK-GKRP interaction also required ATP. Given the combined prominent role of GK on insulin secretion and hepatic glucose metabolism where the GK-GKRP mechanism is involved, activation of GK has a new therapeutic potential in the treatment of type 2 diabetes.

[1] Using a high-resolution climate model, we projected future sea level and its variability based on two scenarios for 21st century greenhouse gas emission. The globally averaged sea level rise attributable to the steric contribution was 23 and 30 cm for the two scenarios. The results of the high-resolution model and a medium-resolution version of the same model for global and local sea level change agreed well. However, the high-resolution model represented more detailed ocean structure changes under global warming. The changes affected not only the spatial distribution of sea level rise, but also the changes in local sea level variability associated with ocean eddies. The enhanced eddy activity was responsible for extreme sea level events.

[1] Using atmosphere-ocean coupled general circulation models (CGCMs) with different resolution, we investigate the dependency on horizontal resolution to reproduce the seasonal variation of the Mindanao Dome (MD). The seasonal cycle of the MD is successfully simulated in the high resolution CGCM. It is generated by local Ekman upwelling and destroyed by westward warm anomaly propagation during late spring. The warm anomaly is caused by Ekman downwelling induced by westward wind stress and negative wind stress curl anomaly associated with southward shift of the inter-tropical convergence zone in the central tropical Pacific. However, in the lower resolution model, the seasonal cycle is not represented owing to the insufficient wind forcing. The higher resolution atmospheric model improves the wind forcing in the CGCM, but it doesn't go far enough. The reproduction of the wind forcing depends not only horizontal resolution of an atmospheric model but also on that of an ocean model.

[1] For the first time, using a high-resolution atmosphere-ocean coupled general circulation model (CGCM), we succeed in reproducing the far-reaching effects of the Hawaiian Islands, recently showed by satellite observations. The model reproduces the distributions of sea surface temperature (SST), surface winds and cloud liquid water (CLW) in the wake of the Hawaiian Islands. It is revealed that these distributions are caused by the Hawaiian Lee Counter Current (HLCC) and that this current is driven by the wind-curls induced by the orographic effect of the islands, as suggested from an observational study. It is also shown that wind changes around the Hawaiian Islands can further affect the speed of the North Equatorial Current (NEC) and SST over the current, and intra-annual variability in CLW to the west of the islands is governed, not only by SST but also by wind speed.

6-N-Amino analogues of NB-506 [6-N- formylamino-12,13-dihydro-1,11-dihydroxy-13-(β- d -glucopyranosyl )-5H- indolo [2,3-a] pyrrolo [3,4-c] carbazole -5,7(6H)- dione ] (3b) were synthesized and tested with respect to topoisomerase inhibition, cytotoxicity and anticancer effects. Among them, a 1,3-dihydroxypropane analogue (J-109,404, 5t) showed more than ten times more potent anticancer activity in MKN-45 human stomach cancer cells implanted in mice than NB-506. 6-N-Amino analogue of NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(β-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione] (3b), J-109,404 (5t), was found to be a more potent anticancer agent in MKN-45 human stomach cancer cells implanted in mice than NB-506.

Acyltrialkylgermanes 4 have been obtained in good yields by the Swern oxidation of trialkyl(1-hydroxyalkyl)germanes 3 which were prepared from aldehydes 1 and trialkylgermyllithium 2. Reaction of 4 with butyllithium 5, tert-butyl lithioacetate 7 or 2-lithiopropionitrile 9 gave the respective 1,2-addition products 6, 8 and 10. However, reaction with 1-lithioethyl phenyl sulfone 11 gave α-(trialkylgermyl) ketones 12, and with the lithium enolate of tert-butyl bromoacetate 14 gave (trialkylgermyl)oxiranes 15 as the main products, respectively. The results of the treatment of 15 with Lewis acids are also discussed.