Discovery of TAK-960: An orally available small molecule inhibitor of polo-like kinase 1 (PLK1)

Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies.     

Phosphodiesterase inhibitors. Part 6: Design,synthesis, and structure–activity relationships of PDE4-inhibitory pyrazolo[1,5-a]pyridines with anti-inflammatory activity

We previously identified KCA-1490 [(?)-6-(7-methoxy-2-trifluoromethyl-pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone], a dual PDE3/4 inhibitor. In the present study, we found highly potent selective PDE4 inhibitors derived from the structure of KCA-1490. Among them, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide (2a) had good anti-inflammatory effects in an animal model.     

Relationship between the expression of Rab family GTPases and neuropeptide hormones in the brain of Bombyx mori

Rab proteins are small GTPases that play essential roles in vesicle transport. In this study, we examined the expression of Rab proteins and neuropeptide hormones in the brain of the silkworm, Bombyx mori. We produced antibodies against B. mori Rab1 and Rab14 in rabbits. Immunoblotting of samples of brain tissue from B. mori revealed a single band for each antibody. Rab1 and Rab14 immunohistochemical labeling in the brain of B. mori was restricted to neurons of the pars intercerebralis and dorsolateral protocerebrum. Rab1, Rab7 and Rab14 co-localized with bombyxin. Rab1 and Rab7 co-localized with eclosion hormone. Rab1 co-localized with prothoracicotropic hormone. These results suggest that Rab1, Rab7 and Rab14 may be involved in neuropeptide transport in the brain of B. mori. This is the first report on the specificity of Rab proteins for the secretion of different neuropeptides in insects.     

Age-related effects of major and trace element concentrations in rat liver and their mutual relationships

The concentrations of 22 major and trace elements in livers from rats aging from 5 to 113 weeks old were determined. The rats investigated were the same rats previously reported with respect to 29 elements in bones (femur) and 26 elements in kidneys. The samples were decomposed with high-purity nitric acid and hydrogen peroxide. Seven elements (Na, Mg, P, K, Ca, Fe and Zn) were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES), and 15 elements (Mn, Co, Cu, As, Se, Rb, Sr, Mo, Cd, Sn, Sb, Cs, Ba, Pb and Bi) were determined by inductively coupled plasma mass spectrometry (ICP-MS). Analysis of variance (ANOVA) for age variations indicated that the concentrations of many elements, such as Mg, P, K, Mn, Fe, Cu, Zn, Sr, Mo and Cd, were almost constant across the ages of the rats with the exception of 5 weeks old (p > 0.05). Arsenic, Pb and Bi showed significant increasing trends, while Na and Co showed decreasing trends (p < 0.01). Selenium showed a decreasing trend except at the initial stage of 5–9 weeks old. Calcium, Rb, Sn, Sb, Cs and Ba showed significant age-related variations, but their patterns were not monotonic. The liver clearly contrasts with the kidneys, in which many elements showed significant age-related variations with increasing trends. The concentration ranges of Mg, P, K, Mn, Cu, Zn, and Mo were controlled within 15% across all ages of rats. The homeostasis of the aforementioned elements may be well established in the liver. The toxic elements, such as Cd, Pb and Bi, showed a narrow concentration range among age-matched rats.     

An Assay of Sterigmatocystin and Related Metabolites of Aspergillus versicolor by High Speed Liquid Chromatography

Among several type cultures that assimilated 1-hexadecene, Corynebacterium equi IFO 3730 was found to best accumulate 1, 2-epoxyhexadecane. The purified product exhibited +9.64 (c = 3.71, n-hexane) and was confirmed to have the (R) absolute configuration by correlating to known analogous compounds. The optical purity was determined to be 100% by PMR measurement of 1-methoxy-2-hexadecanol which was derived stereospecifically from the epoxide. The highest yield (41 % based on consumed 1-hexadecene) was achieved when 2.0% of octane and 0.1 % of Tween 80 were added to the medium containing 0.5 % of the olefin. C. equi also assimilated terminal olefins other than 1-hexadecene and produced the corresponding epoxides from substrates which have carbon chains longer than fourteen.     

Synthesis of 4-Thiazolone Derivatives Related to Firefly Oxyluciferin

Several 4-thiazolone derivatives were synthesized by condensation of appropriate aryl cyanide and ethyl thioglycolate (or derivative), and factors affecting to the reaction rate are discussed. Keto-enol tautomerization of the 4-thiazolones is briefly discussed.     

Structural Analysis of Sydowic Acid by X-ray Diffraction

Streptomyces sp. No. 280 produced several kinds of amylase inhibitors (amylase inhibitor A, B, B' and C). Two amylase inhibitors (designated as AI-A₁ and AI-A₂) were obtained from an amylase inhibitor A fraction by paper chromatography. AI-A₁ inhibited muscle phosphorylase a much more than AI-A₂ and was hydrolyzed by sweet potato β-amylase whereas AI-A₂ was not. Both amylase inhibitors had a carbohydrate and were hydrolyzed by some kinds of amylases or acids. They lost their inhibitory activity against phosphorylase a after treatment with acids or hog pancreatic α-amylase, but they showed increased inhibitory activity toward porcine small intestinal sucrase.

Both AI-A₁ and AI-A₂ were composed of glucose and a basic moiety which gave a positive ninhydrin reaction. The molecular weights of AI-A₁ and AI-A₂ were estimated to be approximately 1300 ? 1500 by gel filtration on a Sephadex G-15 column. The nitrogen content of the amylase inhibitors was found to be about 1.3% by elementary analysis     

Solid State 13C-NMR Analysis of Cell Wall Components of Fusarium oxysporum

An abdominal fat accumulation complicated by high blood triglycerides is regarded as a risk factor of metabolic syndrome. Feeding powdered nacre, mother of pearl, from Pinctada maxima, resulted in reduced body weight, visceral fat amount, and blood triglyceride level without influencing the food intake, body length, or amount of muscular tissue, suggesting that nacre powder specifically could decrease visceral fat.     

Localization of 9- and 13-oxo-octadecadienoic acids in tomato fruit

We previously reported that the two peroxisome proliferator-activated receptor-α agonists, 9- and 13-oxo-octadecadienoic acids (oxo-ODAs), were found in the tomato fruit. However, their localization remains unknown. Herein, we showed that oxo-ODAs localize primarily in the fruit peel and their amount increases after the homogenization of the tomato fruit.