The sulfamide moiety affords higher inhibitory activity and oral bioavailability to a series of coumarin dual selective RAF/MEK inhibitors

Introducing a sulfamide moiety to our coumarin derivatives afforded enhanced Raf/MEK inhibitory activity concomitantly with an acceptable PK profile. Novel sulfamide 17 showed potent HCT116 cell growth inhibition (IC₅₀ = 8 nM) and good PK profile (bioavailability of 51% in mouse), resulting in high in vivo antitumor efficacy in the HCT116 xenograft (ED₅₀ = 4.8 mg/kg). We confirmed the sulfamide moiety showed no negative impact on tests run on the compound to evaluate DMPK (PK profiles in three animal species, CYP inhibition and CYP induction) and the safety profile (hERG and AMES tests). Sulfamide 17 had favorable properties that warranted further preclinical assessment     

Ruminal Fermentation and Sugar Concentrations

The maximal amounts of growth of Selenomonas ruminantium were examined in the media containing various amounts of glucose. The yields of cells per unit weight of glucose are linear functions to glucose concentrations in the ranges between zero to 0.005% and 0.005 to 0.7%, Cell yields per glucose are greater in the former range, indicating greater a-mounts of energy are available per glucose at lower concentrations. Growth responses in lactate media containing various amounts of glucose showed that the preincubation with larger amounts of glucose is inhibitory for the following growth and metabolism of lactate. The organism produces predominantly lactate in the glucose medium. However, volatile fatty acid productions increase when the initial concentrations of glucose become low. Isotopic studies showed that the lactate utilization yielding volatile fatty acids is inhibited by the preceding metabolism of high concentrations of glucose. These results were discussed with regard to normal and abnormal fermentations in the rumen.     

Occurence of a Phosphodiesterase in the Insoluble Fractions from Wheat Seedlings

The volume of carbon dioxide evolved in a shaking apparatus was measured at fixed intervals, and it was confirmed that the fermentation of dry yeast generally depends on three factors and that they are represented with an initial fermenting activity, a power which recovers fermenting activity, and a maximum fermenting activity. This expression of fermenting power was compared with usual expressions and it was proved to be more reasonable, particularly, for deciding the initial fermenting activity.     

2-Nitropropane Dioxygenase from Hansenula mrakii: Re-characterization of the Enzyme and Oxidation of Anionic Nitroalkanes

2-Nitropropane dioxygenase, purified to homogeneity by an improved method from a yeast, Hansenula mrakii, has a molecular weight of 42,000, and consists of a single polypeptide. The enzyme contains 1 mol of FAD per mol of enzyme. The iron protein associated with previous preparations was removed by the present purification procedures. The enzyme catalyzes the oxygenative denitrification of anionic nitroalkanes much more effectively than that of the neutral ones with the optimum pH of 6.5. The Michaelis constants for the anionic substrates are as follows: 2-nitropropane, 1.61 mM; 1-nitropropane, 3.23 mM; nitroethane, 3.13 mM, and 3-nitro-2-butanol, 0.59 mM.     

Effects of Lipids on the Rheological Properties of Aqueous Soybean Protein Dispersions

The flow properties of soybean protein–lipid–water suspension systems and coagulated gels were related to a protein–lipid interaction. For powdered soybean lecithin-added soybean protein suspension systems and their heat-induced gels, the yield stress (σ_y) and the consistency index (K) increased with increasing amounts of added lipid, but the flow behavior index (n) and the thixotropy index (TI) decreased. On the other hand, there were only small changes in the magnitudes of the thixotropic parameters and the viscometric parameters (σ_y, K and n) after adding soybean oil at various concentrations to soybean protein dispersions. These facts suggested that the formation of a protein–phospholipid complex increased the effective particle size, and that the intermolecular entanglements and linkages among the protein molecules or among the protein-phospholipid complexes were weakened by the addition of polar lipids. The thixotropy index defined in this study is available for characterizing the stress decay that occurs within soybean protein dispersions and heat-induced gels as they are sheared.     

Utilization of Amino Acids as a Sole Source of Nitrogen by Obligate Chemolithoautotroph Thiobacillus ferrooxidans

An obligate chemolithoautotroph, Thiobacillus ferrooxidans API 9–3, could utilize amino acids, other than glycine, methionine and phenylalanine, as a sole source of nitrogen. However, both the growth rate and growth yield were lower than those in Fe²⁺-NH4 -salts medium, suggesting that the ammonium ion was a superior nitrogen source for the strain compared to amino acids. Methionine and phenylalanine strongly inhibited the cell growth on Fe²⁺-NH4-salts medium at 10 mm. [¹⁴C]Glycine could not be taken up into the cells, and this meant the strain could not use glycine as a sole source of nitrogen. The uptake of [¹⁴C]leucine into the cells was dependent on the presence of Fe^{2 +}. When the strain was cultured on Fe^{2 +} - leucine (lOmm)-salts medium lacking an inorganic nitrogen source for 5 days at 30°C, 83.5% and 16.5% of the cellular carbon were derived from carbon dioxide and leucine, respectively, indicating that carbon dioxide was a superior carbon source for the bacterium compared to leucine. The ammonium ion did not inhibit the utilization of leucine for cellular carbon. Leucine uptake was markedly inhibited by inhibitors of protein synthesis, such as chloramphenicol (94.3% at 1 mm), streptomycin (57.2% at 5mm) and rifampin (77.2% at 0.1 mm), respectively. Carbon dioxide uptake was also completely inhibited by chloramphenicol at 4mm. These results suggest that the transport of both amino acids and carbon dioxide into the cells was dependent on protein synthesis.     

Studies on Kojic Acid and its Related γ-Pyrone Compounds

The Mannich reaction of kojic acid in both acidic and basic media was studied. Mono-Mannich derivatives (substitution at position 6) were obtained; the reactivity in basic medium was found to be somewhat greater than in acidic medium. Reduction of the Mannich derivatives with zinc dust and acetic acid gave a 6-methyl kojic acid (6-methyl-5-hydroxy-2-hydroxymethyl-γ-pyrone).

Mono-Mannich base of pyromeconic acid was also prepared in a manner similar to that of kojic acid. From this Mannich base, maltol (2-methyl-3-hydroxy-γ-pyrone) was obtained by the reduction with zinc dust and acetic acid.     

Studies on Chlorosis-Inducing Activities and Plant Growth Inhibition of Benzophenone Derivatives

Some benzophenones substituted with methyl, methoxy, hydroxy or halogen groups inhibited growth and induced chlorosis in various plants. The structure activity relationships about the chlorosis-inducing activity and the growth inhibitory activity of the 3-methyl-benzophenones were well expressed by use of hydrophobic contant π, and Hammett’s σ. The highest selectivity for phytotoxic activities against barnyardgrass and the rice plant was with 3,3′-dimethyl-4-methoxybenzophenone (Methoxyphenone).     

Antioxidative and Prooxidative Abilities of some Biological Substances and Physiologically Active Substances on the Oxidation of Unsaturated Fatty Acids

Some biological substances and physiologically active substances such as amino acids, hormones, vitamins, medicines and the other substances were added into the linoleic acid solution; and antioxidative and prooxidative abilities of these substances, the abilities to act as electron donors or acceptors, were tested. Many substances were effective as the antioxidant and some others showed prooxidative effects. These facts suggested the possibility of the occurrence of many reactions involving the transfer of an electron among biological processes.