Semiempirical calculation of electronic spectra of organic compounds by using the improved method of new-γ electron repulsion integral. Part 2. Polycyclic aromatic hydrocarbons (PAHs)

Excitation energies of 123 polycyclic aromatic hydrocarbons were calculated by incorporating the improved method of new-γ for the two-center electron repulsion integral into two semiempirical molecular orbital methods (CNDO/S and INDO/S). This variable method well reproduced experimental excitation energies of them. The average error of the improvement is about 0.162 (CNDO/S) or 0.237 eV (INDO/S) though the average error without the improvement is about 0.541 (CNDO/S) or 0.536 eV (INDO/S). The improvement was useful for the calculations of other organic compounds including hetero atoms, such as organic dye.     

First isolation of 1,3,2-dithiaphosphetane 2-sulfide

The treatment of tert-alkyl phenyl thioketones with Lawesson’s reagent (LR) gave two diastereomeric 1,3,2-dithiaphosphetane 2-sulfides in high yields. The structure of one of the major diastereomers was determined by X-ray crystallography. The reaction of 2-adamantanethione with LR yielded the corresponding spiro-1,3,2-dithiaphosphetane 2-sulfide derivative in 87% yield.     

Stereoselective synthesis of (25R)-25,26-dihydroxy-23-oxovitamin D3 and its enzymatic conversion to (25R)-1α,25,26-trihydroxy-23-oxovitamin D3, a putative metabolite of vitamin D3

(25$\text{R}$)-25,26-Dihydroxy-23-oxovitamin D₃ was synthesized efficiently and stereoselectively, and it was converted enzymatically to (25$\text{R}$)-1α,25,26-trihydroxy-23-oxovitamin D₃, a putative metabolite of 1α,25-dihydroxyvitamin D₃. The spectral and chemical properties of (25$\text{R}$)-25,26-dihydroxy-23-oxovitamin D₃ and its 1α,hydroxylated derivative disagree with those reported for the isolated metabolite.     

Properties of novel aldose reductase inhibitors, M16209 and M16287, in comparison with known inhibitors, ONO-2235 and sorbinil

Properties and efficacies of novel aldose reductase (AR) inhibitors, M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) and M16287 (1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin), were examined in vitro and in vivo, compared with known AR inhibitors, ONO-2235 and sorbinil. These four compounds inhibited partially purified aldose reductases from various origins, and the potencies of M16209 and M16287 were on the whole similar to ONO-2235, and were greater than that of sorbinil. The IC50 values of the four AR inhibitors did not substantially depend on the substrate used. Kinetic studies of inhibition of partially purified bovine lens (BLAR) revealed that M16209, M16287 and sorbinil were uncompetitive with glyceraldehyde and noncompetitive with nicotineamide adenine dinucleotide phosphate (NADPH), whereas ONO-2235 was noncompetitive with both glyceraldehyde and NADPH. Aldose reductase became less sensitive to the four inhibitors as enzyme purification progressed, although the susceptibility to inhibition was partially reversed by incubation with dithiothreitol. In addition, the four compounds slightly affected those enzymes of carbohydrate and glutathione metabolism which were tested. M16209 and M16287 prevented sorbitol accumulation in isolated rat tissues as potently as ONO-2235 and sorbinil. M16209 and M16287 were effective in the prevention of galactosemic cataracts and amelioration of diabetic neuropathy with almost the same potency, while ONO-2235 was effective only in neuropathy, and sorbinil was effective in galactosemic cataracts and diabetic neuropathy with a different potency. These results indicate that M16209 and M16287 are potent aldose reductase inhibitors, which could be applicable to treatment for diabetic complications.     

Synthesis and antiallergy activity of [1,3,4]thiadiazolo[3,2-a]-1,2,3-triazolo[4,5-d]pyrimidin-9(3H)-one derivatives. II. 6-Alkyl- and 6-cycloalkylalkyl derivatives.

A series of 6-alkyl- or 6-(cycloalkylalkyl)-[1,3,4]thiadiazolo[3,2- a]-1,2,3-triazolo[4,5-d]pyrimidin-9(3H)-ones 1b--o was synthesized from the corresponding 1,3,4-thiadiazol-5-amines 3b--o and the antiallergic activities of the products were evaluated. Among the compounds 6-(2-cyclohexylethyl)- [1,3,4]thiadiazolo[3,2-a]-1,2,3-triazolo[4,5-d]pyrimidin-9(3H)-one 1h, whose X-ray crystallographic stereostructure is shown, was found to be a promising new antiallergic agent, which has low toxicity and dual activity as a leukotriene D4 receptor antagonist and as an orally active mast cell stabilizer.     

Structure of an anti-plasmin inhibitor, eckol, isolated from the brown alga Ecklonia kurome Okamura and inhibitory activities of its derivatives on plasma plasmin inhibitors

Eckol (1), a novel phlorotannin with a dibenzo-1,4-dioxin skeleton, has been isolated from the brown alga Ecklonia kurome Okamura as a potent and specific anti-plasmin inhibitor. Its structure has been elucidated based on the spectral data, in particular, by means of negative nuclear Overhauser effect (NOE), and finally established as 1-(3,5-dihydroxyphenoxy)-2,4,7,9-tetrahydroxydibenzo-1,4-dio xin by X-ray analysis. Some partially methoxylated derivatives of eckol were prepared by methylation with diazomethane and also by selective dimethylation of eckol permethylate (1b) to establish the structural requirements for inhibitory activities on alpha 2-macroglobulin and alpha 2-plasmin inhibitor, the main plasmin inhibitors in plasma.     

Protein profiling of rat cerebella during development

Protein profiles of developing rat cerebella were analyzed by means of two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS). The analysis of adult rat cerebellum gave rise to a protein map comprising approximately 3000 spots detectable by silver staining following high resolution 2-DE with a pH range of 3-10 and a mass range of 8-100 kDa. To obtain landmarks for comparison of developmental profiles of cerebellar proteins, 100 spots were subjected to peptide mass fingerprinting using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), and 67 spots were assigned on the map. Analysis of profiles of the developing cerebella revealed significant changes in the expression of proteins during development. In most cases the expression levels of proteins increased as the cerebellum matured, while the expression of 42 spots appeared specific or remarkably abundant in the immature cerebellum. Peptide mass fingerprinting of these spots allowed us to identify 29 proteins, which include, in addition to proteins of unknown function, many proteins known to have roles in the development of the central nervous system. These results suggest that the proteomic approach is valuable for mass identification of proteins involved in cerebellar morphogenesis.